The potential role of stem cells-derived extracellular vesicles in the treatment of musculoskeletal system diseases.

The therapeutic potential of stem cells-derived extracellular vesicles (EVs) has shown a great progress in the regenerative medicine. EVs are rich in a variety of bioactive substances, which are important carriers of signal transmission and interactions between cells, and they play an important role in the processes of tissue repair and regeneration. Several studies have shown that stem cells-derived EVs regulate immunity, promote cell proliferation and differentiation, enhance bone and vascular regeneration, and play an increasingly important role in musculoskeletal system. This review aimed to describe the biological characteristics of stem cells-derived EVs and discuss their potential role in the therapy of musculoskeletal system diseases.

Effects of manipulations of oblique pulling on the biomechanics of the sacroiliac joint: a cadaveric study.

BACKGROUND: There are many reports on the treatment of sacroiliac joint dysfunction by manipulation of oblique pulling (MOP). However, the specific mechanism of MOP on the sacroiliac joint remains unclear. This study aimed to investigate the effect of MOP on the biomechanics of the sacroiliac joint and the effect of the anterior sacroiliac ligament on the stability of the sacroiliac joint. METHODS: First, MOP-F1 (F: force) and MOP-F2 were applied to nine cadaveric pelvises. Then, segmental resection of the anterior sacroiliac ligament was performed. The range of motion of the sacroiliac joint was observed in all procedures. RESULTS: Under MOP-F1 and F2, the average total angles were 0.84° ± 0.59° and 1.52° ± 0.83°, and the displacements were 0.61 ± 0.21 mm and 0.98 ± 0.39 mm, respectively. Compared with MOP-F1, MOP-F2 caused greater rotation angles and displacements of the sacroiliac joint (p = 0.00 and p = 0.01, respectively). In addition, the rotation angles and displacements of the sacroiliac joint significantly increased after complete resection of the anterior sacroiliac ligament (p = 0.01 and p = 0.02, respectively). The increase was mainly due to the transection of the upper part of the anterior sacroiliac ligament. CONCLUSIONS: MOP-F2 caused greater rotation angles and displacements of the sacroiliac joint and was a more effective manipulation. The anterior sacroiliac ligament played an important role in maintaining the stability of the sacroiliac joint; the upper part of the anterior sacroiliac ligament contributed more to the stability of the joint than the lower part.

A novel rat model of interbody fusion based on anterior lumbar corpectomy and fusion (ALCF).

BACKGROUND: Rats have been widely used as experimental animals when performing fundamental research because they are economical, rapidly reproducing, and heal quickly. While the rat interbody fusion model has been applied in basic studies, existing rat models generally have shortcomings, such as insufficiently simulating clinical surgery. The purpose of this study was to develop a novel rat model of interbody fusion which more closely represents clinical surgery. METHODS: The internal fixation was designed based on physical measurements of the rats' lumbar spine. Then, ten rats divided into two groups (A and B) underwent anterior lumbar corpectomy and fusion of the L5 vertebrae. Groups A and B were sacrificed four and 8 weeks post-surgery, respectively. Micro-CT and histological examination were used to evaluate the model. Fusion rate, bone volume fraction (BV/TV), trabecular bone number (Tb.N), trabecular bone thickness (Tb.Th), and the area ratio of newly formed bone (NB) were calculated for quantitative analysis. RESULTS: Based on the L5 body dimensions of individual rats, 3D-printed titanium cage of the appropriate size were printed. The operations were successfully completed in all ten rats, and X-ray confirmed that internal fixation was good without migration. Micro-CT suggested that fusion rates in group B (100%) were greater than group A (40%, P < 0.05). The BV/TV (B: 42.20 ± 10.50 vs. A: 29.02 ± 3.25, P < 0.05) and Tb.N (B: 4.66 ± 1.23 vs. A: 1.97 ± 0.40, P < 0.05) were greater in group B than A, and the Tb.Th in group B was lower than group A (B: 0.10 ± 0.04 vs. A: 0.15 ± 0.02, P < 0.05). Histomorphometry results demonstrated that the area ratio of NB in group B were greater than group A (B: 35.72 ± 12.80 vs. A: 12.36 ± 16.93, P < 0.05). CONCLUSION: A rat interbody fusion model based on anterior lumbar corpectomy and fusion has successfully been constructed and verified. It could provide a new choice for fundamental research using animal models of spinal fusion.

Percutaneous spinal endoscopy with unilateral interlaminar approach to perform bilateral decompression for central lumbar spinal stenosis: radiographic and clinical assessment.

BACKGROUND: Recently, a percutaneous spinal endoscopy unilateral posterior interlaminar approach to perform bilateral decompression has been proposed for use in treatment of lumbar spinal stenosis, As a development and supplement to traditional surgery, its advantages regarding therapeutic effects and prognosis, such as minor soft tissue damage, little intraoperative blood loss, and a quick return to daily life. However, there are few analyses of this surgery with a follow-up of more than 1 year,we conducted this study in order to quantitatively investigate radiographic and clinical efficacies of this surgery for central lumbar spinal stenosis. MATERIALS AND METHODS: Forty-six patients with central lumbar spinal stenosis were enrolled from January 2017 to July 2018. The visual analog scale (VAS) for back pain and leg pain, Oswestry disability index (ODI), modified MacNab criteria were used to evaluate clinical efficiency at preoperative and postoperative time points. The intervertebral height index (IHI), cross-sectional area of the spinal canal (CSAC), calibrated disc signal (CDS) and spinal stability were examined to assess radiographic decompression efficiency via magnetic resonance imaging and X-ray at preoperative and postoperative time points. RESULTS: The VAS score for lower back pain and leg pain improved from 7.50 ± 0.78 to 1.70 ± 0.66 and from 7.30 ± 0.79 to 1.74 ± 0.68, respectively, and the ODI improved from 72.35 ± 8.15 to 16.15 ± 4.51. In terms of modified MacNab criteria, 91.3% of the patients achieved good or excellent outcomes. Furthermore, significant changes after surgery were observed for the percentage of CSAC, increasing from 125.3 ± 53.9 to 201.4 ± 78 mm2; however, no significant differences were observed for the remaining measurement indicators. CONCLUSIONS: The clinical and radiographic efficacies of this surgery for central lumbar spinal stenosis were good in short-term follow-up, and this surgery did not cause meaningful changes in IHI, CDS, and spine stability in short-term follow-up. The effect of long-term follow-up needs further investigation.

Research progress on the biological modifications of implant materials in 3D printed intervertebral fusion cages.

Anterior spine decompression and reconstruction with bone grafts and fusion is a routine spinal surgery. The intervertebral fusion cage can maintain intervertebral height and provide a bone graft window. Titanium fusion cages are the most widely used metal material in spinal clinical applications. However, there is a certain incidence of complications in clinical follow-ups, such as pseudoarticulation formation and implant displacement due to nonfusion of bone grafts in the cage. With the deepening research on metal materials, the properties of these materials have been developed from being biologically inert to having biological activity and biological functionalization, promoting adhesion, cell differentiation, and bone fusion. In addition, 3D printing, thin-film, active biological material, and 4D bioprinting technology are also being used in the biofunctionalization and intelligent advanced manufacturing processes of implant devices in the spine. This review focuses on the biofunctionalization of implant materials in 3D printed intervertebral fusion cages. The surface modifications of implant materials in metal endoscopy, material biocompatibility, and bioactive functionalizationare summarized. Furthermore, the prospects and challenges of the biofunctionalization of implant materials in spinal surgery are discussed. Fig.a.b.c.d.e.f.g As a pre-selected image for the cover, I really look forward to being selected. Special thanks to you for your comments.

Tumor necrosis factor-α: a key contributor to intervertebral disc degeneration.

Intervertebral disc (IVD) degeneration (IDD) is the most common cause leading to low back pain (LBP), which is a highly prevalent, costly, and crippling condition worldwide. Current treatments for IDD are limited to treat the symptoms and do not target the pathophysiology. Tumor necrosis factor-α (TNF-α) is one of the most potent pro-inflammatory cytokines and signals through its receptors TNFR1 and TNFR2. TNF-α is highly expressed in degenerative IVD tissues, and it is deeply involved in multiple pathological processes of disc degeneration, including matrix destruction, inflammatory responses, apoptosis, autophagy, and cell proliferation. Importantly, anti-TNF-α therapy has shown promise for mitigating disc degeneration and relieving LBP. In this review, following a brief description of TNF-α signal transduction, we mainly focus on the expression pattern and roles of TNF-α in IDD, and summarize the emerging progress regarding its inhibition as a promising biological therapeutic approach to disc degeneration and associated LBP. A better understanding will help to develop novel TNF-α-centered therapeutic interventions for degenerative disc disease.

[MicroRNAs: a type of novel regulative factor for intervertebral disc degeneration].

Intervertebral disc degeneration (IDD) is one of major causes for intervertebral disc degenerative diseases, and patients with IDD usually suffer from serious low back pain. The current treatments for patients with IDD only relieve the clinical symptom rather than restore biological balance of IDD, leading to inadequate and unsatisfactory results. MicroRNAs (miRNAs) are endogenous, non-coding, single-stranded RNA molecules, which regulate the gene expression at the post-transcription levels. Research evidences support the involvement of miRNAs in many biological processes, such as lipid metabolism, apoptosis, differentiation and organ development. Accumulating evidences indicate that the expressions of miRNAs change significantly in degenerative tissues. In addition, dysregulated miRNAs contribute to multiple pathological process of IDD, including proliferation and apoptosis of nucleus pulposus and extracellular matrix components, inflammatory response and cartilage endplates degeneration. In this review article, we summarize the expression profiles and roles of miRNAs in IDD, which may provide a novel strategy of biological therapy for the disease.

Clinical effect evaluation of percutaneous vertebroplasty combined with the spinal external fixator for the treatment of osteoporotic compressive fractures with posterior vertebral defect.

PURPOSE: The purpose of this study is to report a new technique and assess clinical outcome of compressive fractures with posterior vertebral defect treated by percutaneous vertebroplasty combined with the spinal external fixator. METHOD: 80 patients (32 males and 48 females), ranging from 62 to 88 years old with the mean age of 71.5 years, underwent surgery for the compressive fractures with posterior vertebral defect by percutaneous vertebroplasty combined with the spinal external fixator. All patients were diagnosed to have fresh compressive fractures with osteoporosis and posterior vertebral defect shown on roentgenograms, computed tomography scans or magnetic resonance imaging preoperatively. They underwent spinal external fixation firstly to be fixed and restored, then to be carried out percutaneous vertebroplasty. The mean follow-up was 24 months (16-42 months). Spinal canal encroachment, spinal cobb angle and vertebral body height loss were measured to assess clinical outcome before and after surgery, at the final follow-up. The Visual Analogue Scale and Oswestry Disability Index were used for pain and functional assessment. In all cases, preoperative and postoperative radiographs and magnetic resonance imaging were obtained. RESULTS: The average time of surgery was 88 min (75-115 min). The mean blood loss was 10 ml (6-12 ml) during surgery. The anterior height loss of vertebral body decreased significantly from 79.3 ± 11% before surgery to 8.0 ± 5.2% after surgery, and 7.6 ± 6.0% at the final follow-up. The spinal canal encroachment significantly reduced from 19.9 ± 2.6 % preoperatively to 4.0 ± 0.7% postoperatively, 4.1 ± 0.7% at the final follow-up. The Cobb angle was corrected from 25.8 ± 7.9° primarily to 8.2 ± 4.1° postoperatively, 7.8 ± 3.1° at the final follow-up. There were significant differences (p < 0.05) among them before and after the surgery. Postoperative VAS and Oswestry scores were both significantly different from the preoperative and follow-up (p < 0.05). CONCLUSION: The preliminary results are encouraging, showing that the spinal external fixator combined with percutaneous vertebroplasty was a safe and effective method to treat the osteoporotic compressive fractures with posterior vertebral defect.

Biomechanical analysis of the tandem spinal external fixation in a multiple-level noncontiguous lumbar fractures model: a finite element analysis.

Objective: This study aimed to investigate the biomechanical characteristics of the tandem spinal external fixation (TSEF) for treating multilevel noncontiguous spinal fracture (MNSF) using finite element analysis and provide a theoretical basis for clinical application. Methods: We constructed two models of L2 and L4 vertebral fractures that were fixed with the TSEF and the long-segment spinal inner fixation (LSIF). The range of motion (ROM), maximum stresses at L2 and L4 vertebrae, the screws and rods, and the intervertebral discs of the two models were recorded under load control. Subsequently, the required torque, the maximum stress at L2 and L4 vertebrae, the screws and rods, and the intervertebral discs were analyzed under displacement control. Results: Under load control, the TSEF model reserved more ROM than the LSIF model. The maximum stresses of screws in the TSEF model were increased, while the maximum stresses of rods were reduced compared to the LSIF model. Moreover, the maximum stresses of L2 and L4 vertebrae and discs in the TSEF model were increased compared to the LSIF model. Under displacement control, the TSEF model required fewer moments (N·mm) than the LSIF model. Compared to the LSIF model, the maximum stresses of screws and rods in the TSEF model have decreased; the maximum stresses at L2 and L4 in the TSEF model were increased. In the flexion condition, the maximum stresses of discs in the TSEF model were less than the LSIF model, while the maximum stresses of discs in the TSEF model were higher in the extension condition. Conclusion: Compared to LSIF, the TSEF has a better stress distribution with higher overall mobility. Theoretically, it reduces the stress concentration of the connecting rods and the stress shielding of the fractured vertebral bodies.

Integrating single-cell and spatial transcriptomics reveals endoplasmic reticulum stress-related CAF subpopulations associated with chordoma progression.

BACKGROUND: With cancer-associated fibroblasts (CAFs) as the main cell type, the rich myxoid stromal components in chordoma tissues may likely contribute to its development and progression. METHODS: Single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, bulk RNA-seq, and multiplexed quantitative immunofluorescence (QIF) were used to dissect the heterogeneity, spatial distribution, and clinical implication of CAFs in chordoma. RESULTS: We sequenced here 72 097 single cells from 3 primary and 3 recurrent tumor samples, as well as 3 nucleus pulposus samples as controls using scRNA-seq. We identified a unique cluster of CAF in recurrent tumors that highly expressed hypoxic genes and was functionally enriched in endoplasmic reticulum stress (ERS). Pseudotime trajectory and cell communication analyses showed that this ERS-CAF subpopulation originated from normal fibroblasts and widely interacted with tumoral and immune cells. Analyzing the bulk RNA-seq data from 126 patients, we found that the ERS-CAF signature score was associated with the invasion and poor prognosis of chordoma. By integrating the results of scRNA-seq with spatial transcriptomics, we demonstrated the existence of ERS-CAF in chordoma tissues and revealed that this CAF subtype displayed the most proximity to its surrounding tumor cells. In subsequent QIF validation involving 105 additional patients, we confirmed that ERS-CAF was abundant in the chordoma microenvironment and located close to tumor cells. Furthermore, both ERS-CAF density and its distance to tumor cells were correlated with tumor malignant phenotype and adverse patient outcomes. CONCLUSIONS: These findings depict the CAF landscape for chordoma and may provide insights into the development of novel treatment approaches.

Exploring the Therapeutic Effects of Multifunctional N-Salicylic Acid Tryptamine Derivative against Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide. Neuroinflammation and oxidative stress play an important role in the whole course of PD, which have been the focus of PD drug development. In our previous research, a series of N-salicylic acid tryptamine derivatives were synthesized, and the biological evaluation showed that the compound LZWL02003 has good anti-neuroinflammatory activity and displayed great therapeutic potency for neurodegenerative disease models. In this work, the neuroprotective efficiency of LZWL02003 against PD in vitro and in vivo has been explored. It was found that LZWL02003 could protect human neuron cells SH-SY5Y from MPP+-induced neuronal damage by inhibiting ROS generation, mitochondrial dysfunction, and cellular apoptosis. Moreover, LZWL02003 could improve cognition, memory, learning, and athletic ability in a rotenone-induced PD rat model. In general, our study has demonstrated that LZWL02003 has good activity against PD in in vitro and in vivo experiments, which can potentially be developed into a therapeutic candidate for PD.

Clinicopathological and Prognostic Characteristics in Spinal Chondroblastomas: A Pooled Analysis of Individual Patient Data From a Single Institute and 27 Studies.

STUDY DESIGN: Retrospective pooled analysis of individual patient data. OBJECTIVES: Spinal chondroblastoma (CB) is a very rare pathology and its clinicopathological and prognostic features remain unclear. Here, we sought to characterize the clinicopathological data of a large spinal CB cohort and determine factors affecting the local recurrence-free survival (LRFS) and overall survival (OS) of patients. METHODS: Electronic searches using Medline, Embase, Google Scholar and Wanfang databases were performed to identify eligible studies per predefined criteria. A retrospective review was also conducted to include additional patients at our center. RESULTS: Twenty-seven studies from the literature and 8 patients from our local institute were identified, yielding a total of 61 patients for analysis. Overall, there were no differences in clinicopathological characteristics between the local and literature cohorts, except for absence or presence of spinal canal invasion by tumor on imagings and chicken-wire calcification in tumor tissues. Univariate Kaplan-Meier analysis revealed that previous treatment, preoperative or postoperative neurological deficits, type of tumor resection, secondary aneurysmal bone cyst (ABC), chicken-wire calcification and radiotherapy correlated closely with LRFS, though only type of tumor resection, chicken-wire calcification and radiotherapy were predictive of outcome based on multivariate Cox analysis. Analyzing OS, we found that a history of preoperative treatment, concurrent ABC, chicken-wire calcification, type of tumor resection and adjuvant radiotherapy had a significant association with survival, whereas only type of tumor resection remained statistically significant after adjusting for other covariables. CONCLUSION: These data may be helpful in prognostic risk stratification and individualized therapy decision making for patients.

Corrigendum: Coexpression of HHLA2 and PD-L1 on tumor cells independently predicts the survival of spinal chordoma patients.

[This corrects the article DOI: 10.3389/fimmu.2021.797407.].

LncRNA HOTAIR influences cell proliferation via miR-130b/PTEN/AKT axis in IDD.

Intervertebral disc degeneration (IDD) constitutes the pathological foundation of most musculoskeletal disorders of the spine. Previous studies have noted that cell proliferation is a common feature of IDD. Bioinformatics indicated that aberrantly expressed long non-coding RNAs (lncRNAs) were involved in the development of IDD. In this study, we aimed to investigate the function of lncRNA HOTAIR in the proliferation of human nucleus pulposus (NP) cells of IDD in vitro and further clarified its mechanism. The expression of HOTAIR and miR-130b was quantified by qRT-PCR in nucleus pulposus (NP) tissues. Furthermore, NP cells proliferation were assayed by CCK8 and Immunostaining. Dual-luciferase reporter and RIP assay were used to examine the expression of HOTAIR, PTEN, and their co-target gene miR-130b. Western blotting was used to test AKT expression. Our in vitro experiments on human normal NP cells observed that HOTAIR was significantly dysregulated in IDD. Further, HOTAIR can suppress proliferation by directly targeting miR-130b. In addition, Both HOTAIR and PTEN were confirmed to target miR-130b, and miR-130b upregulation reversed the phenomenon of ectopic expression of HOTAIR. More importantly, HOTAIR upregulation significantly reduced CyclinD1 protein expression by PTEN/AKT signaling pathway. Our findings suggest that HOTAIR may bind to miR-130b and subsequently increased CyclinD1 expression via PTEN/Akt pathway. Thereby, HOTAIR could become a potential target for the treatment of IDD.Abbreviations : IDD; intervertebral disc degeneration ncRNAs; non-coding RNAs lncRNAs; long non-coding RNAs miRNAs; microRNAs NP; nucleus pulposus qRT-PCR; quantitative reverse transcription-PCR LBP; Low back pain ORF; open reading frame HOTAIR; Hox transcript antisense intergenic RNA FAF1; Fas-associated protein factor-1 Erk; extracellular signal-regulated kinase TUG1; Taurine Up-regulated Gene 1 HIF1A hypoxia-inducible factor 1-alpha PI3K; phosphoinositide-3 kinase AIS; adolescent idiopathic scoliosis ECM; extracellular matrix LN;lupus nephritis CT;computed tomography MRI; magnetic resonance imaging PBS; phosphate-buffered salin PBS; phosphate-buffered salin PVDF; polyvinylidene fluoride TBST; Tris-buffered saline Tween ECL; enhanced chemiluminescence RIP; RNA immunoprecipitation.

Incidence and Risk Factors for Cerebrovascular-Specific Mortality in Patients with Colorectal Cancer: A Registry-Based Cohort Study Involving 563,298 Patients.

BACKGROUND: Colorectal cancer (CRC) is one of the most prevalent diseases and the second leading cause of death worldwide. However, the relationship between CRC and cerebrovascular-specific mortality (CVSM) remains elusive, and less is known about the influencing factors associated with CVSM in CRC. Here, we aimed to analyze the incidence as well as the risk factors of CVSM in CRC. METHODS: Patients with a primary CRC diagnosed between 1973 and 2015 were identified from the Surveillance Epidemiology and End Results database, with follow-up data available until 31 December 2016. Conditional standardized mortality ratios were calculated to compare the incidence of CVSM between CRC patients and the general U.S. POPULATION: Univariate and multivariate survival analyses with a competing risk model were used to interrogate the risk factors for CVSM. RESULTS: A total of 563,298 CRC individuals were included. The CVSM in CRC patients was significantly higher than the general population in all age subgroups. Among the competing causes of death in patients, the cumulative mortality caused by cerebrovascular-specific diseases steadily increased during the study period. While age, surgery, other/unknown race and tumors located at the transverse colon positively influenced CVSM on both univariate and multivariate analyses, male patients and those who had radiotherapy, chemotherapy, a more recent year (2001-2015) of diagnosis, a grade II or III CRC, rectal cancer, or multiple primary or distant tumors experienced a lower risk of CVSM. INTERPRETATION: Our data suggest a potential role for CRC in the incidence of CVSM and also identify several significant predictors of CVSM that may be helpful for risk stratification and the therapeutic optimization of cerebrovascular-specific diseases in CRC patients.

Clinicopathological and Prognostic Characteristics in Dedifferentiated/Poorly Differentiated Chordomas: A Pooled Analysis of Individual Patient Data From 58 Studies and Comparison With Conventional Chordomas.

BACKGROUND: Currently, the clinicopathological and prognostic characteristics of dedifferentiated chordoma (DC) and poorly differentiated chordoma (PDC) remain poorly understood. In this study, we sought to characterize clinicopathological parameters in a large PDC/DC cohort and determine their correlations with progression-free survival (PFS) and overall survival (OS) of patients. We also attempted to compare clinical features between PDC/DC and conventional chordoma (CC). METHODS: Literature searches (from inception to June 01, 2020) using Medline, Embase, Google Scholar and Wanfang databases were conducted to identify eligible studies according to predefined criteria. The local database at our center was also retrospectively reviewed to include CC patients for comparative analysis. RESULTS: Fifty-eight studies from the literature and 90 CC patients from our local institute were identified; in total, 54 PDC patients and 96 DC patients were analyzed. Overall, PDC or DC had distinct characteristics from CC, while PDC and DC shared similar clinical features. Adjuvant radiotherapy and chemotherapy were associated with both PFS and OS in PDC patients in the univariate and/or multivariate analyses. In the DC cohort, tumor resection type, adjuvant chemotherapy and tumor dedifferentiation components significantly affected PFS, whereas none of them were predictive of outcome in the multivariate analysis. By analyzing OS, we found that surgery, resection type and the time to dedifferentiation predicted the survival of DC patients; however, only surgery remained significant after adjusting for other covariables. CONCLUSIONS: These data may offer useful information to better understand the clinical characteristics of PDC/DC and may be helpful in improving the outcome prediction of patients.

Full-Endoscopic Foraminoplasty Using a Visualized Bone Reamer in the Treatment of Lumbar Disc Herniation: A Retrospective Study of 80 Cases.

BACKGROUND: Percutaneous endoscopic lumbar discectomy (PELD) has been widely used, before which foraminoplasty is necessary to widen the foramen for subsequent procedures. However, the learning curve of this technology is high, as the use of traditional reamers requires repeated intraoperative fluoroscopy. We sought to compare the clinical outcomes by using the visualized and traditional reamers in PELD foraminoplasty for the treatment of lumbar disc herniation. METHODS: Eighty patients with lumbar disc herniation who were treated with PELD between 1 January 2017 and 1 January 2019 were retrospectively reviewed. The patients were randomly divided into 2 groups (40 patients in the Visualized Bone Reamer group) and (40 patients in the Traditional Bone Reamer group). Intraoperative fluoroscopy time, cannulation introduction time, visual analog scale, and Macnab criteria score were compared between the 2 groups. RESULTS: The mean follow-up durations were 17.41 ± 1.47 and 18.37 ± 1.69 months in the visualized and traditional groups, respectively. The average cannulation introduction time and intraoperative fluoroscopy times in the visualized group is significantly lower than those in traditional group (29.20 ± 3.31 vs. 39.85 ± 3.98 minutes, P < 0.001; and 12.30 ± 2.38 vs. 20.65 ±3.51 seconds, P < 0.001, respectively). One patient in the traditional group required reoperation, and no complications occurred in the visualized group. There were no severe durotomies or vascular or visceral injuries. CONCLUSIONS: Full-endoscopic foraminoplasty using a visualized reamer is safe and effective and can decrease intraoperative fluoroscopy time in PELD.

Coexpression of HHLA2 and PD-L1 on Tumor Cells Independently Predicts the Survival of Spinal Chordoma Patients.

Background: Immunotherapy only achieves efficacy in some cancer patients, and less is known about other immune checkpoint molecules in chordoma. Here, we aimed to determine the expression of PD-L1, HHLA2, B7H3, IDO-1 and Galectin-9 in spinal chordoma and evaluated their association with tumor infiltrating lymphocytes (TILs), clinicopathological characteristics and survival of patients. Methods: Using multiplexed quantitative immunofluorescence (QIF), we simultaneously measured the levels of five different immune checkpoint molecules and major TIL subsets in 92 human spinal chordoma samples. Results: Tumor HHLA2 and PD-L1 were positive in 80.0% and 86.0% of cases, respectively. However, B7H3, IDO-1 and Galectin-9 positivity on tumor cells were only seen in 21.0% of cases, despite all showing predominantly stromal expression. Coexpression of these QIF markers in the tumor compartment was scarcely detected except for PD-L1 and HHLA2, which was observed in 69.6% of cases. While tumoral HHLA2 and stromal B7H3 expressions were associated with an aggressive tumor phenotype, suppressive immune response (specifically including elevated PD-1+ TILs level and decreased CD8+ TIL density) and poor prognosis, stromal levels of PD-L1 and Galectin-9 predicted the opposite outcomes. Importantly, HHLA2 and PD-L1 coexpression on tumor cells independently predicted both worse local recurrence-free survival and overall survival. Conclusion: These data provide a better understanding of the immunosuppressive mechanism in chordoma and may be useful for the development of combination or novel immunotherapy approaches aiming to improve therapeutic efficacy and survival.

Prognostic Significance of Tumor-Associated Macrophages in Chondroblastoma and Their Association with Response to Adjuvant Radiotherapy.

OBJECTIVE: Chondroblastoma (CB) is a rare and locally growing cartilage-derived tumor. Currently, clinical implications of tumor-associated macrophages (TAMs) in CB remain unclear. In this study, we sought to analyze the relationship between TAM parameters (including densities of CD68+ and CD163+ cells as well as the CD163+/CD68+ ratio) and clinicopathological characteristics and survival of patients. METHODS: Immunohistochemistry was used to assess TAM subtypes for CD68 and CD163, as well as the expression levels of p53, CD34, and Ki-67 on tumor cells in 132 tissue specimens retrieved between July 2002 and April 2020. Then, TAM parameters were retrospectively analyzed for their associations with patient outcomes (local recurrence-free survival [LRFS] and overall survival [OS]) and clinicopathological features. RESULTS: TAM densities were significantly higher in axial chondroblastoma tissue than in extra-axial chondroblastoma tissue. Moreover, the number of CD163+ TAMs was positively correlated with tumor invasion of surrounding tissues and high expression of CD34 and Ki-67 on tumor cells, whereas CD163+ cell density and the CD163/CD68 ratio were negatively associated with patient response to adjuvant radiotherapy. Univariate Kaplan-Meier analysis revealed that the number of CD68+ and CD163+ lymphocytes was significantly associated with both LRFS and OS. Multivariate Cox regression analysis showed that CD163+ and CD68+ cell levels were independent prognostic factors of LRFS, while TAM data independently predicted OS. More importantly, in subgroup analysis based on three significant factors in univariate survival analysis (including tumor location, adjuvant radiotherapy, and surrounding tissue invasion by tumors), the TAM parameters still displayed good prognostic performance. CONCLUSION: These data suggest that TAM may significantly affect the biological behavior of CB. We hypothesize that modulating the TAM level or polarization status in the microenvironment may be an effective approach for CB treatment.

Comprehensive analysis of N6-methyladenosine (m6A) modification during the degeneration of lumbar intervertebral disc in mice.

OBJECTIVE: To study the N6-methyladenosine (m6A) modification pattern of nucleus pulposus (NP) tissue during intervertebral disc degeneration (IDD). METHODS: A standing mouse model was generated, and staining and imaging methods were used to evaluate the IDD model. Methylated RNA immunoprecipitation with next-generation sequencing (MeRIP-seq) was used to analyze m6A methylation-associated transcripts in the NP, and real-time quantitative polymerase chain reaction (qRT-PCR) was used to detect the expression of methylation-related enzymes and conduct bio-informatics analysis. RESULTS: The standing mouse model caused IDD. Continuous axial pressure changed the expression of related methylases in degenerated NP tissue. Relative to the control group, the expression levels of KIAA1429, METTL14, METTL3, METTL4, WTAP, DGCR8, EIF3A and YTHDC1 in the experimental group were higher, while those of FTO, ELAVL1, HNRNPC1 and SRSF2 were lower. We identified 985 differentially expressed genes through MeRIP-Seq, among which 363 genes were significantly up-regulated, and 622 genes were significantly down-regulated. In addition, among the 9648 genes counted, 1319 m6A peaks with significant differences in methylation were identified, among which 933 were significantly up-regulated, and 386 were significantly down-regulated. Genes and pathways that were enriched in IDD have been identified. CONCLUSION: The results of this study elucidated the m6A methylation pattern of NP tissue in degenerated lumbar intervertebral disc of mice and provided new perspectives and clues for research on and the treatment of lumbar disc degeneration. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: As one of the important causes of low back and leg pain, intervertebral disc degeneration brings a huge economic burden to the society, family and medical system. Therefore, understanding the molecular and cellular mechanisms of intervertebral disc degeneration is of great significance for guiding clinical treatment. In this study, methylated RNA immunoprecipitation with next-generation sequencing on mice lumbar nucleus pulposus tissues found that differentially expressed genes and changes in the expression of related methylases, confirming that RNA methylation is involved in intervertebral disc degeneration. The process provides new vision and clues for future research on intervertebral disc degeneration.