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.].

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.

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.

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.

ISSLS prize in basic science 2021: a novel inducible system to regulate transgene expression of TIMP1.

PURPOSE: Inflammatory and oxidative stress upregulates matrix metalloproteinase (MMP) activity, leading to intervertebral disc degeneration (IDD). Gene therapy using human tissue inhibitor of metalloproteinase 1 (hTIMP1) has effectively treated IDD in animal models. However, persistent unregulated transgene expression may have negative side effects. We developed a recombinant adeno-associated viral (AAV) gene vector, AAV-NFκB-hTIMP1, that only expresses the hTIMP1 transgene under conditions of stress. METHODS: Rabbit disc cells were transfected or transduced with AAV-CMV-hTIMP1, which constitutively expresses hTIMP1, or AAV-NFκB-hTIMP1. Disc cells were selectively treated with IL-1ß. NFκB activation was verified by nuclear translocation. hTIMP1 mRNA and protein expression were measured by RT-PCR and ELISA, respectively. MMP activity was measured by following cleavage of a fluorogenic substrate. RESULTS: IL-1ß stimulation activated NFκB demonstrating that IL-1ß was a surrogate for inflammatory stress. Stimulating AAV-NFκB-hTIMP1 cells with IL-1ß increased hTIMP1 expression compared to unstimulated cells. AAV-CMV-hTIMP1 cells demonstrated high levels of hTIMP1 expression regardless of IL-1ß stimulation. hTIMP1 expression was comparable between IL-1ß stimulated AAV-NFκB-hTIMP1 cells and AAV-CMV-hTIMP1 cells. MMP activity was decreased in AAV-NFκB-hTIMP1 cells compared to baseline levels or cells exposed to IL-1ß. CONCLUSION: AAV-NFκB-hTIMP1 is a novel inducible transgene delivery system. NFκB regulatory elements ensure that hTIMP1 expression occurs only with inflammation, which is central to IDD development. Unlike previous inducible systems, the AAV-NFκB-hTIMP1 construct is dependent on endogenous factors, which minimizes potential side effects caused by constitutive transgene overexpression. It also prevents the unnecessary production of transgene products in cells that do not require therapy.

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.

Percutaneous endoscopic cervical foraminotomy as a new treatment for cervical radiculopathy: A systematic review and meta-analysis.

BACKGROUND: Anterior cervical discectomy and fusion (ACDF) is the gold standard treatment for this cervical radiculopathy. Posterior endoscopic cervical foraminotomy (PECF), an effective alternative to ACDF, is becoming widely used by an increasing number of surgeons. However, comparisons of the clinical outcomes of ACDF and PECF remain poorly explored. The purpose of this study was to evaluate and compare visual analog scale (VAS)-arm scores, VAS-neck scores, neck disability index (NDI) scores, reoperation, and complications in PECF and ACDF. MATERIALS AND METHODS: We comprehensively searched electronic databases or platforms, including PubMed, Web of Science, EMBASE, and the Cochrane Controlled Trial Center, using the PRISMA guidelines. The required information, including VAS-arm scores, VAS-neck scores, NDI scores, reoperation, and complications, was extracted from qualified studies and independently tested and compared by 2 researchers. The methodological index for nonrandomized studies was used to evaluate study quality. RESULTS: Nine studies consisting of 230 males and 256 females were included. The mean age of the included patients was 49.6 years, and the mean follow-up time was 20.6 months. The VAS-arm scores were significantly higher, and VAS-neck scores and NDI scores of PECF showed greater improvement trends for PECF than ACDF. The complication proportion of patients with PECF was lower, while the proportion of reoperation was similar between PECF and ACDF. ACDF was the most common revision surgery. The most common complication of PECF was transient paresthesia. CONCLUSION: Compared with ACDF, PECF is safe and effective in patients with unilateral cervical radiculopathy without myelopathy, and PECF does not increase the probability of reoperation and complications.

Development and Validation of a 6-miRNA Prognostic Signature in Spinal Chordoma.

BACKGROUND: Published data have suggested a critical role for microRNA (miRNA) expression in chordoma progression. However, most of these studies focus on single miRNA and no multi-miRNA prognostic signature has been currently established for chordoma. In this study, we sought to develop and validate a 6-miRNA risk score (miRscore) model for survival prediction. METHODS: Medline, Embase, and Google scholar searches (from inception to July 20, 2018) were conducted to identify candidate miRNAs with prognostic value as per predefined criteria. Quantitative RT-PCR was used to measure miRNA levels in 114 spinal chordoma (54 in the training and 60 in the validation cohort) and 20 control specimens. Subsequently, the miRscore was built based on miRNAs data. RESULTS: Literature searches identified six prognostic miRNAs (miR-574-3p, miR-1237-3p, miR-140-3p, miR-1, miR-155, and miR-1290) with differential expression in tumor tissues. Bioinformatical analysis revealed an important regulatory role for miR-574-3p/EGFR signaling in chordoma and showed that the target genes of these prognostic miRNAs were mainly enriched in transcription regulation, protein binding and cancer-related pathways. In both cohorts, the miRscore was associated with surrounding muscle invasion by tumor and/or other aggressive features. The miRscore model well predicted local recurrence-free survival and overall survival, which remained after adjusting for other relevant covariates. Further time-dependent receiver operating characteristics analysis in the two cohorts found that the miRscore classifier had stronger prognostic power than known clinical predictors and improved the ability of Enneking staging to predict outcomes. Importantly, recursive-partitioning analysis of both samples combined separated patients into four prognostically distinct risk subgroups for recurrence and survival (both P < 0.001). CONCLUSIONS: These data suggest the miRscore as a useful prognostic stratification tool in spinal chordoma and may represent an important step toward future personalized treatment of patients.

Interleukin-17A Promotes Human Disc Degeneration by Inhibiting Autophagy Through the Activation of the Phosphatidylinositol 3-Kinase/Akt/Bcl2 Signaling Pathway.

BACKGROUND: Previous studies have suggested that interleukin (IL)-17A is a key factor that contributes to intervertebral disc degeneration (IDD), whereas autophagy has been shown to be a protective mechanism in IDD. However, the relationship between IL-17A and autophagy in IDD remains to be fully elucidated. This study sought to evaluate the association between IL-17 and autophagy and the potential mechanism through which IL-17A affects autophagy in IDD. METHODS: Intervertebral disc specimens were collected from 10 patients with lumbar disc herniation. Human degenerated nucleus pulposus (NP) cells were cultured in the presence or absence of IL-17A treatment. Western blot and monodansylcadaverine staining were used to measure autophagy levels in human degenerated NP cells. Subsequently, phosphatidylinositol 3-kinase (PI3K)/Akt/Bcl-2 pathway inhibitors were used to reveal the potential mechanism. RESULTS: IL-17A treatment inhibited the autophagic activity in human NP cells in a time- and dose-dependent manner. Moreover, monodansylcadaverine staining showed that cells treated with IL-17A had significantly fewer changes in their autophagic vacuoles compared with control-treated cells. After IL-17A treatment, expression levels of PI3K, p-Akt, and Bcl-2 in NP cells were significantly increased. Further assays with PI3K/Akt/Bcl-2 inhibitors revealed that IL-17A suppressed autophagy in NP cells by activating the PI3K/Akt/Bcl-2 signaling pathway. CONCLUSIONS: These data suggest that IL-17A promotes IDD by inhibiting autophagy through activation of the PI3K/Akt/Bcl-2 signaling pathway and may offer new insights for targeted therapy of this disease.

Biomechanical Analysis of a Growing Rod with Sliding Pedicle Screw System for Early-Onset Scoliosis.

Early-onset scoliosis (EOS) remains a challenging condition for which current nonfusion surgeries require iterative lengthening surgeries. A growing rod with sliding pedicle screw system (GRSPSS) was developed to treat spinal deformities without repeated operative lengthening. This study was performed to evaluate whether GRSPSS had similar stability as a conventional pedicle screw system to maintain deformity correction. A serial-linkage robotic manipulator with a six-axis load cell positioned on the end-effector was utilized to evaluate the mechanical stability of the GRSPSS versus conventional fixed scoliosis instrumentation. Ten skeletally mature thoracic female Katahdin sheep spines (T4-L1) were subjected to 2.5 Nm of flexion-extension (FE), lateral bending (LB), and axial rotation (AR) in 2° increments for each state. The overall range of motion (ROM), apical segment ROM, and stiffness were calculated and reported. A two-tailed paired t-test was used to detect significant differences (p < 0.05) between the fixed group and GRSPSS fixation. There were no significant differences in overall range of motion (ROM), apical segment ROM, or stiffness for FE or LB between the GRSPSS group and fixed group. In AR, the GRSPSS group showed increased ROM compared to the fixed group for the overall spine (36.0° versus 19.2°, p < 0.01) and for the instrumented T8-T10 segments (7.0° versus 2.9°, p=0.02). Similarly, the fixed rod elastic zone (EZ) stiffness was significantly greater than the GRSPSS EZ stiffness (0.29 N/m versus 0.17 N/m, p < 0.001). The space around the rod allows for the increased AR observed with the GRSPSS fusion technique and is necessary for axial growth. The GRSPSS fusion model shows equivalent flexion and LB stability to current fusion models and represents a stable fusion technique and may allow for longitudinal growth during childhood.

MiR-21 promotes ECM degradation through inhibiting autophagy via the PTEN/akt/mTOR signaling pathway in human degenerated NP cells.

Intervertebral disc degeneration (IDD) is the most common cause leading to low back pain, a highly prevalent, costly and crippling condition worldwide. Overexpression of miR-21 has been shown to promote proliferation of nucleus pulposus (NP) cells. However, it remains unclear whether miR-21 can promote the degradation of type II collagen (Col II) and aggrecan, two main extracellular matrix components within the disc. Here, the miRNA microassay assay identified 29 differentially expressed miRNAs in NP tissues from IDD patients compared with healthy controls. Following qRT-PCR validation, miR-21 expression was significantly upregulated in degenerated NP tissues, and showed a positive correlation with disc degeneration grade. Through gain-of-function and loss-of-function studies in human NP cells, miR-21 was shown to inhibit autophagy and then upregulate the expression of matrix metalloproteinase (MMP)-3 and MMP-9, leading to increased degradation of Col II and aggrecan. Mechanistically, phosphatase and tensin homolog (PTEN) was identified as a direct target of miR-21, and activated PTEN/ Akt/mammalian target of rapamycin (mTOR) signaling pathway was involved in miR-21-induced autophagy inhibition and Col II and aggrecan breakdown. Taken together, these results suggest that miR-21 contributes to Col II and aggrecan catabolism by inhibiting autophagy via the PTEN/Akt/mTOR signaling pathway in human NP cells.

Application of vascularized fibular graft for reconstruction and stabilization of multilevel cervical tuberculosis: A case report.

Multilevel cervical reconstruction and fusion after cervical tuberculosis has always been a challenge. The current implantation materials for cervical fusion, including titanium mesh, cage, and plate are limited by its inferior biological mechanical characteristics and the properties of the metallic material. This has led to the increased risk of recurrent infection after surgery. In addition, the unique nature of tuberculosis infection results in the low rate of cervical fusion and high risk of recurrence. This case report presents 1 patient who suffered from long segmental cervical tuberculosis and had reconstruction surgery using a vascularized fibula graft. The patient had successful graft incorporation 3 months postsurgery and was followed-up for 30 months. In this review, we detail the advantages of using vascularized fibular grafts and compare it with other types of grafts.

The PI3K/Akt pathway: a critical player in intervertebral disc degeneration.

Intervertebral disc degeneration (IDD) is thought to be the primary cause of low back pain, a severe public health problem worldwide. Current therapy for IDD aims to alleviate the symptoms and does not target the underlying pathological alternations within the disc. Activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway protects against IDD, which is attributed to increase of ECM content, prevention of cell apoptosis, facilitation of cell proliferation, induction or prevention of cell autophagy, alleviation of oxidative damage, and adaptation of hypoxic microenvironment. In the current review, we summarize recent progression on activation and negative regulation of the PI3K/Akt signaling pathway, and highlight its impact on IDD. Targeting this pathway could become an attractive therapeutic strategy for IDD in the near future.

MiR-210 facilitates ECM degradation by suppressing autophagy via silencing of ATG7 in human degenerated NP cells.

Intervertebral disc degeneration (IDD) is thought to be the most common cause of low back pain. Dysregulation of microRNAs (miRNAs) is involved in the development of IDD. The aim of this study was to explore the influence of miR-210 on type II collagen (Col II) and aggrecan expression and possible mechanisms in human degenerated nucleus pulposus (NP) cells. Our results showed that miR-210 levels were significantly increased in degenerated NP tissues compared with healthy controls, and positively correlated with disc degeneration grade. By gain-of-function and loss-of-function studies in human degenerated NP cells, miR-210 was shown to inhibit autophagy and then upregulate MMP-3 and MMP-13 expression, leading to increased degradation of Col II and aggrecan. Autophagy-related gene 7 (ATG7) was identified as a direct target of miR-210. Knockdown of ATG7 by small interfering RNA (siRNA) abrogated the effects of miR-210 inhibitor on MMP-3, MMP-13, Col II and aggrecan expression. Taken together, these results suggest that miR-210 inhibits autophagy via silencing of ATG7, leading to increased Col II and aggrecan degradation in human degenerated NP cells.

Application of Laparoscopic Lumbar Discectomy and Artificial Disc Replacement: At Least Two Years of Follow-Up.

STUDY DESIGN: This prospective observational study included 22 patients who were diagnosed with symptomatic degenerative disc disease treated via artificial disc replacement (ADR) with a laparoscopic technique. OBJECTIVE: The current study aimed to assess the safety and efficacy of ADR using a laparoscopic technique for lumbar disc herniation. SUMMARY OF BACKGROUND DATA: Symptomatic degenerative disc disease is the major cause of low back pain with lumbar segmental instability. ADR has increased in popularity as an alternative treatment for lumbar disc herniation. However, the traditional approach to spinal surgery carries the risk of catastrophic bleeding from injury to major vessels, as well as iatrogenic injury to the viscera and associated structures. Therefore, laparoscopic lumbar discectomy and ADR may represent a useful alternative. METHODS: Twenty-two patients (8 males and 14 females) who were diagnosed with symptomatic degenerative disc disease were included in this study. Seven cases involved the L4/5 level, and 15 cases involved the L5/S1 level. All patients were ineffective after at least 6 months of conservative treatments; all patients were informed of the surgery before the operation and provided consent. Three-dimensional computed tomographic angiography (3D-CTA) of the iliac great blood vessels was completed before the surgery. All surgical procedures were performed under a laparoscope. All patients were followed up. RESULTS: All surgeries were successfully completed. The average operation time was 120 minutes (range 110-150 min), and the average hemorrhage was 145 mL (range 80-360 mL). All cases underwent X-rays at 3 days, 3 months, 6 months, 1 year, and the final postoperative follow-up. The outcome indicated that there was no mobilization, displacement, or subsidence in all patients with the exception of one case with prosthesis migration. The follow-up time was 43.8 months (range 24-64 months). The mean visual analog scale (VAS) and Oswestry scores were decreased postoperatively. The mean improvement rate of the VAS score was 73.5%. CONCLUSION: Lumbar ADR using a laparoscope represents a novel, minimally invasive treatment for symptomatic degenerative disc disease and severe lumbar discogenic pain.