Xiao-Bin Wang

Factors predicting recurrence after resection of clival chordoma using variable surgical approaches and radiation modalities.

BACKGROUND Clival chordomas frequently recur because of their location and invasiveness. OBJECTIVE To investigate clinical, operative, and anatomic factors associated with clival chordoma recurrence. METHODS Retrospective review of clival chordomas treated at our center from 1993 to 2013. RESULTS Fifty patients (56% male) with median age of 59 years (range, 8-76) were newly diagnosed with clival chordoma of mean diameter 3.3 cm (range, 1.5-6.7). Symptoms included headaches (38%), diplopia (36%), and dysphagia (14%). Procedures included transsphenoidal (n=34), transoral (n=4), craniotomy (n=5), and staged approaches (n=7). Gross total resection (GTR) rate was 52%, with 83% mean volumetric reduction, values that improved over time. While the lower third of the clivus was the least likely superoinferior zone to contain tumor (upper third=72%/middle third=82%/lower third=42%), it most frequently contained residual tumor (upper third=33%/middle third=38%/lower third=63%; P<.05). Symptom improvement rates were 61% (diplopia) and 53% (headache). Postoperative radiation included proton beam (n=19), cyberknife (n=7), intensity-modulated radiation therapy (n=6), external beam (n=10), and none (n=4). At last follow-up of 47 patients, 23 (49%) remain disease-free or have stable residual tumor. Lower third of clivus progressed most after GTR (upper/mid/lower third=32%/41%/75%). In a multivariate Cox proportional hazards model, male gender (hazard ratio [HR]=1.2/P=.03), subtotal resection (HR=5.0/P=.02), and the preoperative presence of tumor in the middle third (HR=1.2/P=.02) and lower third (HR=1.8/P=.02) of the clivus increased further growth or regrowth, while radiation modality did not. CONCLUSION Our findings underscore long-standing support for GTR as reducing chordoma recurrence. The lower third of the clivus frequently harbored residual or recurrent tumor, despite staged approaches providing mediolateral (transcranial+endonasal) or superoinferior (endonasal+transoral) breadth. There was no benefit of proton-based over photon-based radiation, contradicting conventional presumptions.

LncRNA-RP11-296A18.3/miR-138/HIF1A Pathway Regulates the Proliferation ECM Synthesis of Human Nucleus Pulposus Cells (HNPCs)

During the process of Intervertebral disc degeneration (IDD), nucleus pulposus apoptosis increases, extracellular matrix (ECM) alters and/or degrades, abnormal proliferation of cells forms cell clusters, and the expression of various inflammatory factors increases. Thus, regulation of human nucleus pulposus cell (HNPC) proliferation and ECM synthesis present promising strategies for IDD treatment. Accumulating evidence indicates that non‐coding RNAs are involved in various cellular processes, including cell proliferation, differentiation, apoptosis, and metastasis. High expression of long non‐coding RNA (lncRNA) RP11‐296A18.3, as well as a low expression of miR‐138 during the IDD process has been reported; yet their functional roles in HNPC proliferation and ECM synthesis still remain unclear. MTT and BrdU assays showed that knockdown of RP11‐296A18.3 inhibited the proliferation of HNPC. The ECM marker, MMP‐13 and Collagen I expressions were also reduced. Bioinformatics target prediction, qPCR, and luciferase assays identified LncRNA‐RP11‐296A18.3 interacted with miR‐138. Moreover, RP11‐296A18.3 regulates HNPC proliferation and ECM synthesis through miR‐138. As the target gene of miR‐138, hypoxia‐inducible factor 1‐alpha (HIF1A) was closely associated with cell proliferation which was also regulated by RP11‐296A18.3 via miR‐138. Immunochemistry and qPCR results showed that miR‐138 expression was inversely correlated to RP11‐296A18.3 and HIF1A in IDD tissues, respectively; RP11‐296A18.3 was positively correlated to HIF1A. We revealed that RP11‐296A18.3 promote HIF1A expression through sponging miR‐138, thus to promote HNPC proliferation and ECM synthesis. Targeting RP11‐296A18.3 to rescue miR‐138 expression in HNPCs and IDD tissues presents a promising strategy for IDD improvement. J. Cell. Biochem. 118: 4862–4871, 2017.

Surgical treatment based on pedicle screw instrumentation for thoracic or lumbar spinal Langerhans cell histiocytosis complicated with neurologic deficit in children

BACKGROUND CONTEXT Surgical indications and procedures for spinal Langerhans cell histiocytosis (LCH) in children are still controversial. Reports containing large samples of surgically treated patients are few in the currently available literature, and the reported operative procedures were also somewhat obsolete. So, further investigation based on large-sample cases and using improved surgical techniques is beneficial and helpful to refine the treatment strategy. PURPOSE To recommend a reasonable treatment strategy for thoracic or lumbar spine LCH in children complicated with neurologic deficit. STUDY DESIGN/SETTING Retrospective/academic medical center. PATIENT SAMPLE Twelve children aged from 2 to 16 years old with the diagnosis of thoracic or lumbar spinal LCH accompanied by neurologic deficit received surgical treatment from January 2005 to January 2010. OUTCOME MEASURES Frankel scale for neurologic function, fusion of the mass, and recurrence of the lesion. METHODS All 12 patients presented initially with local pain and progressive neurologic detriment. Neurologic evaluation revealed two patients with Frankel Grade B, eight with Grade C, and two with Grade D. Radiographic features were positive for typical vertebra plana, a space-occupying mass in the spinal canal compressing neural elements, and a spinal canal encroachment rate more than 50%. Posterior instrumentation with pedicle screw combined with anterior corpectomy, decompression, and support bone graft was performed in the first seven patients as a one-stage procedure. In the remaining five patients, posterior pedicle screw fixation, laminectomy for decompression (via excision of the tumor-like mass), and repair of laminae with allograft bone block were performed. The collapsed vertebral body was left untouched. No chemotherapy or radiotherapy was administrated postoperatively in any of the cases. RESULTS The mean follow-up duration was 43.3 months. The mean operation time was 330 minutes with combined procedure and 142 minutes with single posterior approach (p=.000). The average blood loss was 933 mL with combined procedure and 497 mL with single posterior approach (p=.039). Three of seven patients who received combined surgery encountered approach-related complications, that is, one with intercostal neuralgia and two with pleural effusion. No severe neurologic deteriorate, instrumentation failure, or disease recurrence was detected at follow-up. Neurologic function completely recovered in all 12 patients from 2 to 12 weeks after surgery. The anterior bone graft fused and shaped well in all seven patients, and allograft bone block for lamina repair also achieved complete fusion in the remaining five patients. The internal fixator was removed at 3 to 5 years (average 4.1 years) after initial operation in six patients. No deformity, including scoliosis and kyphosis, has been identified during follow-up period in both procedures. CONCLUSIONS For spinal LCH patients, neurologic deficit is a main indication for operative treatment to prevent permanent and serious consequences. Surgery provides an opportunity for rapid recovery of neurologic function. Both combined and single-stage posterior approaches based on pedicle screw instrumentation techniques are similarly effective in relieving neurologic compression. However, single-stage posterior approach is more favorable with less complications, and preserving involved vertebral body is not a latent hazard of recurrence.

Spinal tuberculosis of the lumbar spine after percutaneous vertebral augmentation (vertebroplasty or kyphoplasty)

BACKGROUND CONTEXT Spinal tuberculosis occurring after percutaneous vertebral augmentation has rarely been described. To date, only two such cases have been documented in the literature. Vertebral augmentation may reactivate a quiescent tuberculous lesion and promote the infective process in elderly patients with or without immunosuppression, thereby resulting in poor outcomes. PURPOSE The purposes of this study were to present two cases in which spinal tuberculosis occurred after vertebroplasty or kyphoplasty, to highlight the clinical features and need for early diagnosis of this pathology, and to postulate probable reasons for this association. STUDY DESIGN This study is based on a clinical case series and literature review. METHODS In this report, we review the clinical histories of two old women undergoing vertebral augmentation with subsequent spinal tuberculosis. RESULTS The first patient responded favorably to conservative treatment with multidrug antitubercular therapy and spinal braces. The second patient underwent surgical debridement through a posterior approach alone, without instrumentation, combined with adjuvant chemotherapy. By 1 year after treatment, both patients had experienced almost complete recovery and continued to be seen for follow-up visits. CONCLUSIONS Suspicion should be high, and magnetic resonance imaging is warranted in cases with deteriorating clinical symptoms and signs of acute infection after vertebral augmentation. We propose obtaining exhaustive microbiologic and histologic evidence via needle biopsy or open surgery in a timely fashion to establish an accurate diagnosis because tubercular spondylitis occurring in such a situation may progress rapidly.

Surgical treatment of large abdominally involved primary dumbbell tumor in the lumbar region.

Study Design: This was a retrospective clinical study. Objective: The aim of this study was to assess the efficacy of a combined anterior and posterior approach, or single-stage posterior extensive approach for resection of large abdominally involved dumbbell tumor in the lumbar region. Background: Resection of the large spinal-retroperitoneal involved dumbbell tumor is particularly controversial and challenging because of unique exposure requirements. Methods: From June 2006 to October 2011, 18 consecutive patients suffering from large dumbbell tumors in the lumbar region were involved. In the initial 8 patients, a combined posterior and anterior surgical approach was applied. The remaining 10 patients were surgically treated with a single posterior extensive approach to excise both the intraspinal and intra-abdominal tumors. Reconstruction with bone or mesh grafts was also performed simultaneously in 3 of the 10 patients in this group. Results: The perioperative period was uneventful for 7 of 8 patients who underwent combined surgery. However, 1 patient encountered right nephrectomy because of a ruptured renal vein and refractory bleeding during anterior tumor exposure. Histopathology revealed the presence of schwannoma (n=4), neurofibroma (n=3), and neuroblastoma (n=1). With the mean of 52 months of follow-up, metastasis occurred in 1 patient with neuroblastoma. In the 10 patients with only the posterior approach, histopathology demonstrated schwannoma (n=5), neurofibroma (n=3), small round cell mesenchymal tumor (n=1), and benign fibrous histiocytoma (n=1). No recurrence was detected at the mean follow-up of 24 months. Conclusions: The posterior extensive approach is safe and effective to remove the large abdominally involved dumbbell tumors, and also facilitates simultaneously reconstruction of the vertebral body, as compared with the combined posterior and anterior approach.

Prognostic Factors in Skull Base Chordoma: A Systematic Literature Review and Meta-Analysis

OBJECTIVE Currently, there are a lack of reviews assessing the complete range of prognostic factors in skull base chordoma (SBC). This study aimed to systematically review the published literature on prognostic factors in SBC and establish pooled hazard ratios (HRs) of such factors. METHODS MEDLINE and Embase searches (inception to April 4, 2017) were conducted. Two reviewers independently selected papers involving SBC prognostic factors, and studied them for methodologic quality and valuable factors. Pooled HRs and 95% confidence intervals (CIs) were calculated. The main end points determined were progression-free survival (PFS) and overall survival (OS). RESULTS Twenty-two studies with 1754 subjects were included in this systematic review. However, only 18 of the studies provided sufficient data for quantitative synthesis. Preoperative visual deficit (pooled HR, 2.77; 95% CI, 1.57-4.89 for PFS), older patient age (pooled HR, 1.03; 95% CI, 1.1-1.05 for PFS; pooled HR, 1.03; 95% CI, 1.2-1.04 for OS), and nontotal or intralesional tumor resection (pooled HR, 2.01; 95% CI, 1.54-2.62 for PFS; pooled HR, 5.16; 95% CI, 2.27-11.70 for OS) were negative predictors of survival outcomes. However, adjunctive radiotherapy (pooled HR, 0.30; 95% CI, 0.16-0.56) and chondroid chordoma type (pooled HR, 0.5; 95% CI, 0.36-0.69) portended a favorable PFS. In addition, several prognostic biomarkers were promising. CONCLUSIONS This study demonstrated that several clinicopathologic or molecular parameters are associated with survival up to tumor progression or mortality in SBC patients. However, further methodologically high-quality reports are still required to clarify the effects of these factors.

LncRNA H19 targets miR-22 to modulate H2O2-induced deregulation in nucleus pulposus cell senescence, proliferation, and ECM synthesis through Wnt signaling

Intervertebral disc (IVD) degeneration (IDD) is a major contributor to low back pain. During IDD progression, ROS can be produced in the form of H2O2 in nucleus pulposus cells (NPCs) in response to elevated cytokines, leading to subsequent alternations of cell fate and metabolic processes. Genetic factors are considered as main contributors to IDD pathopoiesis. Herein, we investigated the detailed function and mechanism of H19, one of the most up‐regulated lncRNAs in IDD specimens, in H2O2‐induced cell senescence model in NPCs. H19 could accelerate H2O2‐induced degenerative changes by promoting cell senescence, increasing ADAMTS‐5 and MMPs protein levels and Collagen I content, as well as suppressing NPC proliferation through activating Wnt/β‐catenin signaling. Moreover, miR‐22, a direct target of H19, could bind to the 3′UTR of LEF1 to inhibit its expression and reverse the effect of H19 on NPCs, thus inhibiting Wnt/β‐catenin signaling. Taken together, H19 acts as a ceRNA to compete with LEF1 for miR‐22, thus modulating downstream Wnt/β‐catenin signaling in NPCs; H19/miR‐22/LEF1 might be a novel target for improving H2O2‐induced NPC senescence and treatment for IDD.

Prognostic factors in spinal chordoma: An update of current systematic review and meta-analysis

Dear Editor, We read with great interest the recent article entitled “Prognostic factors in surgical resection of sacral chordoma” by Angelini et al. The authors performed a retrospective cohort analysis of 71 patients in a single center. They found that tumor volume was an independent prognostic factor of local recurrence-free survival (LRFS), while resection level, tumor volume, and surgical margin were independent predictors of overall survival (OS) in the patients on multivariate analysis. We commend the authors for performing this interesting study as these helpful results would be useful to make a balanced treatment decision. However, we noted that the authors did not find extent of tumor invasion or worse preoperative Frankel score to be an independent predictor, which contradicts the results from previous studies. To date, an increasing number of clinical and histopathologic factors as well as molecular biomarkers have been investigated for their association with spinal chordoma prognosis, but the results are still inconclusive or controversial. We previously performed a systematic review on prognostic factors in spinal chordoma, but no definitive conclusions could be derived due to heterogeneity and the scarcity of included studies. Furthermore, several recent studies involving large sample sizes and long-term results published in 2015 or 2016were not included in this literature review. Therefore, we believe an updated systematic review is required. The aim of this study was to systematically review the prognostic factors in spinal chordoma and to establish pooled estimates of the effect of specific prognostic factors by performing a meta-analysis. A total of 18 papers (Supplementary material 1) met the initial methodological criteria and were thus included. Characteristics of the included studies are shown in Table I. All studies were retrospective cohort studies with a low chance of bias (level of evidence, 2+ or 2++). Patients ranged from 23 to 215. Most studies performed multivariate analysis on factors found significant in univariate analysis. Seven studies evaluated type of surgical resection as a factor of LRFS, but six studies provided data comparing Enneking inappropriate (EI) resection with Enneking appropriate (EA) resection and three studies provided data comparing marginal resection with wide resection.We performed a subgroup sensitive analysis and found no subgroup difference between the results from six studies comparing EI resection with EA resection and three studies comparing marginal resection with wide resection (I= 0%, P for subgroup heterogeneity = 0.38) (Fig. 1). Six studies comparing EI resection with EA resection yielded a pooled RR of 3.49 (95%CI: 2.48-4.92, P < 0.00001; I= 0%, P for heterogeneity = 0.49) (Fig. 1). Three studies comparing marginal resection with wide resection yielded a pooled RR of 2.78 (95%CI: 1.92-4.04, P < 0.00001; I= 0%, P for heterogeneity = 0.58) (Fig. 1). Five studies evaluated age as a factor of OS in multivariate analyses by regarding it as a continuous variable and pooled analysis showed that an increasing age was associatedwith an increased risk of death (HR = 1.03, 95%CI: 1.02-1.05, P < 0.0001) (Supplementary material 2). Four studies contributed to the pooled analysis of prognostic role of tumor invasion on OS and the results showed that increasing tumor invasion was associated with an increased risk of death (HR = 2.14, 95%CI: 1.40-3.26, P = 0.0005) (Supplementary material 3). Five studies evaluated type of surgical resection as a factor of OS, but four studies provided data comparing EI resection with EA resection and three studies provided data comparing marginal resection with wide resection. Similarly, a subgroup sensitive analysis was also performed and we observed no strong subgroup difference between the results from four studies comparing EI resection with EA resection and three studies comparing marginal resection with wide resection (I = 33.9%, P for subgroup heterogeneity = 0.22) (Supplementary material 4). Four studies comparing EI resection with EA resection yielded a pooled RR of 1.97 (95%CI: 1.29-2.99, P = 0.002; I = 0%, P for heterogeneity = 0.66) (Supplementary material 4). Three studies comparing marginal resection with wide resection yielded a pooled RR of 1.31 (95%CI: 0.81-2.14, P = 0.002; I = 0%, P for heterogeneity = 0.61) (Supplementary material 4). In conclusion, we provided a comprehensive overview of the current knowledge regarding prognostic factors in spinal chordoma. Although heterogeneity of the included studies, we have identified several clinical factors (especially EI resection and increasing tumor invasion) and molecular biomarkers are associated with survival up to tumor recurrence or mortality in spinal chordoma patients. These data may be helpful in guiding treatment planning to prolong survival and suggest targets for development of potential therapies. However, high-quality, prospective studies are still required to clarify and evaluate the effects of these factors. Ethical Review Committee Statement: The study protocol was approved by the Institutional Review Board of The Second Xiangya Hospital of Central South University, Hunan, China.

Letter to the Editor concerning "Surgical treatment of sacral chordoma: survival and prognostic factors" by C. Ruosi et al. (Eur Spine J; 2015; 24(Suppl 7):S912-S917.

We read with great interest the recent article by Ruosi et al. [1] on prognostic factors in sacral chordoma after surgical resection. The authors performed a retrospective cohort analysis of 14 patients in a single center. They found that wide surgical margins were associated with increased survivalship to local recurrence in the patients, while the level of resection and tumor size (presented as volume) showed no statistically significant correlation with patient survival on univariate analysis. We commend the authors for performing this interesting study as these helpful results would be useful to make a balanced treatment decision planning to prolong patient survival. However, we have several suggestions and queries that we would like to communicate with the authors. First, lack of multivariate adjustment for statistical analysis in this study may have introduced bias to the results [2]. Furthermore, this study only involved a very small sample size, which might increase the statistical error rate, and thus even a very powerful prognostic factor may not be significant in this situation [3]. Second, it has been suggested that adequacy of resection margins is likely the most important factor determining the risk of chordoma recurrence and long-term patient prognosis [4, 5]. However, due to likely infiltration or proximity to vital visceral organs and neurovascular structures, chordomas with a large tumor size at presentation in clinical practice may make it more difficult to obtain wide resection margins, which can therefore lead to poor patient survival. Third, it has been reported that a large tumor lesion often expressed more human telomerase reverse transcriptase (hTERT) and Ki-67 index due to a higher proliferation potential [6, 7]. Further, previous studies have shown that high hTERT and Ki-67 expression were associated with increased risk of local recurrence or mortality in spinal chordoma patients [8, 9]. These data suggest that a large spinal chordoma, which is postulated to express more hTERT and Ki-67 index, may be likely predictive of poor patient outcomes. Finally, although the possible prognostic value of tumor size in spinal chordoma as we proposed, the results from previous studies are still inconclusive or controversial. For example, two researchers showed that tumor size had significant implications in predicting local relapse-free survival (LRFS) and overall survival of patients with spinal chordoma [10, 11], but other authors found no significant predictive value for tumor size on LRFS [12–16]. Although the difference in categorization or definition for tumor size between papers may contribute to the inconsistent findings, it is the fact that we still cannot derive valid conclusions regarding prognostic role of tumor size in spinal chordoma according to the evidence available. We believe that subsequent well-designed prospective studies involving large sample sizes will be helpful to further clarify the role of tumor size in spinal chordoma prognosis.

The significance of removing ruptured intervertebral discs for interbody fusion in treating thoracic or lumbar type B and C spinal injuries through a one-stage posterior approach.

Objectives To identify the negative effect on treatment results of reserving damaged intervertebral discs when treating type B and type C spinal fracture-dislocations through a one-stage posterior approach. Methods This is a retrospective review of 53 consecutive patients who were treated in our spine surgery center from January 2005 to May 2012 due to severe thoracolumbar spinal fracture-dislocation. The patients in Group A (24 patients) underwent long-segment instrumentation laminectomy with pedicle screw-rod fixators for neural decompression. In Group B (29 patients), the patients underwent long-segment instrumentation laminectomy with pedicle screw-rod fixators for neural decompression evacuating of the ruptured disc and inserting of a bone graft into the evacuated disc space for interbody fusion. The mean time between injury and operation was 4.1 days (range 2–15 days). The clinical, radiologic and complication outcomes were analyzed retrospectively. Results Periodic follow-ups were carried out until an affirmative union or treatment failure took place. A progressive kyphosis angle larger than 10°, loss of disc height, pseudoarthrosis, recurrence of dislocation or subluxation, or instrument failure before fusion were considered treatment failures. Treatment failures were detected in 13 cases in Group A (failure rate was 54.2%). In Group B, there were 28 cases in which definitive bone fusion was demonstrated on CT scans, and CT scans of the other cases demonstrated undefined pseudoarthrosis without hardware failure. There were statistically significant differences between the two groups (p<0.001 chi-square test). The neurologic recoveries, assessed by the ASIA scoring system, were not satisfactory for the neural deficit patients in either group, indicating there was no significant difference with regard to neurologic recovery between the two groups (p>0.05 Fishers exact test). Conclusion Intervertebral disc damage is a common characteristic in type B and C spinal fracture-dislocation injuries. The damaged intervertebral disc should be removed and substituted with a bone graft because reserving the damaged disc in situ increases the risk of treatment failure.