Ming-Xiang Zou

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.

Treatment of thoracic or lumbar spinal tuberculosis complicated by resultant listhesis at the involved segment

PURPOSE The purpose of this study was to present a singular pathological process of thoracic or lumbar spinal tuberculosis contributing to listhesis at the involved site, with special focus on clinical features and management of this disorder. METHODS We retrospectively reviewed the medical records of 14 patients (5 males and 9 females, including 2 boys) admitted to our institution from April 2007 to March 2010 and were subsequently diagnosed with thoracic or lumbar spinal tuberculosis with resultant listhesis at the involved level. All patients underwent posterior instrumentation and reduction combined with single-stage anterior radical debridement and interbody fusion. Patients were followed-up clinically and radiographically. RESULTS The average follow-up duration was 54.6 months. All patients had a successful fusion. Complete reduction was achieved in 10 cases. Preoperative neurological injury was observed in six patients and all recovered after surgery. The average postoperative Frankel grade improvement was 1.2. The preoperative median value of the extent of listhesis was 26.2%, which fell to zero at the final follow-up (Z=-3.296, P=0.001). Pre- and postoperative median spinal stenosis rates were 45.9% and 8.4%, respectively (Z=-3.296, P=0.001). The preoperative neurologic level was positively correlated with the listhesis distance before surgery (rs=0.770, P=0.001). Postoperatively, the spinal stenosis rate was positively correlated with listhesis distance (rs=0.691, P=0.006). The correlation between neurologic level and age or spinal stenosis rate was not significant. The standardized coefficient of listhesis distance was greater than that of spinal stenosis rate in our multiple linear regression analysis model. No implant failure or recurrence of tuberculosis occurred. CONCLUSION Treatment of this rare pathology aims to restore good spinal alignment, radical debridement, and permanent stability. A reasonable surgical strategy may be the combination of posterior reduction, anterior debridement, and supportive graft fusion. This strategy can safely and effectively achieve all of the therapeutic goals in one step.

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.

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.

Letter to the Editor. Prognostic factors in skull base chordoma

TO THE EDITOR: Chordoma is a very rare mesenchymal tumor with a low to intermediate malignant grade. Clinically, chordoma has a high risk of local recurrence and responds poorly to conventional chemotherapy or radiotherapy. Currently, despite the refinement of surgical techniques and adjuvant radiotherapy, prognostication of the clinical outcomes in chordoma is still challenging. Recently, Wang et al.2 conducted a retrospective analysis of 238 patients on clinical features and surgical outcomes in skull base chordoma (SBC) (Wang L, Wu Z, Tian K, et al: Clinical features and surgical outcomes of patients with skull base chordoma: a retrospective analysis of 238 patients. J Neurosurg 127:1257–1267, December 2017). The authors found that recurrent tumor and intralesional resection were statistically significant predictors of worse long-term outcome in the patients on univariate analysis. We commend the authors for performing this interesting study as these helpful results would be useful to customize postsurgical monitoring and allow stratification of patients into prognostic groups. However, we noted that the authors did not perform multivariate adjustment for their statistical analysis in this study, which may have introduced bias to the results, as many factors can affect patient survival in SBC.1,4 Furthermore, we found that the authors did not further address the important issue with regard to which prognostic factors are important for patients with SBCs. Currently, although many studies have been conducted to correlate clinical and histopathological features, as well as molecular biomarkers, with chordoma prognosis, the results are still inconclusive or controversial. Given this fact, we believe a systematic review on prognostic factors in chordoma would be helpful to make a balanced treatment decision in clinical practice. To date, although previous evidence-based reviews on prognostic factors in spinal chordoma have been published in the literature,3,5 a rigorous systematic review assessing the association of such factors with prognosis of SBC is warranted at this time.

Letter to the Editor: Influence of age on survival outcomes in patients with spinal chordoma

TO THE EDITOR: We read with great interest the recent article by Gokaslan et al.3 (Gokaslan ZL, Zadnik PL, Sciubba DM, et al: Mobile spine chordoma: results of 166 patients from the AOSpine Knowledge Forum Tumor database. J Neurosurg Spine 24:644–651, April 2016). The authors performed a retrospective multicenter cohort analysis of prognostic factors in mobile spine chordoma after resection in 166 patients. They found on multivariate analysis that Enneking-inappropriate resection was significantly associated with an increased risk of local recurrence in the patients. We commend the authors for performing this interesting study as their helpful results will be useful in making balanced treatment decisions to prolong patient survival. However, we noted that the authors did not find patient age to be an independent predictor, which contradicts the results from previous studies.7,8,10 Furthermore, although an increasing number of studies have investigated the influence of age on spinal chordoma prognosis, the results are still inconclusive or controversial. Therefore, we aimed to further examine the prognostic role of age in spinal chordoma by performing a systematic review and to grade the evidence according to the quality of included studies. We also attempted to establish pooled estimates of the effect of age on the survival of spinal chordoma patients by performing a meta-analysis. We searched the MEDLINE and Embase databases to identify eligible English-language studies from database inception to September 9, 2016. We included only those studies that specifically evaluated age as a factor predicting survival in spinal chordoma patients. Methodological quality for study inclusion was assessed according to the criteria previously described.1,5,11 Studies without sufficient detailed data for statistical pooling were excluded. Level of evidence was determined according to the criteria proposed by Harbour and Miller.4 A total of 11 papers met the initial methodological criteria and were thus included.2,3, 6–10, 12–15 Characteristics of the included studies are shown in Table 1. All studies were retrospective, and most (9/11) provided Level 2++ evidence. Sample size ranged from 36 to 167 patients with spinal chordoma. Most studies (10/11) only evaluated the prognostic role of age on survivorship to local recurrence or death.2,6–10, 12–15 Although most studies (8/11) found that patient age had no significant predictive value,2,3, 6,9,10,12, 13,15

Letter to the Editor concerning “Risk factors of new symptomatic vertebral compression fractures in osteoporotic patients undergone percutaneous vertebroplasty” by HL. Ren et al. (Eur Spine J; 2015;24(4):750–758)

We read with great interest the recent article by Ren et al. [1] on risk factors of new symptomatic vertebral compression fractures (VCFs) after percutaneous vertebroplasty (PVP) in patients with osteoporosis. The authors performed a retrospective cohort analysis of 182 patients in a single center. They found that a total of 21 (11.5%) patients had secondary VCFs after PVP, and the number of initial fractures and body mass index were significantly correlated with the subsequent occurrence of VCFs 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 planning in clinical practice. However, we have several suggestions and queries that we would like to communicate with the authors. First, the authors reported both new remote and adjacent vertebral fractures after the initial vertebroplasty, but they did not conduct a subgroup analysis to identify risk factors for adjacent and remote fractures, respectively. This method may compromise the credibility and accuracy of the outcomes as these two classifications of new VCFs may likely have different causes and characteristics in clinical course. Second, previous studies have shown that many factors can affect the presence of VCFs following vertebroplasty [2], several other important factors, such as nonsteroidal anti-inflammatory drug usage, thoracolumbar junction, preexisting old vertebral compression fractures as well as altered spinopelvic parameters (including segmental kyphotic angle, sacral slope, sagittal vertical axis, and lumbar lordosis) [2–5], should have been controlled for more statistically meaningful results. Third, fracture-free survival defined as the time intervals from the index PVP to subsequent recurrent VCFs is an important data that can provide valuable consultation for the choice of an optimal follow-up duration, and can also be helpful for the clinical treatment of patients with new VCFs in a timely fashion within follow-up period. However, in this study, the authors used logistic regression model in their statistical analysis to identify risk factors of new VCFs by treating the event (new VCFs after PVP) as a dichotomous outcome instead of time-to-event data, which may likely result in less precise parameter estimates as new VCFs after PVP is not uncommon and there are strong risk factors reported to be associated with its occurrence [6, 7]. We believe that by taking into account the time until event occurs, a Cox proportional hazards model as used in several previous studies [5, 8, 9] may be more appropriate to obtain outcomes with more reliability and statistical power. Finally, we noted that the authors did not find intradiscal cement leakage to be a risk predictor of secondary new VCFs after vertebroplasty, which contradicts the results from previous studies [5, 9–11]. Currently, although an increasing number of studies have been conducted to investigate the relationship between cement leakage into disk and the development of new VCFs following vertebroplasty, the results are still inconclusive or controversial [2, 12, 13]. For example, some researchers showed that & Ming Yang spine_ym@163.com