Roy Xiao

Proangiogenic Properties of Thrombospondin-4

Objective—Thrombospondin-4 (TSP-4) is 1 of the 5 members of the thrombospondin protein family. TSP-1 and TSP-2 are potent antiangiogenic proteins. However, angiogenic properties of the 3 other TSPs, which do not contain the domains associated with the antiangiogeneic activity of TSP-1 and TSP-2, have not been explored. In our previous studies, we found that TSP-4 is expressed in the vascular matrix of blood vessels of various sizes and is especially abundant in capillaries. We sought to identify the function of TSP-4 in the regulation of angiogenesis. Approach and Results—The effect of TSP-4 in in vivo angiogenesis models and its effect on angiogenesis-related properties in cultured cells were assessed using Thbs4−/− mice, endothelial cells (EC) derived from these mice, and recombinant TSP-4. Angiogenesis was decreased in Thbs4−/− mice compared with wild-type mice. TSP-4 was detected in the lumen of the growing blood vessels. Mice expressing the P387 TSP-4 variant, which was previously associated with coronary artery disease and found to be more active in its cellular interactions, displayed greater angiogenesis compared with A387 form. Lung EC from Thbs4−/− mice exhibited decreased adhesion, migration, and proliferation capacities compared with EC from wild-type mice. Recombinant TSP-4 promoted proliferation and the migration of EC. Integrin &agr;2 and gabapentin receptor &agr;2&dgr;-1 were identified as receptors involved in regulation of EC adhesion, migration, and proliferation by TSP-4. Conclusion—TSP-4, an extracellular matrix protein previously associated with tissue remodeling, is now demonstrated to possess proangiogenic activity.

Thrombospondin-4 mediates TGF-β-induced angiogenesis

TGF-β is a multifunctional cytokine affecting many cell types and implicated in tissue remodeling processes. Due to its many functions and cell-specific effects, the consequences of TGF-β signaling are process-and stage-dependent, and it is not uncommon that TGF-β exerts distinct and sometimes opposing effects on a disease progression depending on the stage and on the pathological changes associated with the stage. The mechanisms underlying cell- and process-specific effects of TGF-β are poorly understood. We are describing a novel pathway that mediates induction of angiogenesis in response to TGF-β1. We found that in endothelial cells (EC) thrombospondin-4 (TSP-4), a secreted extracellular matrix (ECM) protein, is upregulated in response to TGF-β1 and mediates the effects of TGF-β1 on angiogenesis. Upregulation of TSP-4 does not require the synthesis of new protein, is not caused by decreased secretion of TSP-4, and is mediated by activation of SMAD3. Using Thbs4−/− mice and TSP-4 shRNA, we found that TSP-4 mediated pro-angiogenic functions in cultured EC and angiogenesis in vivo in response to TGF-β1. We observed~3-fold increases in tumor mass and levels of angiogenesis markers in animals injected with TGF-β1, and these effects did not occur in Thbs4−/− animals. Injections of an inhibitor of TGF-β1 signaling SB-431542 also decreased the weights of tumors and cancer angiogenesis. Our results from in vivo angiogenesis models and cultured EC document that TSP-4 mediates upregulation of angiogenesis by TGF-β1. Upregulation of pro-angiogenic TSP-4 and selective effects of TSP-4 on EC may contribute to stimulation of tumor growth by TGF-β despite the inhibition of cancer cell proliferation.

The impact of diabetes upon quality of life outcomes after lumbar decompression.

BACKGROUND CONTEXT Patients with comorbid disease may experience suboptimal quality of life (QOL) improvement following decompression spinal surgery. Prior studies have suggested the deleterious effect of diabetes upon postoperative QOL; however, these studies have not used minimal clinically important differences (MCIDs) or multivariable statistical techniques. PURPOSE The purpose of this study was to assess the effect of preoperative diabetes upon postoperative change in QOL. STUDY DESIGN/SETTING A retrospective cohort study at a single tertiary-care center was carried out. PATIENT SAMPLE Patients who underwent lumbar decompression between 2008 and 2014 were included in the study. Inclusion necessitated a minimum follow-up of 6 months. OUTCOMES MEASURES Postoperative changes in the EuroQol 5-Dimensions (EQ-5D), Pain Disability Questionnaire (PDQ), and Patient Health Questionnaire 9 (PHQ-9) at last follow-up were the primary outcome measures. The secondary outcome variable was postoperative change in QOL measures exceeding the MCID. METHODS Quality of life data were collected using the institutional prospectively collected database of patient-reported health status measures. Simple and multivariable logistic regressions were used to assess the impact of diabetes upon normalized change in QOL and improvement exceeding the MCID. RESULTS There were 212 patients who met inclusion criteria. Whereas non-diabetics experienced significant improvements in EQ-5D, PDQ, and PHQ-9 (p<.01), diabetics experienced no significant changes in any measures. More non-diabetics achieved the EQ-5D MCID compared with diabetics (55% vs. 23%, p<.01). Following multivariable regression, chronic kidney disease (CKD, β=-0.15, p=.04) and diabetes (β=-0.05, p=.04) were identified as significant independent predictors of diminished improvement in EQ-5D postoperatively. Furthermore, diabetes was also identified as a significant independent predictor of failure to achieve an EQ-5D MCID (OR 0.20, p<.01), whereas CKD trended toward predicting diminished improvement (OR<0.01, p=.09). CONCLUSION The burden of comorbidities may impact the QOL benefit of decompression spine surgery. In the present study, diabetes was found to independently predict diminished improvement in QOL after lumbar decompression.

Quality of life outcomes following cervical decompression for coexisting Parkinson's disease and cervical spondylotic myelopathy

BACKGROUND CONTEXT Coexisting Parkinsons disease (PD) and cervical spondylotic myelopathy (CSM) presents a diagnostic and therapeutic challenge due to symptomatic similarities between the diseases. Whereas CSM patients are routinely treated with surgery, PD patients face poorer outcomes following spine surgery. No studies have investigated the quality of life (QOL) outcomes following decompression in coexisting PD and CSM. PURPOSE The purpose of the present study was to characterize QOL outcomes for patients with coexisting PD and CSM following cervical decompression. STUDY DESIGN/SETTING This is a matched cohort study at a single tertiary-care center. PATIENT SAMPLE Patients with coexisting PD and CSM undergoing cervical decompression between June 2009 and December 2014 were included. These patients were matched to controls with CSM alone by age, gender, American Society of Anesthesiologists classification, Modified Japanese Orthopaedic Association scores, and operative parameters. OUTCOME MEASURES The primary outcome measure was QOL outcomes assessed by change in the EuroQol 5-Dimensions (EQ-5D), Pain Disability Questionnaire (PDQ), and Patient Health Questionnaire-9 (PHQ-9) at last follow-up (LFU). Change in QOL exceeding the minimal clinically important difference (MCID) was secondary. METHODS QOL data were collected using the institutional prospectively collected database of patient-reported health status measures. Simple and multivariable regressions were used to assess the impact of PD upon change in QOL. RESULTS Eleven PD patients were matched to 44 controls. Control patients experienced QOL improvement across all three measures, whereas PD patients only improved with respect to PDQ(89.9-80.7, p=.03). Despite no significant differences in preoperative QOL, PD patients experienced poorer QOL at LFU in EQ-5D (0.526 vs. 0.707, p=.01) and PDQ (80.7 vs. 51.4, p=.03), and less frequently achieved an EQ-5D MCID (18% vs. 57%, p=.04). However, no differences in the achievement of an MCID in PDQ or PHQ-9 were observed between cohorts. Multivariable regression identified PD as a significant independent predictor of poorer improvement in EQ-5D (β=-0.09, p<.01) and failure to achieve an EQ-5D MCID (odds ratio: 0.08, p<.01). CONCLUSIONS This is the first study to characterize QOL outcomes following cervical decompression for patients with coexisting PD and CSM. Although myelopathy may have been less severe among PD patients, a significant reduction in pain-related disability was observed following decompression. However, PD predicted diminished improvement in overall QOL measured by the EQ-5D.

Clinical Outcomes Following Surgical Management of Coexisting Parkinson Disease and Cervical Spondylotic Myelopathy

BACKGROUND Distinguishing the causes of weakness and gait instability in patients with Parkinson disease (PD) and cervical spondylotic myelopathy (CSM) is a diagnostic and therapeutic challenge due to symptomatic similarities. No study has reported outcomes following decompression in patients with PD and CSM. OBJECTIVE To report outcomes following cervical decompression for patients with coexisting PD and CSM. METHODS A retrospective matched cohort study of all patients with PD and CSM undergoing cervical decompression at a tertiary-care center between January 1996 and December 2014 was conducted. PD patients were matched to patients with CSM alone by age, gender, American Society of Anesthesiologists classification, and operative parameters. Myelopathy was assessed by Nurick and modified Japanese Orthopaedic Association (mJOA) scales. The effect of PD on mJOA was modeled using multivariable regression. RESULTS Twenty-one matched pairs were included. PD patients experienced poorer improvement in Nurick (0.0 vs -1.0, P < .01) and mJOA (0.9 vs 2.5, P < .01) composite scores. However, no significant changes in absolute improvement in the upper extremity motor, upper extremity sensory, or sphincter mJOA components were observed. Multivariable regression identified PD as a significant predictor of decreased improvement in mJOA (β = -0.89, P < .01) and failure to achieve a minimal clinically important difference in change in mJOA (OR 0.18, P = .03). CONCLUSION This study is the first to characterize outcomes following cervical decompression in patients with PD and CSM. PD patients experienced symptomatic improvement but less overall improvement in myelopathy compared to controls. However, PD patients demonstrated improvement in upper extremity motor, upper extremity sensory, and sphincter symptoms no worse than control patients.

Predicting the progression of vertebral fractures in patients with multiple myeloma.

BACKGROUND CONTEXT Patients with multiple myeloma (MM) incur significant degradation in quality of life because of progressive osteolytic vertebral fractures. No studies have investigated predictors of fracture progression, and limited data are available for predicting the development of future fractures. PURPOSE The purpose of this study was to identify independent predictors of vertebral fracture progression and the development of future vertebral fracture. STUDY DESIGN/SETTING This is a consecutive retrospective chart review at a single tertiary-care center. PATIENT SAMPLE Patients with MM and pathologic vertebral fracture with radiographic follow-up between January 2007 and December 2013 were included. Radiographic measurements were recorded at presentation with fracture and first follow-up (FFU) after at least three months. Patients with a history of vertebral fracture not associated with MM were excluded. OUTCOME MEASURES The primary outcome measure was the rate of vertebral body height loss. The development of future vertebral fracture was secondary. METHODS Anterior, middle, and posterior vertebral body heights were measured from midline sagittal T1-weighted magnetic resonance imaging (MRI). Future fracture-free survival was calculated using Kaplan-Meier analysis. Multivariable regression was used to identify independent predictors of the rate of vertebral height loss. Multivariable Cox proportional hazards modeling was used to identify predictors of developing future vertebral fracture. RESULTS Thirty-three patients with 67 fractures were followed for a median of 10.8 months to FFU. Sixty-four percent of the patients were female and the median age was 66. The median additional vertebral height loss between presentation and FFU was 15%, whereas the median rate of vertebral height loss was 1.01%/month. More rapid vertebral height loss was predicted by dyslipidemia (β=0.36, p=.05), previous non-vertebral pathologic fracture related to MM (β=0.51, p=.01), and Durie-Salmon Stage III (β=0.66, p=.06). The median time to future fracture was 25.1 months; the 5-year future fracture-free survival rate was 34%. Osteopenia/osteoporosis (hazard ratio [HR]: 9.28, p<.01), serum light chains (HR: 1.37, p=.06), and serum calcium (HR: 1.62, p=.05) predicted the development of future vertebral fracture. CONCLUSIONS We observed significant fracture progression over a short follow-up period. Several comorbidities and laboratory measures predicted more rapid vertebral height loss and the development of future fracture. Identifying risk factors for increased fracture burden may allow spine specialists to pursue earlier and appropriate intervention to optimize function and minimize morbidity.

347 Clinical Outcomes Following Spinal Fusion Using an Intraoperative Computed Tomographic Three-Dimensional Imaging System.

demographic/clinical variables (age 1⁄4 65, sex, race, body mass index (BMI), ASA score, functional status, inpatient/outpatient status, smoking, hypertension, Charlson Comorbidity Index) using multivariable regression. Means, standard errors, odds ratio (OR), and 95% confidence intervals (CIs) are reported. Significance was assessed at P, .05. RESULTS: Of 18 067 subjects (ACDF 1⁄4 17 296, C-ADR 1⁄4 771), C-ADR subjects were on average younger (,65 years: 97.4% vs 84.2%; P , .001), less obese (nonobese: 6.10% vs 49.1%; P , .001), less physically burdened (ASA 1: 13.1% vs 4.3%; ASA 3-4: 17.9% vs 38.3%; P , .001), less functionally dependent (0.5% vs 2.2%; P , .001), and presented with fewer overall comorbidities (3.9% vs 6.4%; P , .001). Overall, 31 (0.17%) patients died. Univariate analyses showed that C-ADR had shorter operation time (111.27 6 1.89-minutes vs 125.59 6 0.53-minutes; P , .001), shorter hospital length of stay (HLOS) (1.06 6 0.03 days vs 1.64 6 0.04 days; P 1⁄4 .003), and higher likelihood of being discharged to home (99.5% vs 96.9%, P , .001). Multivariable analysis confirmed C-ADR association with shorter operation time (B 1⁄4 29.37; 95% CI, 214.34 to 24.01) and with greater likelihood of returning home (OR, 2.74 [1.01, 7.41]), while a nonsignificant statistical trend was demonstrated for HLOS (B 1⁄4 20.35; 95% CI, 20.73 to 0.03). Incidences of early complications did not differ between C-ADR and ACDF (1.4% vs 2.5%, P 1⁄4 .620).INTRODUCTION The O-arm Multidimensional Surgical Imaging System provides superior accuracy of pedicle screw insertion compared with free-hand and fluoroscopic approaches. However, no studies have investigated the clinical relevance of increased accuracy. The objective of this study was to investigate the clinical outcomes following spinal fusion using O-arm navigation. We hypothesized that increased accuracy with O-arm navigation decreases the risk of reoperation compared with free-hand and fluoroscopic guidance. METHODS A consecutive retrospective review of all patients undergoing noncervical spinal fusion at a single tertiary-care institution between December 2012 and December 2014 was conducted. Multivariable linear and Cox proportional hazards regression were used to investigate the association between O-arm navigation and outcomes. RESULTS Among 1208 procedures, 614 were performed with O-arm navigation, 356 using free-hand techniques, and 238 using fluoroscopy. The most common indication for surgery was spondylolisthesis (56.2%), and most patients underwent posterolateral fusion (75.7%). The average fusion spanned 4.53 vertebral levels. O-arm patients experienced shorter hospital stays than patients undergoing free-hand and fluoroscopy approaches (4.72 vs 5.07 days, P < .01), and multivariable linear regression revealed O-arm as an independent predictor of shorter hospital stays compared with fluoroscopy (β = 0.50, P < .01). O-arm was significantly associated with decreased risk of reoperation for hardware failure (2.9% vs 5.9%, relative risk [RR] 0.50, P = .01), screw misplacement (1.6% vs 4.2%, RR 0.39, P < .01), and all-cause reoperation (5.2% vs 10.9%, RR 0.48, P < .01); these findings were corroborated with Kaplan-Meier survival analysis. Cox proportional hazards modeling revealed that O-arm navigation was an independent predictor of reoperation risk, because free-hand (hazard ratio [HR] 1.97, P < .01) and fluoroscopic (HR 2.32, P < .01) methods both predicted greater risk of reoperation. CONCLUSION This is the first study to investigate clinical outcomes associated with O-arm navigation following spinal fusion. O-arm navigation predicted decreased length of hospital stay and decreased the risk of reoperation to half the risk of free-hand and fluoroscopic approaches.

331 Association Between Radiation Necrosis and Tumor Biology Following Stereotactic Radiosurgery for Brain Metastasis.

INTRODUCTION Over the past decade, there has been tremendous interest in biological risk stratification and precision medicine. The chief dose-limiting toxicity of stereotactic radiosurgery (SRS) is radiation necrosis (RN), which occurs following approximately 5% to 10% of treatments. This complication may worsen neurological deficits, increase the frequency and cost of imaging, and necessitate prolonged treatment with steroids or antiangiogenic agents. We hypothesized that tumor biology is associated with RN, and that biological risk stratification may be used to guide dose escalation and dose reduction. METHODS All patients presenting with brain metastasis between 1997 and 2015 who underwent SRS at a single tertiary-care institution were eligible for inclusion. The primary outcome was the cumulative incidence of radiation necrosis, which was diagnosed based on pathological and/or radiographic evidence with the expertise of a tumor board. Multivariate competing risks regression was used to identify independent predictors of RN. RESULTS Among 1939 included patients (5747 lesions), 285 (15%) developed RN following treatment of 427 (7%) lesions. After SRS, the 6-, 12-, and 18-month cumulative incidences of RN were 3.2%, 5.6%, and 6.7%. Following multivariate analysis, prognostic group, renal pathology, left-sided lesions, lesion diameter, and the homogeneity index remained independently predictive of RN. In subset analyses, HER2-amplified status (hazard ratio [HR], 2.05, P = .02), BRAF V600E+ mutational status (HR, 0.33; P = .04), adenocarcinoma histology (HR, 1.89; P = .04), and ALK rearrangement (HR, 6.36; P < .01) were associated with RN. The rate of RN was nonsignificantly increased among EGFR+ lesions (HR, 1.65; P = .20). CONCLUSION Strategic dose adjustment may offer superior local control while sparing the morbidity and cost associated with RN. In the present investigation, we report the largest series of lesions developing radiation necrosis, and identify biological features associated with this complication, including adenocarcinoma histology, HER2 amplification, and mutations of the BRAF and ALK genes. Future studies determining the optimal timing of targeted therapies and SRS are warranted.

Quality of Life Outcomes Following Resection of Adult Intramedullary Spinal Cord Tumors.

BACKGROUND Intramedullary spinal cord tumors are rare but clinically significant entities. Resection is critical to prevent permanent neurological deficits. However, no studies have investigated the quality of life (QOL) benefit of resection in adults. OBJECTIVE To investigate QOL outcomes after intramedullary spinal cord tumors resection. METHODS A consecutive retrospective review of all patients who underwent intramedullary spinal cord tumors resection at a single tertiary care institution between January 2008 and December 2013 was conducted. QOL was measured by the EuroQol 5-Dimensions (EQ-5D), Pain Disability Questionnaire (PDQ), and Patient Health Questionnaire-9 (PHQ-9). Multivariable regression was used to identify independent predictors of outcomes. RESULTS Among 45 patients, the most common pathology was ependymoma (60%). No significant changes between preoperative and postoperative EQ-5D, PDQ, or PHQ-9 were observed. Improvements exceeding the minimal clinically important difference occurred in 28% of patients in EQ-5D, 28% in PDQ, and 16% in PHQ-9. Worse preoperative neurological status predicted worsened EQ-5D (β = -0.09, P = .04) and PDQ (β = 20.77, P < .01), while ependymomas predicted QOL improvement exceeding the minimal clinically important difference in PDQ (OR 14.98, P = .04) and approached significance in EQ-5D (OR 43.52, P = .06). Conversely, cervical tumors predicted worsened PDQ (β = 18.32, P < .01) and failure to achieve EQ-5D minimal clinically important difference (OR <0.01, 95% CI <0.01-0.65, P = .02). Postoperative complications, such as syrinx formation (β = -0.09, P = .04) and cerebrospinal fluid leak (β = 13.85, P = .04), predicted diminished improvement in EQ-5D and PDQ, respectively. CONCLUSION Although resection did not significantly improve QOL, it is likely necessary to arrest QOL deterioration. Patients with better preoperative neurological status or ependymoma experienced QOL improvement, while postoperative complications negatively impacted long-term QOL. ABBREVIATIONS EQ-5D, EuroQol 5-DimensionsGTR, gross total resectionIMSCT, intramedullary spinal cord tumorsMCID, minimal clinically important differenceMMS, Modified McCormick ScalePDQ, Pain Disability QuestionnairePHQ-9, Patient Health Questionnaire-9POD, plane of dissectionQOL, quality of lifeSSI, surgical site infection.

Molecular and clinical prognostic factors for favorable outcome following surgical resection of adult intramedullary spinal cord astrocytomas

OBJECTIVE Intramedullary spinal cord astrocytomas are uncommon but important entities. Aggressive surgical resection is believed to be critical to prevent subsequent neurological deterioration; however, the prognostic significance of numerous patient and molecular variables remains unclear. We sought to investigate the clinical and molecular factors associated with outcomes following surgical resection of adult spinal cord astrocytomas. METHODS A consecutive retrospective chart review of all patients who underwent intramedullary spinal cord astrocytoma resection at a single tertiary-care institution between January 1996 and December 2011 was conducted. Molecular data collected included p53 mutation status, proliferative activity (Ki-67), 1p/19q chromosome loss, and EGFR amplification. Multivariable logistic and Cox proportional hazards regression were used to identify variable associated with postoperative outcomes. RESULTS Among 13 patients undergoing surgical resection followed for a median of 54 months, 54% experienced improvement in neurological status, while 15% remained unchanged and 31% deteriorated. Following resection, the 5-year local control (LC), progression-free survival (PFS), and overall survival (OS) rates were 83%, 63%, and 83%. Median PFS time was found to be 5.6 years. Multivariable regression revealed limited characteristics associated with postoperative outcomes, though no molecular characteristics were found to be prognostic. Older age at surgery predicted decreased probability of PFS (HR 0.91, 95% CI 0.81-0.99, p=0.03) and trended towards predicting lack of neurological improvement (OR 0.94, 95% CI 0.83-1.02, p=0.21) and decreased OS (HR 0.93, 95% CI 0.81, 1.03, p=0.15). Preoperative motor symptoms (OR 0.12, 95% CI <0.01-1.91, p=0.14) and adjuvant chemotherapy (OR 0.07, 95% CI <0.01-1.82, p=0.12) also trended towards predicting lack of neurological improvement. CONCLUSION Age was the only patient variable found to have a statistically significant association with profession-free survival and no other factors were significantly associated with postoperative outcomes. These findings were limited by a relatively small sample size; thus, future studies with increased power investigating the prognostic effects of molecular characteristics could provide further clarity in identifying patients most likely to benefit from surgical resection.