Genetic Predisposition to Symptomatic Lumbar Disk Herniation in Pediatric and Young Adult Patients.

STUDY DESIGN: Case-control whole-genome sequencing analysis of a highly select, young cohort with symptomatic lumbar disk herniation (LDH) compared with the standard variation in a large reference population. OBJECTIVE: To assess genetic influences predisposing pediatric and young adult patients to symptomatic LDH. SUMMARY OF BACKGROUND DATA: LDH has traditionally been attributed to natural weakening or mechanical insult, but recent literature supports a potential genetic influence. METHODS: Young patients with symptomatic, clinically confirmed LDH who underwent surgical treatment were included. Patients were younger than the average age of presentation, limiting the influence of environmental risks. DNA collected from these patients was compared with a reference genome (1000 Genomes Project). A genome-wide association study using whole-genome sequencing was used to characterize genetic mutations potentially associated with LDH. RESULTS: Among the 61 candidate genes flagged, 20 had missense mutations in 2 or more LDH cases. Missense mutations in collagen-encoding genes were observed in 12 of 15 patients (80%). A potential association with clinical presentation was indicated by odds ratios of key single-nucleotide polymorphism (SNP) variants in genes that encode collagen. Relative to the reference population, the LDH cohort demonstrated two statistically significant SNP variants in the gene encoding for aggrecan, a protein that facilitates load-bearing properties in the cartilaginous end plate. Aggrecan genes SNPs rs3817428 and rs11638262 were significantly associated with decreased odds of symptomatic LDH: odds ratio 0.05 (0.02-0.11) and 0.04 (0-0.26), respectively (P < 1 × 10 for both). CONCLUSION: These results suggest that collagen-encoding variants may be a genetic risk factor for LDH. They also shed new light on the role of variants that impact aggrecan, which sustains the cartilaginous end plate. Genetic predisposition to LDH may therefore be related to a multimodal combination of mutations that affect the nucleus pulposus, annulus fibrosus, and the cartilaginous end plates. LEVEL OF EVIDENCE: 4.

Management of extranodal lymphoma of the spine: a study of 30 patients.

Extranodal lymphoma of the spine is often a late manifestation of systemic disease, and may result in symptoms of pain, neurologic compromise or spinal instability. Symptomatic relief is generally achieved by radiotherapy alone, but is not sufficient in addressing spinal instability. The indications for surgery remain controversial, but may be required for spinal stabilization, or refractory disease. Currently, there is a lack of studies that compare the indications and clinical outcomes of patients receiving surgical and nonsurgical management of spinal extranodal lymphoma. Medical records of 30 patients seen from March 2006 to August 2015, with histologically confirmed spinal lymphoma, were retrospectively reviewed. Demographic information, clinical factors, imaging, treatment and clinical outcomes were recorded. 19 patients were treated surgically and 11 nonsurgically (i.e., chemotherapy, radiation or combination). Surgery was performed for emergent neurological deterioration, mechanical stabilization, refractoriness to medical management or to perform an open biopsy for pathological diagnosis. Among those treated surgically, significantly fewer patients could carry on normal activities (KPS <70) at baseline, compared with those treated nonsurgically. However, there were no significant differences regarding pain medication use, functional status at 1 year, or mean survival (87.6 months) between groups. Surgery for extranodal lymphoma may be required in specific cases, resulting in favorable and similar outcomes compared with nonsurgical management.

Predictors of complications and readmission following spinal stereotactic radiosurgery.

AIM: to identify preoperative factors associated with morbidity/mortality, hospital length of stay (LOS), 30-day readmission and operation rates following spinal stereotactic radiosurgery (SRS) for spinal tumors. METHODS: The American College of Surgeons National Quality Improvement Program was queried from 2012 to 2014 to identify patients undergoing SRS for spinal tumors. Logistic regression was performed to identify predictors. RESULTS: 2714 patients were identified; 6.8% had major morbidity or mortality, 6.9% were readmitted within 30 days and 4.3% had a subsequent operation within 30 days. Age, BMI and American Society of Anesthesiologist (ASA) class were predictive of LOS. Major morbidity was predicted by age >80, BMI >35, high ASA, pretreatment functional dependence and baseline comorbidities. Predictors of operation within 30 days included preoperative steroid use, renal failure, BMI >35 and if the treatment was nonelective. DISCUSSION: 4-7% of patients undergoing SRS for spinal tumors have morbidity following the procedure. Factors predictive of morbidity, LOS, and subsequent operation included age, BMI, baseline comorbidities and functional status. CONCLUSION: Identification of preoperative patient-specific factors that are predictive of post-treatment outcome will aid in patient selection and patient counseling leading to greater patient satisfaction and hospital efficiency.

Metastatic human breast cancer to the spine produces mechanical hyperalgesia and gait deficits in rodents.

BACKGROUND CONTEXT: Metastases to the spine are a common source of severe pain in cancer patients. The secondary effects of spinal metastases include pain, bone fractures, hypercalcemia, and neurological deficits. As the disease progresses, pain severity can increase until it becomes refractory to medical treatments and leads to a decreased quality of life for patients. A key obstacle in the study of pain-induced spinal cancer is the lack of reliable and reproducible spine cancer animal models. In the present study, we developed a reproducible and reliable rat model of spinal cancer using human-derived tumor tissue to evaluate neurological decline using imaging and behavioral techniques. PURPOSE: The present study outlines the development and characterization of an orthotopic model of human breast cancer to the spine in immunocompromised rats. STUDY DESIGN/SETTING: This is a basic science study. METHODS: Female immunocompromised rats were randomized into three groups: tumor (n=8), RBC3 mammary adenocarcinoma tissue engrafted in the L5 vertebra body; sham (n=6), surgery performed but not tumor engrafted; and control (n=6), naive rats, no surgery performed. To evaluate the neurological impairment due to tumor invasion, functional assessment was done in all rodents at day 40 after tumor engraftment using locomotion gait analysis and pain response to a mechanical stimulus (Randall-Selitto test). Bioluminescence (BLI) was used to evaluate tumor growth in vivo and cone beam computed tomography (CBCT) was performed to evaluate bone changes due to tumor invasion. The animals were euthanized at day 45 and their spines were harvested and processed for hematoxylin and eosin (H&E) staining. RESULTS: Tumor growth in the spine was confirmed by BLI imaging and corroborated by histological analysis. Cone beam computed tomography images were characterized by a decrease in the bone intensity in the lumbar spine consistent with tumor location on BLI. On H&E staining of tumor-engrafted animals, there was a near-complete ablation of the ventral and posterior elements of the L5 vertebra with severe tumor invasion in the bony components displacing the spinal cord. Locomotion gait analysis of tumor-engrafted rats showed a disruption in the normal gait pattern with asignificant reduction in length (p=.02), duration (p=.002), and velocity (p=.002) of right leg strides and only in duration (p=.0006) and velocity (p=.001) of left leg strides, as compared with control and sham rats. Tumor-engrafted animals were hypersensitive to pain stimulus shown as a significantly reduced response in time (p=.02) and pressure (p=.01) applied when compared with control groups. CONCLUSIONS: We developed a system for the quantitative analysis of pain and locomotion in an animal model of metastatic human breast cancer of the spine. Tumor-engrafted animals showed locomotor and sensory deficits that are in accordance with clinical manifestation in patients with spine metastasis. Pain response and locomotion gait analysis were performed during follow-up. The Randall-Selitto test was a sensitive method to evaluate pain in the rat's spine. We present a model for the study of bone-associated cancer pain secondary to cancer metastasis to the spine, as well as for the study of new therapies and treatments to lessen pain from metastatic cancer to the neuroaxis.

Impact of Smoking on 30-day Morbidity and Mortality in Adult Spinal Deformity Surgery.

STUDY DESIGN: A retrospective cohort study of a prospectively collected surgical database. OBJECTIVE: The aim of this study was to investigate the effect of smoking on 30-day morbidity and mortality in patients undergoing surgery for adult spinal deformity (ASD). SUMMARY OF BACKGROUND DATA: There is conflicting evidence regarding the impact of smoking on short-term outcomes after spinal fusion. METHODS: A retrospective review of the prospectively collected American College of Surgeons National Surgical Quality Improvement database was performed for the years 2007 to 2013. Patients who underwent spinal fusion for ASD were identified. Thirty-day morbidity and mortality were compared between current smokers and nonsmokers. The independent effect of smoking was investigated via multivariate logistic regression analysis. RESULTS: A total of 1368 patients met inclusion criteria and were included in this study. Of the 1368 patients, 15.9% were smokers and 84.1% nonsmokers. The proportion of smokers who developed at least one complication was 9.7% versus 13.6% for nonsmokers (P = 0.119). Major complication rates (including 30-day mortality) were 6.5% for smokers and 8.4% for nonsmokers (P = 0.328). Current smoking status was not associated with increased odds of developing any complication [odds ratio (OR) 0.90; 95% confidence interval (95% CI), 0.47-1.71; P = 0.752] or major complications (OR 1.32; 95% CI 0.64-2.70; P = 0.447) after multivariate analysis. CONCLUSION: Smoking was not associated with higher 30-day complications or mortality after corrective surgery for ASD in this study. However, given the negative effects of smoking on overall health and spine surgery outcomes in the long term, smoking cessation before spinal fusion is still recommended. LEVEL OF EVIDENCE: 3.

Camptothecin and Fas receptor agonists synergistically induce medulloblastoma cell death: ROS-dependent mechanisms.

Medulloblastoma, a common malignant pediatric brain tumor, is highly resistant to death receptor-mediated apoptosis despite death receptor expression by tumor cells. Developing new strategies to overcome this resistance to death receptor activation could positively impact therapeutic outcomes. We explored the modulation of death receptor-induced medulloblastoma cell death by the topoisomerase I inhibitor camptothecin (CPT). CPT significantly increased the human medulloblastoma DAOY cell death response to agonistic anti-Fas antibody (CH-11). Cell death after CPT, CH-11, and CPT+CH-11 treatment was 9, 7, and 33%, respectively. Isobologram analysis showed that CH-11 and CPT act synergistically to induce cell death in DAOY cells. A similar pattern of synergism between CPT and CH-11 was found in ONS-76 medulloblastoma cells. Synergistic cell death was found to be predominantly apoptotic involving both extrinsic and intrinsic pathways as evidenced by annexin V staining, cleavage of caspases (3, 8, and 9), Bid and PARP, and cytoprotection by caspase inhibitors. Flow cytometric analyses showed that expression of cell surface Fas or Fas ligand did not change with drug treatment. Western blot analyses showed that the combination of CH-11+CPT induced a significant decrease in XIAP levels. Furthermore, reactive oxygen species, especially O2, were elevated after CPT treatment, and even more so by the CH-11+CPT treatment. The antioxidants glutathione and N-acetyl-cysteine prevented cell death induced by CPT+CH-11. Moreover, the mitochondrial respiratory chain complex I inhibitor rotenone potentiated CH-11-induced apoptosis in DAOY cells. Taken together, these findings show that CPT synergizes with Fas activation to induce medulloblastoma apoptosis through a mechanism involving reactive oxygen species and oxidative stress pathways.