Miat and interacting protein Metadherin maintain a stem-like niche to promote medulloblastoma tumorigenesis and treatment resistance.

Long noncoding RNAs (lncRNAs) play essential roles in the development and progression of many cancers. However, the contributions of lncRNAs to medulloblastoma (MB) remain poorly understood. Here, we identify Miat as an lncRNA enriched in the sonic hedgehog group of MB that is required for maintenance of a treatment-resistant stem-like phenotype in the disease. Loss of Miat results in the differentiation of tumor-initiating, stem-like MB cells and enforces the differentiation of tumorigenic stem-like MB cells into a nontumorigenic state. Miat expression in stem-like MB cells also facilitates treatment resistance by down-regulating p53 signaling and impairing radiation-induced cell death, which can be reversed by therapeutic inhibition of Miat using antisense oligonucleotides. Mechanistically, the RNA binding protein Metadherin (Mtdh), previously linked to resistance to cytotoxic therapy in cancer, binds to Miat in stem-like MB cells. Like the loss of Miat, the loss of Mtdh reduces tumorigenicity and increases sensitivity to radiation-induced death in stem-like MB cells. Moreover, Miat and Mtdh function to regulate the biogenesis of several microRNAs and facilitate tumorigenesis and treatment resistance. Taken together, these data reveal an essential role for the lncRNA Miat in sustaining a treatment-resistant pool of tumorigenic stem-like MB cells.

An analysis of tumor-related potential spinal column instability (Spine Instability Neoplastic Scores 7-12) eventually requiring surgery with a 1-year follow-up.

OBJECTIVE: Within the Spine Instability Neoplastic Score (SINS) classification, tumor-related potential spinal instability (SINS 7-12) may not have a clear treatment approach. The authors aimed to examine the proportion of patients in this indeterminate zone who later required surgical stabilization after initial nonoperative management. By studying this patient population, they sought to determine if a clear SINS cutoff existed whereby the spine is potentially unstable due to a lesion and would be more likely to require stabilization. METHODS: Records from patients treated at the University of California, San Francisco, for metastatic spine disease from 2005 to 2019 were retrospectively reviewed. Seventy-five patients with tumor-related potential spinal instability (SINS 7-12) who were initially treated nonoperatively were included. All patients had at least a 1-year follow-up with complete medical records. A univariate chi-square test and Student t-test were used to compare categorical and continuous outcomes, respectively, between patients who ultimately underwent surgery and those who did not. A backward likelihood multivariate binary logistic regression model was used to investigate the relationship between clinical characteristics and surgical intervention. Recursive partitioning analysis (RPA) and single-variable logistic regression were performed as a function of SINS. RESULTS: Seventy-five patients with a total of 292 spinal metastatic sites were included in this study; 26 (34.7%) patients underwent surgical intervention, and 49 (65.3%) did not. There was no difference in age, sex, comorbidities, or lesion location between the groups. However, there were more patients with a SINS of 12 in the surgery group (55.2%) than in the no surgery group (44.8%) (p = 0.003). On multivariate analysis, SINS > 11 (OR 8.09, CI 1.96-33.4, p = 0.004) and Karnofsky Performance Scale (KPS) score < 60 (OR 0.94, CI 0.89-0.98, p = 0.008) were associated with an increased risk of surgery. KPS score was not correlated with SINS (p = 0.4). RPA by each spinal lesion identified an optimal cutoff value of SINS > 10, which were associated with an increased risk of surgical intervention. Patients with a surgical intervention had a higher incidence of complications on multivariable analysis (OR 2.96, CI 1.01-8.71, p = 0.048). CONCLUSIONS: Patients with a mean SINS of 11 or greater may be at increased risk of mechanical instability requiring surgery after initial nonoperative management. RPA showed that patients with a KPS score of 60 or lower and a SINS of greater than 10 had increased surgery rates.

Spinal stereotactic body radiotherapy following intralesional curettage with separation surgery for initial or salvage chordoma treatment.

OBJECTIVE Chordoma is a rare malignant tumor for which en bloc resection with wide margins is advocated as primary treatment. Unfortunately, due to anatomical constraints, en bloc resection to achieve wide or marginal margins is not feasible for many patients as the resulting morbidity would be prohibitive. The objective of this study was to evaluate the efficacy of intralesional curettage and separation surgery followed by spinal stereotactic body radiation therapy (SBRT) in patients with chordomas in the mobile spine. METHODS The authors performed a retrospective chart review of all patients with chordoma in the mobile spine treated from 2004 to 2016. Patients were identified from a prospectively collected database. Initially 22 patients were identified with mobile spine chordomas. With inclusion criteria of cytoreductive separation surgery followed closely by SBRT and a minimum of 6 months of follow-up imaging, 12 patients were included. Clinical and pathological characteristics of each patient were collected and data were analyzed. Patients were divided into two cohorts-those undergoing intralesional resection followed by SBRT as initial chordoma treatment at Memorial Sloan Kettering Cancer Center (MSKCC) (Cohort 1) and those undergoing salvage treatment following recurrence (Cohort 2). Treatment toxicities were classified according to the Common Terminology Criteria for Adverse Events version 4.03. Overall survival was analyzed using Kaplan-Meier analysis. RESULTS The 12 patients had a median post-SBRT follow-up time of 26 months. Cohort 1 had 5 patients with median post-SBRT follow-up time of 65.9 months and local control rate of 80% at last follow-up. Only one patient had disease progression, at 48.2 months following surgery and SBRT. Cohort 2 had 7 patients who had been treated at other institutions prior to undergoing both surgery and SBRT (salvage therapy) at MSKCC. The local control rate was 57.1% and the median follow-up duration was 10.7 months. One patient required repeat irradiation. Major surgery- and radiation-related complications occurred in 18% and 27% of patients, respectively. Epidural spinal cord compression scores were collected for each patient pre- and postoperatively. CONCLUSIONS The combination of surgery and SBRT provides excellent local control following intralesional curettage and separation surgery for chordomas in the mobile spine. Patients who underwent intralesional curettage and spinal SBRT as initial treatment had better disease control than those undergoing salvage therapy. High-dose radiotherapy may offer several biological benefits for tumor control.

Nuchal thickness and increased risk of surgical site infection in posterior cervical operations.

OBJECTIVE: Surgical site infections (SSI) are a common post-operative complication, which increase cost, length of stay, and morbidity. Many risk factors have been, identified including body mass index (BMI). The purpose of this study was to evaluate, whether nuchal thickness rather than BMI increases risk for post-operative SSI in, posterior approach cervical spine operations. METHODS: A retrospective review of 180 patients who underwent posterior cervical spine, surgery at the University of Florida was performed. Nuchal thickness was measured, from the ventral most point of the spinous process of C5 to the skin on mid-sagittal preoperative, imaging. Diabetes status, BMI, smoking status, duration of anesthesia, prior, operations, and subcutaneous layer thickness was also collected. Infections were, identified according to the Centers for Disease Control (CDC) definitions for SSI. Univariate and multivariate analyses were performed by a biostatistician. RESULTS: Twenty patients (11%) had SSI. Smoking status, nuchal thickness of greater, than 55 mm or less than 29.8 mm, and subcutaneous fat thickness were all associated, with SSI. Age (OR 0.99, p = 0.45), diabetes (OR 0.50, p = 0.37), BMI (OR 1.03, p = 0.35), and use of intraoperative antibiotic powder (OR 0.62, p = 0.35) were not associated with, infection. On multivariate analysis (adjusted for smoking status), nuchal thickness, (p < 0.0001), subcutaneous fat thickness (p < 0.0001), and the ratio of subcutaneous fat to, nuchal thickness (p < 0.0001) all remained associated with SSI. CONCLUSIONS: Nuchal thickness and subcutaneous fat thickness are associated with SSI, in patients undergoing posterior cervical spine surgery. Risk of infection increases with very thin and very thick nuchal measurements.

Correlation of perioperative risk scores with hospital costs in neurosurgical patients.

OBJECTIVE: The American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) online surgical risk calculator uses inherent patient characteristics to provide predictive risk scores for adverse postoperative events. The purpose of this study was to determine if predicted perioperative risk scores correlate with actual hospital costs. METHODS: A single-center retrospective review of 1005 neurosurgical patients treated between September 1, 2011, and December 31, 2014, was performed. Individual patient characteristics were entered into the NSQIP calculator. Predicted risk scores were compared with actual in-hospital costs obtained from a billing database. Correlational statistics were used to determine if patients with higher risk scores were associated with increased in-hospital costs. RESULTS: The Pearson correlation coefficient (R) was used to assess the correlation between 11 types of predicted complication risk scores and 5 types of encounter costs from 1005 health encounters involving neurosurgical procedures. Risk scores in categories such as any complication, serious complication, pneumonia, cardiac complication, surgical site infection, urinary tract infection, venous thromboembolism, renal failure, return to operating room, death, and discharge to nursing home or rehabilitation facility were obtained. Patients with higher predicted risk scores in all measures except surgical site infection were found to have a statistically significant association with increased actual in-hospital costs (p < 0.0005). CONCLUSIONS: Previous work has demonstrated that the ACS NSQIP surgical risk calculator can accurately predict mortality after neurosurgery but is poorly predictive of other potential adverse events and clinical outcomes. However, this study demonstrates that predicted high-risk patients identified by the ACS NSQIP surgical risk calculator have a statistically significant moderate correlation to increased actual in-hospital costs. The NSQIP calculator may not accurately predict the occurrence of surgical complications (as demonstrated previously), but future iterations of the ACS universal risk calculator may be effective in predicting actual in-hospital costs, which could be advantageous in the current value-based healthcare environment.

Adjacent level fracture incidence in single fraction high dose spinal radiosurgery.

BACKGROUND: Vertebral body compression fracture (VCF) is a complication following spinal stereotactic radiosurgery (SRS). However, the incidence of VCF in vertebrae adjacent to the level of SRS is unknown. This study aimed to determine the incidence of adjacent level VCF (adjVCF) following spinal SRS. METHODS: A retrospective review of 239 lesions treated with single-fraction SRS from 2011-2014 was performed. Clinical and pathologic factors were collected including evaluation of VCFs in adjacent levels to SRS site. In patients with adjVCFs, dose-volume histograms for adjacent-level endplates were calculated. Cox regression analysis was performed to determine any association among clinical factors and adjVCF occurrence. RESULTS: Median follow-up was 14.7 months. Twenty-six adjVCFs occurred (10.8%). Of the adjVCFs, 19 had metastases following SRS, and seven did not (2.9% of total treatments). Median time to fracture post-SRS was 13.5 months. In adjVCFs, median of the mean dose to adjacent level fractured endplate was 23.3 Gy, and median of the mean dose of sixteen non-fractured endplates immediately adjacent to the SRS site was 19.1 Gy. Age, gender, and histology were not associated with adjVCF. CONCLUSIONS: AdjVCF after spinal SRS occurs at a rate of 2.9%, when excluding metastatic sites of disease. Adjacent level endplates should be investigated as an organ at risk during SRS planning.

Myositis following spine radiosurgery for metastatic disease: a case series.

OBJECTIVE Spinal stereotactic body radiation therapy (SBRT) has emerged as an attractive method to deliver high doses of radiation to oligometastatic spinal tumors with radioresistant histology. Because SBRT is a palliative therapy, attention to potential radiation toxicities is paramount when counseling patients. The objective of this study was to report radiation-induced myositis after SBRT, a previously undescribed complication. METHODS A total of 667 patients received 891 spine SBRT treatments (either 24 Gy in 1 fraction or 27 Gy in 3 fractions) from 2011 to 2016 and underwent retrospective review. Eleven patients were identified as having radiographic evidence of myositis following SBRT. Clinical and pathologic results were collected, including receipt of anti-vascular endothelial growth factor (VEGF) therapy, radiation dose, equivalent dose in 2-Gy fractions (EQD2), biologically effective dose (BED), and volume of muscle treated. Treatment toxicities were classified according to the Common Terminology Criteria for Adverse Events (CTCAE; version 4.03). Univariate statistical analyses were performed to evaluate the relationships between radiation fractionation schedule and myositis and between anti-VEGF therapy and myositis. RESULTS The cumulative incidence of myositis was 1.9% at 1 year. The median of the mean dose administered to muscle with myositis was 17.5 Gy. The median EQD2 was 55.1 Gy, and the median BED was 82.7 Gy. The median time to the development of clinical symptoms was 1.4 months, while the median time to imaging evidence was 4.7 months. Two patients (18.2%) had CTCAE grade 3 complications. Single-fraction spine SBRT (HR 4.5, 95% CI 1.2-16.9; p = 0.027) was associated with increased risk of developing myositis whereas receipt of anti-VEGF therapy was not (HR 2.2, 95% CI 0.6-7.1; p = 0.2). CONCLUSIONS Radiation myositis following spinal radiosurgery is a rare but important complication. Single-fraction treatment schedules may be associated with increased risk of myositis but should be validated in a larger series.

Prophylactic Antiepileptic Drug Use in Patients with Brain Tumors Undergoing Craniotomy.

BACKGROUND: Prophylactic use of antiepileptic drugs (AEDs) for patients undergoing brain tumor surgery is common practice despite lack of clear evidence. We hypothesized that prophylactic AED (pAED) use did not affect seizure rates in patients with brain tumor who underwent craniotomy for tumor resection. METHODS: A retrospective review was performed of 606 patients who underwent surgery for brain tumors from 2006 to 2013 at the University of Florida, excluding patients with preexisting seizure condition before tumor diagnosis. Data were analyzed to determine seizure incidence, AED use, and AED toxicities. RESULTS: Most patients (81%) had no seizure on presentation. Eight patients did not present with seizure but had seizure postoperatively, and 9 patients did not present with seizure or have seizure postoperatively but did have seizure on follow-up. Despite not presenting with a seizure preoperatively, 208 patients (43%) were placed on pAED preoperatively, 313 patients (64%) were on AED in the postoperative period, and 274 patients (56%) remained on AED at discharge. The pAED use odds ratio for seizures was 1.3 (95% confidence interval, 0.5-3.4; P = 0.599). At last follow-up, 34% of patients with no seizure on presentation remained on pAEDs. CONCLUSIONS: pAEDs did not significantly reduce postoperative seizures in patients with brain tumor in this analysis. In addition, pAED was often continued once prescribed even if the patient remained seizure free.

External ventricular drain practice variations: results from a nationwide survey.

OBJECTIVE While guidelines exist for many neurosurgical procedures, external ventricular drain (EVD) insertion has yet to be standardized. The goal of this study was to survey the neurosurgical community and determine the most frequent EVD insertion practices. The hypothesis was that there would be no standard practices identified for EVD insertion or methods to avoid EVD-associated infections. METHODS The American Association of Neurological Surgeons membership database was queried for all eligible neurosurgeons. A 16-question, multiple-choice format survey was created and sent to 7217 recipients. The responses were collected electronically, and the descriptive results were tabulated. Data were analyzed using the chi-square test. RESULTS In total, 1143 respondents (15.8%) completed the survey, and 705 respondents (61.6%) reported tracking EVD infections at their institution. The most common self-reported infection rate ranged from 1% to 3% (56.1% of participants), and 19.7% of respondents reported a 0% infection rate. In total, 451 respondents (42.7%) indicated that their institution utilizes a formal protocol for EVD placement. If a respondent's institution had a protocol, only 258 respondents (36.1%) always complied with the protocol. Protocol utilization for EVD insertion was significantly more frequent among residents, in academic/hybrid centers, in ICU settings, and if the institution tracked EVD-associated infection rates (p < 0.05). A self-reported 0% infection rate was significantly more commonly associated with a higher level of training (e.g., attending physicians), private center settings, a clinician performing 6 to 10 EVD insertions within the previous 12 months, and prophylactic continuous antibiotic utilization (p < 0.05). CONCLUSIONS This survey demonstrated heterogeneity in the practices for EVD insertion. No standard practices have been proposed or adopted by the neurosurgical community for EVD insertion or complication avoidance. These results highlight the need for the nationwide standardization of technique and complication prevention measures.

Bupivacaine for pain reduction after iliac crest bone graft harvest.

Iliac crest bone graft remains the gold standard in achieving spinal arthrodesis, but chronic pain from graft harvest occurs in up to 39% of patients. Studies have shown that a single administration of local anesthetic reduces short-term pain, but they have not adequately investigated possible longer-term benefits. The goal of this study was to determine whether local administration of bupivacaine after iliac crest bone graft harvesting reduces pain and improves patient-reported outcomes. In this prospective, randomized, controlled, and blinded clinical study, 40 patients were identified who underwent posterior spine fusion with iliac crest bone graft and were randomized to receive either bupivacaine (treatment group, n=20) or saline (control group, n=20) at the iliac crest bone graft site. Pain at the harvest site was determined by a series of 12 visual and numeric pain scale assessments. Short Form-12 mental and physical component scores, EuroQol-5D, and Oswestry Disability Index assessments were made, along with determination of patient satisfaction and self-reported outcome of surgery. Baseline pain and outcome assessments were statistically similar (P>.05). Average pain scores were lower for all 12 assessments in the treatment group at mean follow-up of 5 weeks (significant differences in 6 assessments) and 20 weeks (significant differences in 2 assessments). No significant differences were found in Short Form-12 and EuroQol-5D scores. For patients who underwent lumbar fusion, the treatment group had significantly improved Oswestry Disability Index scores (mean±SD=10.8±7.1 vs 18.7±5.9, P=.012). Significantly more patients in the treatment group reported that surgery met all expectations (90% vs 50%, P=.016). This study is the 1st to show that a single administration of bupivacaine at the iliac crest bone graft harvest site during posterior spine fusion surgery can result in improved outcomes and reduced pain far beyond the anesthetic duration of activity.

Percutaneous stereotactic radiofrequency lesioning for trigeminal neuralgia: determination of minimum clinically important difference in pain improvement for patient-reported outcomes.

BACKGROUND: The Visual Analog Scale (VAS) and the Barrow Neurological Institute Pain Scale (BNI-PS) are 2 patient-reported outcome (PRO) tools frequently used to rate pain from trigeminal neuralgia (TN). Outcomes studies often use these patient-reported outcomes to assess treatment effectiveness, but it is unknown exactly what degree of change in the numerical scores constitutes the minimum clinically important difference (MCID). MCID remains uninvestigated for percutaneous stereotactic radiofrequency lesioning (RFL), a common surgical procedure for TN. OBJECTIVE: To determine MCID values for the VAS and BNI-PS in patients undergoing RFL. METHODS: Forty-three consecutive patients with TN who underwent RFL by a single surgeon were prospectively assessed with the VAS and BNI-PS preoperatively and 3 years postoperatively. Three anchors were used to assign each patient's outcome: satisfaction, willingness to have the surgery again, and Health Transition Index. We then used 3 well-established, anchor-based methods to calculate MCID: average change, minimum detectable change, and change difference. RESULTS: Patients experienced substantial improvement in both VAS (9.81 vs 3.35; P < .001) and BNI-PS (4.95 vs 2.44; P < .001) after RFL. The 3 MCID calculation methods generated a range of MCID values for each of the PROs (VAS, 4.13-8.20; BNI-PS, 1.03-3.30). The area under the receiver-operating characteristic curve was greater for BNI-PS compared with VAS for all 3 anchors, indicating that BNI-PS is probably better suited for calculating MCID. CONCLUSION: RFL-specific MCID is variable on the basis of the calculation technique. With the use of the minimum detectable change calculation method with the Health Transition Index anchor, the minimum clinically important difference is 4.49 for VAS and 1.16 for BNI-PS after RFL for TN. ABBREVIATIONS: AUC, area under the receiver-operating characteristic curveBNI-PS, Barrow Neurological Institute Pain ScaleHTI, Health Transition IndexMCID, minimum clinically important differenceMDC, minimum detectable changePRO, patient-reported outcomeRFL, percutaneous stereotactic radiofrequency lesioningTN, trigeminal neuralgiaVAS, Visual Analog Scale.

Microvascular decompression for classic trigeminal neuralgia: determination of minimum clinically important difference in pain improvement for patient reported outcomes.

BACKGROUND: Outcomes studies use patient-reported outcome (PRO) measurements to assess treatment effectiveness, but can lack direct clinical meaning. Minimum clinically important difference (MCID) calculation provides a point estimate of the critical threshold needed to achieve clinically relevant treatment effectiveness. MCID remains uninvestigated for microvascular decompression (MVD), a common surgical procedure for trigeminal neuralgia. OBJECTIVE: We aimed to determine MCID for the most commonly used PRO measures of pain after MVD: Visual Analog Scale (VAS) and Barrow Neurological Institute Pain Scale (BNI-PS). METHODS: Sixty consecutive patients with classic trigeminal neuralgia who decided to undergo MVD by a single surgeon were prospectively assessed with VAS and BNI-PS preoperatively and 2 years postoperatively. Three anchors were used to assign each patient's outcome. We then used 3 well-established, anchor-based methods to calculate MCID. RESULTS: Patients experienced significant improvement in both VAS (9.9 vs. 2.0, P < .001) and BNI-PS (5.0 vs. 1.9, P < .001) after MVD. The area under the receiver-operating characteristic curve was greater for BNI-PS than for VAS for all 3 anchors, indicating that BNI-PS is probably better suited for calculating MCID. The 3 MCID calculation methods generated a range of MCID values for each of the PROs (VAS: 1.40-8.87, BNI-PS: 0.95-3.26). CONCLUSION: MVD-specific MCID is highly variable based on calculation technique. Some of these calculations appear to either overestimate or underestimate the patients' preoperative expectations. When the different MCID methods are averaged, the results are clinically appropriate and consistent with preoperative expectations. The average MCID for VAS is 6.25 and for BNI-PS is 2.44.