Dissecting the energetic architecture within an RNA tertiary structural motif via high-throughput thermodynamic measurements.

Structured RNAs and RNA/protein complexes perform critical cellular functions. They often contain structurally conserved tertiary contact "motifs," whose occurrence simplifies the RNA folding landscape. Prior studies have focused on the conformational and energetic modularity of intact motifs. Here, we turn to the dissection of one common motif, the 11nt receptor (11ntR), using quantitative analysis of RNA on a massively parallel array to measure the binding of all single and double 11ntR mutants to GAAA and GUAA tetraloops, thereby probing the energetic architecture of the motif. While the 11ntR behaves as a motif, its cooperativity is not absolute. Instead, we uncovered a gradient from high cooperativity amongst base-paired and neighboring residues to additivity between distant residues. As expected, substitutions at residues in direct contact with the GAAA tetraloop resulted in the largest decreases to binding, and energetic penalties of mutations were substantially smaller for binding to the alternate GUAA tetraloop, which lacks tertiary contacts present with the canonical GAAA tetraloop. However, we found that the energetic consequences of base partner substitutions are not, in general, simply described by base pair type or isostericity. We also found exceptions to the previously established stability-abundance relationship for 11ntR sequence variants. These findings of "exceptions to the rule" highlight the power of systematic high-throughput approaches to uncover novel variants for future study in addition to providing an energetic map of a functional RNA.

Racial disparities in the management and outcomes of primary osseous neoplasms of the spine: a SEER analysis.

PURPOSE: Primary osseous neoplasms of the spine, including Ewing's sarcoma, osteosarcoma, chondrosarcoma, and chordoma, are rare tumors with significant morbidity and mortality. The present study aims to identify the prevalence and impact of racial disparities on management and outcomes of patients with these malignancies. METHODS: The 2000 to 2020 Surveillance, Epidemiology, and End Results (SEER) Registry, a cancer registry, was retrospectively reviewed to identify patients with Ewing's sarcoma, osteosarcoma, chondrosarcoma, or chordoma of the vertebral column or sacrum/pelvis. Study patients were divided into race-based cohorts: White, Black, Hispanic, and Other. Demographics, tumor characteristics, treatment variables, and mortality were assessed. RESULTS: 2,415 patients were identified, of which 69.8% were White, 5.8% Black, 16.1% Hispanic, and 8.4% classified as "Other". Tumor type varied significantly between cohorts, with osteosarcoma affecting a greater proportion of Black patients compared to the others (p < 0.001). A lower proportion of Black and Other race patients received surgery compared to White and Hispanic patients (p < 0.001). Utilization of chemotherapy was highest in the Hispanic cohort (p < 0.001), though use of radiotherapy was similar across cohorts (p = 0.123). Five-year survival (p < 0.001) and median survival were greatest in White patients (p < 0.001). Compared to non-Hispanic Whites, Hispanic (p < 0.001) and "Other" patients (p < 0.001) were associated with reduced survival. CONCLUSION: Race may be associated with tumor characteristics at diagnosis (including subtype, size, and site), treatment utilization, and mortality, with non-White patients having lower survival compared to White patients. Further studies are necessary to identify underlying causes of these disparities and solutions for eliminating them.

High-throughput dissection of the thermodynamic and conformational properties of a ubiquitous class of RNA tertiary contact motifs.

Despite RNA's diverse secondary and tertiary structures and its complex conformational changes, nature utilizes a limited set of structural "motifs"-helices, junctions, and tertiary contact modules-to build diverse functional RNAs. Thus, in-depth descriptions of a relatively small universe of RNA motifs may lead to predictive models of RNA tertiary conformational landscapes. Motifs may have different properties depending on sequence and secondary structure, giving rise to subclasses that expand the universe of RNA building blocks. Yet we know very little about motif subclasses, given the challenges in mapping conformational properties in high throughput. Previously, we used "RNA on a massively parallel array" (RNA-MaP), a quantitative, high-throughput technique, to study thousands of helices and two-way junctions. Here, we adapt RNA-MaP to study the thermodynamic and conformational properties of tetraloop/tetraloop receptor (TL/TLR) tertiary contact motifs, analyzing 1,493 TLR sequences from different classes. Clustering analyses revealed variability in TL specificity, stability, and conformational behavior. Nevertheless, natural GAAA/11ntR TL/TLRs, while varying in tertiary stability by ∼2.5 kcal/mol, exhibited conserved TL specificity and conformational properties. Thus, RNAs may tune stability without altering the overall structure of these TL/TLRs. Furthermore, their stability correlated with natural frequency, suggesting thermodynamics as the dominant selection pressure. In contrast, other TL/TLRs displayed heterogenous conformational behavior and appear to not be under strong thermodynamic selection. Our results build toward a generalizable model of RNA-folding thermodynamics based on the properties of isolated motifs, and our characterized TL/TLR library can be used to engineer RNAs with predictable thermodynamic and conformational behavior.

Unraveling molecular advancements in chordoma tumorigenesis and treatment response: a review of scientific discoveries and clinical implications.

Chordomas are tumors thought to originate from notochordal remnants that occur in midline structures from the cloves of the skull base to the sacrum. In adults, the most common location is the sacrum, followed by the clivus and then mobile spine, while in children a clival origin is most common. Most chordomas are slow growing. Clinical presentation of chordomas tend to occur late, with local invasion and large size often complicating surgical intervention. Radiation therapy with protons has been proven to be an effective adjuvant therapy. Unfortunately, few adjuvant systemic treatments have demonstrated significant effectiveness, and chordomas tend to recur despite intensive multimodal care. However, insight into the molecular underpinnings of chordomas may guide novel therapeutic approaches including selection for immune and molecular therapies, individualized prognostication of outcomes, and real-time noninvasive assessment of disease burden and evolution. At the genomic level, elevated levels of brachyury stemming from duplications and mutations resulting in altered transcriptional regulation may introduce druggable targets for new surgical adjuncts. Transcriptome and epigenome profiling have revealed promoter- and enhancer-dependent mechanisms of protein regulation, which may influence therapeutic response and long-term disease history. Continued scientific and clinical advancements may offer further opportunities for treatment of chordomas. Single-cell transcriptome profiling has further provided insight into the heterogeneous molecular pathways contributing to chordoma propagation. New technologies such as spatial transcriptomics and emerging biochemical analytes such as cell-free DNA have further augmented the surgeon-clinician's armamentarium by facilitating detailed characterization of intra- and intertumoral biology while also demonstrating promise for point-of-care tumor quantitation and assessment. Recent and ongoing clinical trials highlight accelerating interest to translate laboratory breakthroughs in chordoma biology and immunology into clinical care. In this review, the authors dissect the landmark studies exploring the molecular pathogenesis of chordoma. Incorporating this into an outline of ongoing clinical trials and discussion of emerging technologies, the authors aimed to summarize recent advancements in understanding chordoma pathogenesis and how neurosurgical care of chordomas may be augmented by improvements in adjunctive treatments.

Directed Evolution of Aptamer Discovery Technologies.

Although antibodies are a powerful tool for molecular biology and clinical diagnostics, there are many emerging applications for which nucleic acid-based aptamers can be advantageous. However, generating high-quality aptamers with sufficient affinity and specificity for biomedical applications is a challenging feat for most research laboratories. In this Account, we describe four techniques developed in our laboratory to accelerate the discovery of high-quality aptamer reagents that can achieve robust binding even for challenging molecular targets. The first method is particle display, in which we convert solution-phase aptamers into aptamer particles that can be screened via fluorescence-activated cell sorting (FACS) to quantitatively isolate individual aptamer particles based on their affinity. This enables the efficient isolation of high-affinity aptamers in fewer selection rounds than conventional methods, thereby minimizing selection biases and reducing the emergence of artifacts in the final aptamer pool. We subsequently developed the multiparametric particle display (MPPD) method, which employs two-color FACS to isolate aptamer particles based on both affinity and specificity, yielding aptamers that exhibit excellent target binding even in complex matrixes such as serum. The third method is an alkyne-azide chemistry ("click chemistry")-based particle display (click-PD) that enables the generation and screening of "non-natural" aptamers with a wide range of base modifications. We have shown that these base-modified aptamers can achieve robust affinity and specificity for targets that have proven challenging or inaccessible with natural nucleotide-based aptamer libraries. Finally, we describe the non-natural aptamer array (N2A2) platform in which a modified benchtop sequencing instrument is used to characterize base-modified aptamers in high throughput, enabling the efficient identification of molecules with excellent affinity and specificity for their targets. This system first generates aptamer clusters on the flow-cell surface that incorporate alkyne-modified nucleobases and then performs a click reaction to couple those nucleobases to an azide-modified chemical moiety. This yields a sequence-defined array of tens of millions of base-modified sequences, which can then be characterized for affinity and specificity in a high-throughput fashion. Collectively, we believe that these advancements are helping to make aptamer technology more accessible, efficient, and robust, thereby enabling the use of these affinity reagents for a wider range of molecular recognition and detection-based applications.

Atlantoaxial instability associated with ALDH18A1 mutation.

We report a 10-year-old boy with a de novo pathogenic variant in ALDH18A1, a rare form of metabolic cutis laxa, which was complicated by atlantoaxial instability and spinal cord compression following a fall from standing height. The patient required emergent cervical spine fusion and decompression followed by a 2-month hospitalization and rehabilitation. In addition to the core clinical features of joint and skin laxity, hypotonia, and developmental delays, we expand the connective tissue phenotype by adding a new potential feature of cervical spine instability. Patients with pathogenic variants in ALDH18A1 may warrant cervical spine screening to minimize possible morbidity. Neurosurgeons, geneticists, primary care providers, and families should be aware of the increased risk of severe cervical injury from minor trauma.

A current review of spinal meningiomas: epidemiology, clinical presentation and management.

PURPOSE: To provide an up-to-date review of the epidemiology, histopathology, molecular biology, and etiology of spinal meningiomas, as well as discuss the clinical presentation, clinical evaluation, and most recent treatment recommendations for these lesions. METHODS: PubMed and Google Scholar search was performed for studies related to meningiomas of the spine. The terms "meningioma," "spinal meningioma," "spine meningioma," "meningioma of the spine," "benign spinal tumors," and "benign spine tumors," were used to identify relevant studies. All studies, including primary data papers, meta-analyses, systematic reviews, general reviews, case reports, and clinical trials were considered for review. RESULTS: Eighty-four studies were identified in the review. There were 22 studies discussing adverse postoperative outcomes, 21 studies discussing tumor genetics, 19 studies discussing epidemiology and current literature, 9 studies discussing radiation modalities and impact on subsequent tumor development, 5 studies on characteristic imaging findings, 5 studies discussing hormone use/receptor status on tumor development, 2 discussing operative techniques and 1 discussing tumor identification. CONCLUSION: Investigations into spinal meningiomas generally lag behind that of intracranial meningiomas. Recent advancements in the molecular profiling of spinal meningiomas has expanded our understanding of these tumors, increasing our appreciation for their heterogeneity. Continued investigation into the defining characteristics of different spinal meningiomas will aid in treatment planning and prognostication.

Effect of race, sex, and socioeconomic factors on overall survival following the resection of intramedullary spinal cord tumors.

INTRODUCTION: Intramedullary spinal cord tumors (IMSCTs) account for 2-4% of all primary CNS tumors. Given their low prevalence and the intricacy of their diagnosis and management, it is critical to address the surrounding racial and socioeconomic factors that impact the care of patients with IMSCTs. This study aimed to investigate the association between race and socioeconomic factors with overall 5 year mortality following the resection of IMSCTs. METHODS: The study used the National Cancer Database to retrospectively analyze patients who underwent resection of IMSCTs from 2004 to 2017. Patients were divided into four cohorts by race/ethnicity, facility type, insurance, median income quartiles, and living area. The primary outcome of interest was 5 year survival, and secondary outcomes included postoperative length of stay and 30 day readmission. Descriptive and multivariable analyses were used to identify independent factors associated with mortality, with statistical significance assessed at a 2-sided p < 0.05. RESULTS: We evaluated the patient characteristics and outcomes for 8,028 patients who underwent surgical treatment for IMSCTs between 2004 and 2017. Most patients were white males (52.4%) with a mean age of 44 years where 7.17% of patients were Black, 7.6% were Hispanic, and 3% were Asian. Most were treated in an academic/research program (72.4%) and had private insurance (69.2%). Black patients had a higher odd of 5 year mortality (OR 1.4; 95% CI 1.1 to 1.77; p = 0.04) compared to white patients, while no significant differences in mortality were observed among other races. Factors associated with lower odds of mortality included being female (OR 0.89; 95% CI 0.78 to 1.02; p < 0.01), receiving treatment in an academic/research program (OR 0.51; 95% CI 0.33 to 0.79; p = 0.04), having private insurance (OR 0.65; 95% CI 0.45 to 0.93; p = 0.02), and having higher income quartiles (OR 0.77; 95% CI 0.62 to 0.96; p = 0.02). CONCLUSION: Our study sheds light on the healthcare disparities that exist in the surgical management of IMSCTs. Our findings indicate that race, sex, socioeconomic status, and treatment facility are independent predictors of 5 year mortality, with Black patients, males, those with lower socioeconomic status, and those treated at non-academic centers experiencing significantly higher mortality rates. These alarming disparities underscore the urgent need for policymakers and researchers to address the underlying factors contributing to these discrepancies and provide equal access to high-quality surgical care for patients with IMSCTs.

Gross total resection of spinal chondrosarcoma is associated with improved locoregional relapse-free survival and overall survival.

BACKGROUND: Spinal chondrosarcomas are rare malignant osseous tumors. The low incidence of spinal chondrosarcomas and the complexity of spine anatomy have led to heterogeneous treatment strategies with varying curative and survival rates. The goal of this study is to investigate prognostic factors for locoregional recurrence-free survival (LRFS) and overall survival (OS) comparing en bloc vs. piecemeal resection for the management of spinal chondrosarcoma. METHODS: We retrospectively identified patients who underwent curative-intent resection of primary and metastatic spinal chondrosarcoma over a 25-year period. Univariate and multivariate survival analyses were conducted with LRFS as primary endpoint and OS as secondary endpoint. LRFS and OS were modeled using the Kaplan-Meier method and assessed using Cox regression analysis. RESULTS: For 72 patients who underwent first resection, the median follow-up time was 5.1 years (95% CI 2.2-7.0). Thirty-three patients (45.8%) had en bloc resection, and 39 (54.2%) had piecemeal resection. Of the 68 patients for whom extent of resection was known, 44 patients had gross total resection (GTR) and 24 patients had subtotal resection. In survival analyses, both LRFS and OS showed statistically significant difference based on the extent of resection (p = 0.001; p = 0.04, respectively). However, only LRFS showed statistically significant difference when assessing the type of resection (p = 0.02). In addition, higher tumor grade and more invasive disease were associated with worse LRFS and OS rates. CONCLUSION: Although in our study en bloc and GTR were associated with improved survival, heterogenous and complex spinal presentations may limit total resection. Therefore, the surgical management should be tailored individually to ensure the best local control and maximum preservation of function.

The prognostic nutritional index (PNI) is independently associated with 90-day and 12-month mortality after metastatic spinal tumor surgery.

INTRODUCTION: Estimated postoperative survival is an important consideration during the decision-making process for patients with spinal metastases. Nutritional status has been associated with poor outcomes and limited survival in the general cancer population. The objective of this study was to evaluate the predictive utility of the prognostic nutritional index (PNI) for postoperative mortality after spinal metastasis surgery. METHODS: A total of 139 patients who underwent oncologic surgery for spinal metastases between April 2012 and August 2022 and had a minimum 90-day follow-up were included. PNI was calculated using preoperative serum albumin and total lymphocyte count, with PNI < 40 defined as low. The mean PNI of our cohort was 43 (standard deviation: 7.7). The primary endpoint was 90-day mortality, and the secondary endpoint was 12-month mortality. Multivariate logistic regression analyses were performed. RESULTS: The 90-day mortality was 27% (37/139), and the 12-month mortality was 56% (51/91). After controlling for age, ECOG performance status, total psoas muscle cross-sectional area (TPA), and primary cancer site, the PNI was associated with 90-day mortality [odds ratio 0.86 (95% confidence interval 0.79-0.94); p = 0.001]. After controlling for ECOG performance status and primary cancer site, the PNI was associated with 12-month mortality [OR 0.89 (95% CI 0.82-0.97); p = 0.008]. Patients with a low PNI had a 50% mortality rate at 90 days and an 84% mortality rate at 12 months. CONCLUSION: The PNI was independently associated with 90-day and 12-month mortality after metastatic spinal tumor surgery, independent of performance status, TPA, and primary cancer site.

Association of frailty with healthcare resource utilization after open thoracic/thoracolumbar posterior spinal fusion for adult spinal deformity.

PURPOSE: The Hospital Frailty Risk Score (HFRS) is a frailty-identifying metric developed using ICD-10-CM codes. While other studies have examined frailty in adult spinal deformity (ASD), the HFRS has not been assessed in this population. The aim of this study was to utilize the HFRS to investigate the impact of frailty on outcomes in ASD patients undergoing posterior spinal fusion (PSF). METHODS: A retrospective study was performed using the 2016-2019 National Inpatient Sample database. Adults with ASD undergoing elective PSF were identified using ICD-10-CM codes. Patients were categorized into HFRS-based frailty cohorts: Low (HFRS < 5) and Intermediate-High (HFRS ≥ 5). Patient demographics, comorbidities, intraoperative variables, and outcomes were assessed. Multivariate regression analyses were used to determine whether HFRS independently predicted extended length of stay (LOS), non-routine discharge, and increased cost. RESULTS: Of the 7500 patients identified, 4000 (53.3%) were in the Low HFRS cohort and 3500 (46.7%) were in the Intermediate-High HFRS cohort. On average, age increased progressively with increasing HFRS scores (p < 0.001). The frail cohort experienced more postoperative adverse events (p < 0.001), greater LOS (p < 0.001), accrued greater admission costs (p < 0.001), and had a higher rate of non-routine discharge (p < 0.001). On multivariate analysis, Intermediate-High HFRS was independently associated with extended LOS (OR: 2.58, p < 0.001) and non-routine discharge (OR: 1.63, p < 0.001), though not increased admission cost (OR: 1.01, p = 0.929). CONCLUSION: Our study identified HFRS to be significantly associated with prolonged hospitalizations and non-routine discharge. Other factors that were found to be associated with increased healthcare resource utilization include age, Hispanic race, West hospital region, large hospital size, and increasing number of AEs.

Systemic considerations for the surgical treatment of spinal metastatic disease: a scoping literature review.

Systemic assessment is a pillar in the neurological, oncological, mechanical, and systemic (NOMS) decision-making framework for the treatment of patients with spinal metastatic disease. Despite this importance, emerging evidence relating systemic considerations to clinical outcomes following surgery for spinal metastatic disease has not been comprehensively summarised. We aimed to conduct a scoping literature review of this broad topic. We searched MEDLINE, Embase, Scopus, Cochrane Central Register of Controlled Trials, Web of Science, and CINAHL databases from Jan 1, 2000, to July 31, 2021. 61 articles were included, accounting for a total of 22 335 patients. Preoperative systemic variables negatively associated with postoperative clinical outcomes included demographics (eg, older age [>60 years], Black race, male sex, low or elevated body-mass index, and smoking status), medical comorbidities (eg, cardiac, pulmonary, hepatic, renal, endocrine, vascular, and rheumatological), biochemical abnormalities (eg, hypoalbuminaemia, atypical blood cell counts, and elevated C-reactive protein concentration), low muscle mass, generalised motor weakness (American Spinal Cord Injury Association Impairment Scale grade and Frankel grade) and poor ambulation, reduced performance status, and systemic disease burden. This is the first comprehensive scoping review to broadly summarise emerging evidence relevant to the systemic assessment component of the widely used NOMS framework for spinal metastatic disease decision making. Medical, surgical, and radiation oncologists can consider these findings when prognosticating spinal metastatic disease-related surgical outcomes on the basis of patients' systemic condition. These factors might inform a shared decision-making approach with patients and their families.

Clinical Prediction Modeling in Intramedullary Spinal Tumor Surgery.

Artificial intelligence is poised to influence various aspects of patient care, and neurosurgery is one of the most uprising fields where machine learning is being applied to provide surgeons with greater insight about the pathophysiology and prognosis of neurological conditions. This chapter provides a guide for clinicians on relevant aspects of machine learning and reviews selected application of these methods in intramedullary spinal cord tumors. The potential areas of application of machine learning extend far beyond the analyses of clinical data to include several areas of artificial intelligence, such as genomics and computer vision. Integration of various sources of data and application of advanced analytical approaches could improve risk assessment for intramedullary tumors.

Microsurgical resection of foramen magnum meningioma: multi-institutional retrospective case series and proposed surgical risk scoring system.

PURPOSE: Foramen magnum meningiomas (FMMs) are a major surgical challenge, due to relevant surgical morbidity and mortality. The paper aims to review the clinical (symptomatic improvement, complication rate, length of hospital stay) and radiological outcome (completeness of resection) of microsurgical resection of FMMs, and to identify predictors of complications. METHODS: A multi-institutional retrospective review of prospectively maintained database of FMMs included 51 patients (74.5% females) with a median tumor volume of 8.18 cm3 (range, 1.77-57.9 cm3) and median follow-up of 36 months (range, 0.30-180.0 months). Tumors were resected though suboccipital approach (58.8%) or posterior-lateral approaches (39.3%), including far-lateral, extreme lateral and transcondylar approaches. RESULTS: Gross-total resection (GTR) was achieved in 80.4% and 98% of cases did not present tumor regrowth or recurrence. Clinical symptoms improved in 34 patients (66.7%) and worsened in 5 (9.8%). The median length of hospital stay was 5 days. Mortality was null. Postoperative complications developed in 15 patients (29.4%), with cerebrospinal fluid leak (7.8%) and lower cranial nerves deficits (7.8%) as the most frequent. Craniospinal location (p = 0.03), location anterior to the dentate ligament (DL) (p = 0.02), involvement of vertebral artery (VA) (p = 0.03) were significantly associated with complication rate. These three elements allow calculating the Foramen Magnum Meningioma Risk Score (FRMMRS), to estimate the risk of post-operative complications. CONCLUSION: Microsurgical resection allows for high GTR rate and low rate of tumor regrowth or recurrence, despite complications in one third of the patients. The FMMRS allows classifying FMMs and estimating the risk of post-operative complications.

Assessment of the efficacy of teriparatide treatment for osteoporosis on lumbar fusion surgery outcomes: a systematic review and meta-analysis.

Treatment of osteoporosis with medications like teriparatide, a parathyroid hormone, is known to improve bone density and reduce the risk of osteoporotic vertebral fractures. Anecdotal and limited surgical series have described the utility of this treatment for osteoporotic patients prior to spinal fusion surgery, but there is variability in adoption of this strategy as well as consensus regarding optimal treatment duration before and after surgery. In this study, the clinical results of the use of teriparatide for this application are reviewed and critically examined. We conducted a systematic review of electronic databases using different MeSH terms from 1980 to 2020. Pooled and subgroup analyses were performed using fixed and random effect models based upon the heterogeneity (I2). The results were reported as either mean difference (MD) or odds ratio (OR) with 95% confidence interval (CI). A total of 771 patients from 12 studies were identified. Three hundred seventy-seven patients (90.8% females) were treated with teriparatide. Lumbar spinal fusion rates were significantly higher among patients who received teriparatide compared to the non-teriparatide group (OR 2.15, 95%CI 1.56-2.97, p < 0.00001). Subgroup analysis revealed that patients receiving teriparatide demonstrated 2.12-fold and 2.23-fold higher likelihood of fusion compared to those in the bisphosphonate (OR 2.12, 95%CI 1.45-3.11, p = 0.0001) and placebo (OR 2.23, 95%CI 1.22-4.08, p = 0.009) cohorts, respectively. The treatment effect of teriparatide was associated with significantly reduced subsequent vertebral fractures (OR 0.16, 95%CI 0.06-0.41, p = 0.0002), sagittal malalignment (MD - 3.85, 95%CI: -6.49 to - 1.21, p = 0.004), limb visual analogue score (VAS) (MD - 0.36, 95%CI - 0.64 to - 0.09, p = 0.008), and spinal VAS (MD - 0.24, 95%CI - 0.44 to - 0.04, p = 0.02) compared to the non-teriparatide group. Patients using teriparatide had 30% less likelihood of screw loosening at last follow-up compared to the non-teriparatide group; however, this was not statistically significant (OR 0.70, 95%CI 0.43-1.14, p = 0.15). There did not exist any statistically significant difference between the two comparative groups in terms of pseudoarthrosis (OR 0.54, 95%CI 0.24-1.21, p = 0.13), cage subsidence (OR 1.30, 95%CI 0.38-4.52, p = 0.68), and bone mineral density (MD 0.04, 95%CI - 0.19-0.29, p = 0.74) at last follow-up examination. This meta-analysis corroborates the effectiveness of teriparatide resulting in higher fusion rates. Further study is required to determine the optimal duration of treatment and timing of surgery.

Advances in surgical hemostasis: a comprehensive review and meta-analysis on topical tranexamic acid in spinal deformity surgery.

Tranexamic acid (TXA) is an effective and commonly used hemostatic agent for perioperative blood loss in various surgical specialties. It is being increasingly used in spinal deformity surgery. We aimed to evaluate the safety and efficacy of topical TXA (tTXA) compared to both placebo and/or intravenous (IV) TXA in patients undergoing spinal deformity surgery. We conducted a systematic review of the electronic databases using different MeSH terms from January 1970 to August 2019. Pooled and subgroup analysis was performed using fixed and random-effect model based upon the heterogeneity (I2). A total of 609 patients (tTXA: n = 258, 42.4%) from 8 studies were included. We found that there was a statistically significant difference in terms of (i) postoperative blood loss [mean difference (MD) - 147.1, 95% CI - 189.5 to - 104.8, p < 0.00001], (ii) postoperative hemoglobin level (MD 1.09, 95% CI 0.45 to 1.72, p = 0.0008), (iii) operative time (MD 7.47, 95% CI 2.94 to 12.00, p < 0.00001), (iv) postoperative transfusion rate [odds ratio (OR) 0.39, 95% CI 0.20 to 0.78, p = 0.007], postoperative drain output (MD, - 184.0, 95% CI - 222.03 to - 146.04, p < 0.00001), and (v) duration of hospital stay (MD - 1.14, 95% CI - 1.44 to - 0.85, p < 0.00001) in patients treated with tTXA compared to the control group. However, there was no significant difference in terms of intraoperative blood loss (p = 0.13) and complications (p = 0.23) between the two comparative groups. Furthermore, low-dose (250-500 mg) tTXA (p < 0.00001) reduced postoperative blood loss more effectively compared to high-dose tTXA (1-3 g) (p = 0.001). Our meta-analysis corroborates the effectiveness and safety of tTXA in spinal deformity surgery.

Safety and efficacy of cement augmentation with fenestrated pedicle screws for tumor-related spinal instability.

OBJECTIVE: Achieving rigid spinal fixation can be challenging in patients with cancer-related instability, as factors such as osteopenia, radiation, and immunosuppression adversely affect bone quality. Augmenting pedicle screws with cement is a strategy to overcome construct failure. This study aimed to assess the safety and efficacy of cement augmentation with fenestrated pedicle screws in patients undergoing posterior, open thoracolumbar surgery for spinal metastases. METHODS: A retrospective review was performed for patients who underwent surgery for cancer-related spine instability from 2016 to 2019 at the Massachusetts General Hospital. Patient demographics, surgical details, radiographic characteristics, patterns of cement extravasation, complications, and prospectively collected Patient-Reported Outcomes Measurement Information System Pain Interference and Pain Intensity scores were analyzed using descriptive statistics. Logistic regression was performed to determine factors associated with cement extravasation. RESULTS: Sixty-nine patients underwent open posterior surgery with a total of 502 cement-augmented screws (mean 7.8 screws per construct). The median follow-up period for those who survived past 90 days was 25.3 months (IQR 10.8-34.6 months). Thirteen patients (18.8%) either died within 90 days or were lost to follow-up. Postoperative CT was performed to assess the instrumentation and patterns of cement extravasation. There was no screw loosening, pullout, or failure. The rate of cement extravasation was 28.9% (145/502), most commonly through the segmental veins (77/145, 53.1%). Screws breaching the lateral border of the pedicle but with fenestrations within the vertebral body were associated with a higher risk of leakage through the segmental veins compared with screws without any breach (OR 8.77, 95% CI 2.84-29.79; p < 0.001). Cement extravasation did not cause symptoms except in 1 patient who developed a symptomatic thoracic radiculopathy requiring decompression. There was 1 case of asymptomatic pulmonary cement embolism. Patients experienced significant pain improvement at the 3-month follow-up, with decreases in Pain Interference (mean change 15.8, 95% CI 14.5-17.1; p < 0.001) and Pain Intensity (mean change 28.5, 95% CI 26.7-30.4; p < 0.001). CONCLUSIONS: Cement augmentation through fenestrated pedicle screws is a safe and effective option for spine stabilization in the cancer population. The risk of clinically significant adverse events from cement extravasation is very low.

Systematic review of charged-particle therapy for chordomas and sarcomas of the mobile spine and sacrum.

OBJECTIVE: Long-term local control in patients with primary chordoma and sarcoma of the spine and sacrum is increasingly reliant upon en bloc resection with negative margins. At many institutions, adjuvant radiation is recommended; definitive radiation is also recommended for the treatment of unresectable tumors. Because of the high off-target radiation toxicities associated with conventional radiotherapy, there has been growing interest in the use of proton and heavy-ion therapies. The aim of this study was to systematically review the literature regarding these therapies. METHODS: The PubMed, OVID, Embase, and Web of Science databases were queried for articles describing the use of proton, combined proton/photon, or heavy-ion therapies for adjuvant or definitive radiotherapy in patients with primary sarcoma or chordoma of the mobile spine and sacrum. A qualitative synthesis of the results was performed, focusing on overall survival (OS), progression-free survival (PFS), disease-free survival (DFS), and disease-specific survival (DSS); local control; and postradiation toxicities. RESULTS: Of 595 unique articles, 64 underwent full-text screening and 38 were included in the final synthesis. All studies were level III or IV evidence with a high risk of bias; there was also significant overlap in the reported populations, with six centers accounting for roughly three-fourths of all reports. Five-year therapy outcomes were as follows: proton-only therapies, OS 67%-82%, PFS 31%-57%, and DFS 52%-62%; metastases occurred in 17%-18% and acute toxicities in 3%-100% of cases; combined proton/photon therapy, local control 62%-85%, OS 78%-87%, PFS 90%, and DFS 61%-72%; metastases occurred in 12%-14% and acute toxicities in 84%-100% of cases; and carbon ion therapy, local control 53%-100%, OS 52%-86%, PFS (only reported for 3 years) 48%-76%, and DFS 50%-53%; metastases occurred in 2%-39% and acute toxicities in 26%-48%. There were no studies directly comparing outcomes between photon and charged-particle therapies or comparing outcomes between radiation and surgical groups. CONCLUSIONS: The current evidence for charged-particle therapies in the management of sarcomas of the spine and sacrum is limited. Preliminary evidence suggests that with these therapies local control and OS at 5 years are comparable among various charged-particle options and may be similar between those treated with definitive charged-particle therapy and historical surgical cohorts. Further research directly comparing charged-particle and photon-based therapies is necessary.

Performance assessment of the metastatic spinal tumor frailty index using machine learning algorithms: limitations and future directions.

OBJECTIVE: Frailty is recognized as an important consideration in patients with cancer who are undergoing therapies, including spine surgery. The definition of frailty in the context of spinal metastases is unclear, and few have studied such markers and their association with postoperative outcomes and survival. Using national databases, the metastatic spinal tumor frailty index (MSTFI) was developed as a tool to predict outcomes in this specific patient population and has not been tested with external data. The purpose of this study was to test the performance of the MSTFI with institutional data and determine whether machine learning methods could better identify measures of frailty as predictors of outcomes. METHODS: Electronic health record data from 479 adult patients admitted to the Massachusetts General Hospital for metastatic spinal tumor surgery from 2010 to 2019 formed a validation cohort for the MSTFI to predict major complications, in-hospital mortality, and length of stay (LOS). The 9 parameters of the MSTFI were modeled in 3 machine learning algorithms (lasso regularization logistic regression, random forest, and gradient-boosted decision tree) to assess clinical outcome prediction and determine variable importance. Prediction performance of the models was measured by computing areas under the receiver operating characteristic curve (AUROCs), calibration, and confusion matrix metrics (positive predictive value, sensitivity, and specificity) and was subjected to internal bootstrap validation. RESULTS: Of 479 patients (median age 64 years [IQR 55-71 years]; 58.7% male), 28.4% had complications after spine surgery. The in-hospital mortality rate was 1.9%, and the mean LOS was 7.8 days. The MSTFI demonstrated poor discrimination for predicting complications (AUROC 0.56, 95% CI 0.50-0.62) and in-hospital mortality (AUROC 0.69, 95% CI 0.54-0.85) in the validation cohort. For postoperative complications, machine learning approaches showed a greater advantage over the logistic regression model used to develop the MSTFI (AUROC 0.62, 95% CI 0.56-0.68 for random forest vs AUROC 0.56, 95% CI 0.50-0.62 for logistic regression). The random forest model had the highest positive predictive value (0.53, 95% CI 0.43-0.64) and the highest negative predictive value (0.77, 95% CI 0.72-0.81), with chronic lung disease, coagulopathy, anemia, and malnutrition identified as the most important predictors of postoperative complications. CONCLUSIONS: This study highlights the challenges of defining and quantifying frailty in the metastatic spine tumor population. Further study is required to improve the determination of surgical frailty in this specific cohort.

Interhospital transfer status for spinal metastasis patients in the United States is associated with more severe clinical presentations and higher rates of inpatient complications.

OBJECTIVE: In patients with metastatic spinal disease (MSD), interhospital transfer can potentially impact clinical outcomes as the possible benefits of transferring a patient to a higher level of care must be weighed against the negative effects associated with potential delays in treatment. While the association of clinical outcomes and transfer status has been examined in other specialties, the relationship between transfer status, complications, and risk of mortality in patients with MSD has yet to be explored. The purpose of this study was to examine the impact of transfer status on in-hospital mortality and clinical outcomes in patients diagnosed with MSD. METHODS: The National (Nationwide) Inpatient Sample (NIS) database was retrospectively queried for adult patients diagnosed with vertebral pathological fracture and/or spinal cord compression in the setting of metastatic disease between 2012 and 2014. Demographics, baseline characteristics (e.g., metastatic spinal cord compression [MSCC] and paralysis), comorbidities, type of intervention, and relevant patient outcomes were controlled in a multivariable logistic regression model to analyze the association of transfer status with patient outcomes. RESULTS: Within the 10,360 patients meeting the inclusion and exclusion criteria, higher rates of MSCC (50.2% vs 35.9%, p < 0.001) and paralysis (17.3% vs 8.4%, p < 0.001) were observed in patients transferred between hospitals compared to those directly admitted. In univariable analysis, a higher percentage of transferred patients underwent surgical intervention (p < 0.001) when compared with directly admitted patients. After controlling for significant covariates and surgical intervention, transferred patients were more likely to develop in-hospital complications (OR 1.34, 95% CI 1.18-1.52, p < 0.001), experience prolonged length of stay (OR 1.33, 95% CI 1.16-1.52, p < 0.001), and have a discharge disposition other than home (OR 1.70, 95% CI 1.46-1.98, p < 0.001), with no significant difference in inpatient mortality rates. CONCLUSIONS: Patients with MSD who were transferred between hospitals demonstrated more severe clinical presentations and higher rates of inpatient complications compared to directly admitted patients, despite demonstrating no difference in in-hospital mortality rates.