Rapid Tumor DNA Analysis of Cerebrospinal Fluid Accelerates Treatment of Central Nervous System Lymphoma.

Delays and risks associated with neurosurgical biopsies preclude timely diagnosis and treatment of central nervous system (CNS) lymphoma and other CNS neoplasms. We prospectively integrated targeted rapid genotyping of cerebrospinal fluid (CSF) into the evaluation of 70 patients with CNS lesions of unknown etiology. Participants underwent genotyping of CSF-derived DNA using a qPCR-based approach for parallel detection of single-nucleotide variants in the MYD88, TERT promoter, IDH1, IDH2, BRAF and H3F3A genes within 80 minutes of sample acquisition. Canonical mutations were detected in 42% of patients with neoplasms, including cases of primary and secondary CNS lymphoma, glioblastoma, IDH-mutant brainstem glioma and H3K27M-mutant diffuse midline glioma. Genotyping results eliminated the need for surgical biopsies in 7/33 (21.2%) cases of newly diagnosed neoplasms, resulting in significantly accelerated initiation of disease-directed treatment (median 3 vs 12 days; p = 0.027). This assay was then implemented in a Clinical Laboratory Improvement Amendments (CLIA) environment, with 2-day median turnaround for diagnosis of central nervous system lymphoma from 66 patients across 4 clinical sites. Our study prospectively demonstrates that targeted rapid CSF genotyping influences oncologic management for suspected CNS tumors.

Radical surgical resection with molecular margins is associated with improved survival in IDH wildtype GBM.

BACKGROUND: Survival is variable in patients with glioblastoma IDH wild-type (GBM), even after comparable surgical resection of radiographically-detectable disease, highlighting the limitations of radiographic assessment of infiltrative tumor anatomy. The majority of post-surgical progressive events are failures within 2cm of the resection margin, motivating supramaximal resection strategies to improve local control. However, which patients benefit from such radical resections remains unknown. METHODS: We developed a predictive model to identify which IDH wild-type GBM are amenable to radiographic gross total resection (GTR). We then investigated whether GBM survival heterogeneity following GTR is correlated with microscopic tumor burden a by analyzing tumor cell content at the surgical margin with a rapid qPCR-based method for detection of TERT promoter mutation. RESULTS: Our predictive model for achievable GTR, developed on retrospective radiographic and molecular data of GBM patients undergoing resection, had an AUC of 0.83, sensitivity of 62%, and specificity of 90%. Prospective analysis of this model in 44 patients found 89% of patients were correctly predicted to achieve a RV<4.9cc. Of the 44 prospective patients undergoing rapid qPCR TERT promoter mutation analysis at the surgical margin, 7 had undetectable TERT mutation, of which 5 also had a gross total resection (RV<1cc). In these 5 patients at 30 months follow up, 75% showed no progression, compared to 0% in the group with TERT mutations detected at the surgical margin (p=0.02). CONCLUSIONS: These findings identify a subset of patients with GBM that may derive local control benefit from radical resection to undetectable molecular margins.

Cerebrospinal fluid cfDNA sequencing for classification of central nervous system glioma.

PURPOSE: Primary central nervous system (CNS) gliomas can be classified by characteristic genetic alterations. In addition to solid tissue obtained via surgery or biopsy, cell-free DNA (cfDNA) from cerebrospinal fluid (CSF) is an alternative source of material for genomic analyses. EXPERIMENTAL DESIGN: We performed targeted next-generation sequencing (NGS) of CSF cfDNA in a representative cohort of 85 patients presenting at two neurooncological centers with suspicion of primary or recurrent glioma. Copy-number variation (CNV) profiles, single nucleotide variants (SNVs), and small insertions/ deletions (indels) were combined into a molecular-guided tumor classification. Comparison with the solid tumor was performed for 38 cases with matching solid tissue available. RESULTS: Cases were stratified into four groups: glioblastoma (n = 32), other glioma (n = 19), non-malignant (n = 17) and non-diagnostic (n = 17). We introduced a molecular-guided tumor classification, which enabled identification of tumor entities and/ or cancer specific alterations in 75.0 % (n = 24) of glioblastoma and 52.6 % (n = 10) of other glioma cases. The overlap between CSF and matching solid tissue was highest for CNVs (26-48 %) and SNVs at pre-defined gene loci (44 %), followed by SNVs/ indels identified via uninformed variant calling (8-14 %). A molecular-guided tumor classification was possible for 23.5 % (n = 4) of non-diagnostic cases. CONCLUSIONS: We developed a targeted sequencing workflow for CSF cfDNA as well as a strategy for interpretation and reporting of sequencing results based on a molecular-guided tumor classification in glioma.

Genetic characterization and mutational profiling of foramen magnum meningiomas: a multi-institutional study.

OBJECTIVE: Foramen magnum (FM) meningiomas pose significant surgical challenges and have high morbidity and mortality rates. This study aimed to investigate the distribution of clinically actionable mutations in FM meningiomas and identify clinical characteristics associated with specific mutational profiles. METHODS: The authors conducted targeted next-generation sequencing of 62 FM meningiomas from three international institutions, covering all relevant meningioma genes (AKT1, KLF4, NF2, POLR2A, PIK3CA, SMO, TERT promoter, and TRAF7). Patients with a radiation-induced meningioma or neurofibromatosis type 2 (NF2) were excluded from the study. Additionally, patient and tumor characteristics, including age, sex, radiological features, and tumor location, were retrospectively collected and evaluated. RESULTS: The study cohort consisted of 46 female and 16 male patients. Clinically significant driver mutations were detected in 58 patients (93.5%). The most commonly observed alteration was TRAF7 mutations (26, 41.9%), followed by AKT1E17K mutations (19, 30.6%). Both mutations were significantly associated with an anterolateral tumor location relative to the brainstem (p = 0.0078). NF2 mutations were present in 11 cases (17.7%) and were associated with posterior tumor location, in contrast to tumors with TRAF7 and AKT1E17K mutations. Other common mutations in FM meningiomas included POLR2A mutations (8, 12.9%; 6 POLR2AQ403K and 2 POLR2AH439_L440del), KLF4K409Q mutations (7, 11.3%), and PIK3CA mutations (4, 6.5%; 2 PIK3CAH1047R and 2 PIK3CAE545K). POLR2A and KLF4 mutations exclusively occurred in female patients and showed no significant association with specific tumor locations. All tumors harboring AKT1E17K and POLR2A mutations displayed meningothelial histology. Ten tumors exhibited intratumoral calcification, which was significantly more frequent in NF2-mutant compared with AKT1-mutant FM meningiomas (p = 0.047). CONCLUSIONS: These findings provide important insights into the molecular genetics and clinicopathological characteristics of FM meningiomas. The identification of specific genetic alterations associated with tumor location, volume, calcification, histology, and sex at diagnosis may have implications for personalized treatment strategies in the future.

Emergence of nanoscale viscoelasticity from single cancer cells to established tumors.

Tumors are complex materials whose physical properties dictate growth and treatment outcomes. Recent evidence suggests time-dependent physical properties, such as viscoelasticity, are crucial, distinct mechanical regulators of cancer progression and malignancy, yet the genesis and consequences of tumor viscoelasticity are poorly understood. Here, using Wide-bandwidth AFM-based ViscoElastic Spectroscopy (WAVES) coupled with mathematical modeling, we probe the origins of tumor viscoelasticity. From single carcinoma cells to increasingly sized carcinoma spheroids to established tumors, we describe a stepwise evolution of dynamic mechanical properties that create a nanorheological signature of established tumors: increased stiffness, decreased rate-dependent stiffening, and reduced energy dissipation. We dissect this evolution of viscoelasticity by scale, and show established tumors use fluid-solid interactions as the dominant mechanism of mechanical energy dissipation as opposed to fluid-independent intrinsic viscoelasticity. Additionally, we demonstrate the energy dissipation mechanism in spheroids and established tumors is negatively correlated with the cellular density, and this relationship strongly depends on an intact actin cytoskeleton. These findings define an emergent and targetable signature of the physical tumor microenvironment, with potential for deeper understanding of tumor pathophysiology and treatment strategies.

Intraoperative Integrated Diagnostic System for Malignant Central Nervous System Tumors.

PURPOSE: The 2021 World Health Organization (WHO) classification of central nervous system (CNS) tumors uses an integrated approach involving histopathology and molecular profiling. Because majority of adult malignant brain tumors are gliomas and primary CNS lymphomas (PCNSL), rapid differentiation of these diseases is required for therapeutic decisions. In addition, diffuse gliomas require molecular information on single-nucleotide variants (SNV), such as IDH1/2. Here, we report an intraoperative integrated diagnostic (i-ID) system to classify CNS malignant tumors, which updates legacy frozen-section (FS) diagnosis through incorporation of a qPCR-based genotyping assay. EXPERIMENTAL DESIGN: FS evaluation, including GFAP and CD20 rapid IHC, was performed on adult malignant CNS tumors. PCNSL was diagnosed through positive CD20 and negative GFAP immunostaining. For suspected glioma, genotyping for IDH1/2, TERT SNV, and CDKN2A copy-number alteration was routinely performed, whereas H3F3A and BRAF SNV were assessed for selected cases. i-ID was determined on the basis of the 2021 WHO classification and compared with the permanent integrated diagnosis (p-ID) to assess its reliability. RESULTS: After retrospectively analyzing 153 cases, 101 cases were prospectively examined using the i-ID system. Assessment of IDH1/2, TERT, H3F3AK27M, BRAFV600E, and CDKN2A alterations with i-ID and permanent genomic analysis was concordant in 100%, 100%, 100%, 100%, and 96.4%, respectively. Combination with FS and intraoperative genotyping assay improved diagnostic accuracy in gliomas. Overall, i-ID matched with p-ID in 80/82 (97.6%) patients with glioma and 18/19 (94.7%) with PCNSL. CONCLUSIONS: The i-ID system provides reliable integrated diagnosis of adult malignant CNS tumors.

Machine learning-based detection of sarcopenic obesity and association with adverse outcomes in patients undergoing surgical treatment for spinal metastases.

OBJECTIVE: The distributions and proportions of lean and fat tissues may help better assess the prognosis and outcomes of patients with spinal metastases. Specifically, in obese patients, sarcopenia may be easily overlooked as a poor prognostic indicator. The role of this body phenotype, sarcopenic obesity (SO), has not been adequately studied among patients undergoing surgical treatment for spinal metastases. To this end, here the authors investigated the role of SO as a potential prognostic factor in patients undergoing surgical treatment for spinal metastases. METHODS: The authors identified patients who underwent surgical treatment for spinal metastases between 2010 and 2020. A validated deep learning approach evaluated sarcopenia and adiposity on routine preoperative CT images. Based on composition analyses, patients were classified with SO or nonsarcopenic obesity. After nearest-neighbor propensity matching that accounted for confounders, the authors compared the rates and odds of postoperative complications, length of stay, 30-day readmission, and all-cause mortality at 90 days and 1 year between the SO and nonsarcopenic obesity groups. RESULTS: A total of 62 patients with obesity underwent surgical treatment for spinal metastases during the study period. Of these, 37 patients had nonsarcopenic obesity and 25 had SO. After propensity matching, 50 records were evaluated that were equally composed of patients with nonsarcopenic obesity and SO (25 patients each). Patients with SO were noted to have increased odds of nonhome discharge (OR 6.0, 95% CI 1.69-21.26), 30-day readmission (OR 3.27, 95% CI 1.01-10.62), and 90-day (OR 4.85, 95% CI 1.29-18.26) and 1-year (OR 3.78, 95% CI 1.17-12.19) mortality, as well as increased time to mortality after surgery (12.60 ± 19.84 months vs 37.16 ± 35.19 months, p = 0.002; standardized mean difference 0.86). No significant differences were noted in terms of length of stay or postoperative complications when comparing the two groups (p > 0.05). CONCLUSIONS: The SO phenotype was associated with increased odds of nonhome discharge, readmission, and postoperative mortality. This study suggests that SO may be an important prognostic factor to consider when developing care plans for patients with spinal metastases.

Implication of nutritional status for adverse outcomes after surgery for metastatic spine tumors.

OBJECTIVE: Surgery for metastatic spinal tumors can have a substantial impact on patients' quality of life by alleviating pain, improving function, and correcting spinal instability when indicated. The decision to operate is difficult because many patients with cancer are frail. Studies have highlighted the importance of preoperative nutritional status assessments; however, little is known about which aspects of nutrition accurately inform clinical outcomes. This study investigates the interaction and prognostic importance of various nutritional and frailty measures in patients with spinal metastases. METHODS: A retrospective analysis of consecutive patients who underwent surgery for spinal metastases between 2014 and 2020 at the Massachusetts General Hospital was performed. Patients were stratified according to the New England Spinal Metastasis Score (NESMS). Frailty was assessed using the metastatic spinal tumor frailty index. Nutrition was assessed using the prognostic nutritional index (PNI), preoperative body mass index, albumin, albumin-to-globulin ratio, and platelet-to-lymphocyte ratio. Outcomes included postoperative survival and complication rates, with focus on wound-related complications. RESULTS: This study included 154 individuals (39% female; mean [SD] age 63.23 [13.14] years). NESMS 0 and NESMS 3 demonstrated the highest proportions of severely frail patients (56.2%) and nonfrail patients (16.1%), respectively. Patients with normal nutritional status (albumin-to-globulin ratio and PNI) had a better prognosis than those with poor nutritional status when stratified by NESMS. Multivariable regression adjusted for NESMS and frailty showed that a PNI > 40.4 was significantly associated with decreased odds of 90-day complications (OR 0.93, 95% CI 0.85-0.98). After accounting for age, sex, primary tumor pathology, physical function, nutritional status, and frailty, a preoperative nutrition consultation was associated with a decrease in postoperative wound-related complications (average marginal effect -5.00%; 95% CI -1.50% to -8.9%). CONCLUSIONS: The PNI was most predictive of complications and may be a key biomarker for risk stratification in the 90 days following surgery. Nutrition consultation was associated with a reduced risk of wound-related complications, attesting to the importance of this preoperative intervention. These findings suggest that nutrition plays an important role in the postsurgical course and should be considered when developing a treatment plan for spinal metastases.

Neurotoxicity and management of primary and secondary central nervous system lymphoma after adoptive immunotherapy with CD19-directed chimeric antigen receptor T-cells.

BACKGROUND: Chimeric antigen receptor (CAR) T-cells targeting CD19 have been established as a leading engineered T-cell therapy for B-cell lymphomas; however, data for patients with central nervous system (CNS) involvement are limited. METHODS: We retrospectively report on CNS-specific toxicities, management, and CNS response of 45 consecutive CAR T-cell transfusions for patients with active CNS lymphoma at the Massachusetts General Hospital over a 5-year period. RESULTS: Our cohort includes 17 patients with primary CNS lymphoma (PCNSL; 1 patient with 2 CAR T-cell transfusions) and 27 patients with secondary CNS lymphoma (SCNSL). Mild ICANS (grade 1-2) was observed after 19/45 transfusions (42.2%) and severe immune effector cell-associated neurotoxicity syndrome (ICANS) (grade 3-4) after 7/45 transfusions (15.6%). A larger increase in C-reactive protein (CRP) levels and higher rates of ICANS were detected in SCNSL. Early fever and baseline C-reactive protein levels were associated with ICANS occurrence. CNS response was seen in 31 cases (68.9%), including a complete response of CNS disease in 18 cases (40.0%) which lasted for a median of 11.4 ±â€…4.5 months. Dexamethasone dose at time of lymphodepletion (but not at or after CAR T-cell transfusion) was associated with an increased risk for CNS progression (hazard ratios [HR] per mg/d: 1.16, P = .031). If bridging therapy was warranted, the use of ibrutinib translated into favorable CNS-progression-free survival (5 vs. 1 month, HR 0.28, CI 0.1-0.7; P = .010). CONCLUSIONS: CAR T-cells exhibit promising antitumor effects and a favorable safety profile in CNS lymphoma. Further evaluation of the role of bridging regimens and corticosteroids is warranted.

Can We Use Artificial Intelligence Cluster Analysis to Identify Patients with Metastatic Breast Cancer to the Spine at Highest Risk of Postoperative Adverse Events?

OBJECTIVE: Group patients who required open surgery for metastatic breast cancer to the spine by functional level and metastatic disease characteristics to identify factors that predispose to poor outcomes. METHODS: A retrospective analysis included patients managed at 2 tertiary referral centers from 2008 to 2020. The primary outcome was a 90-day adverse event. A 2-step unsupervised cluster analysis stratified patients into cohorts using function at presentation, preoperative spine radiation, structural instability, epidural spinal cord compression (ESCC), neural deficits, and tumor location/hormone status. Comparisons were performed using χ2 test and one-way analysis of variance. RESULTS: Five patient "clusters" were identified. High function (HIGH) had thoracic metastases and an Eastern Cooperative Oncology Group (ECOG) score of 1.0 ± 0.8. Low function/irradiated (LOW + RADS) had preoperative radiation and the lowest Karnofsky scores (56.0 ± 10.6). Estrogen receptor or progesterone receptor (ER/PR) positive patients had >90% estrogen/progesterone positivity and moderate Karnofsky scores (74.0 ± 11.5). Lumbar/noncompressive (NON-COMP) had the fewest patients with ESCC grade 2 or 3 epidural disease (42.1%, P < 0.001). Low function/neurologic deficits (LOW + NEURO) had ESCC grade 2 or 3 disease and neurologic deficits. Adverse event rates were 25.0% in the HIGH group, 73.3% in LOW + RADS, 24.0% in ER/PR, 31.6% in NON-COMP, and 60.0% in LOW + NEURO (P = 0.003). CONCLUSIONS: Function at presentation, tumor hormone signature, radiation history, and epidural compression delineated postoperative trajectory. We believe our results can aid in expectation management and the identification of at-risk patients who may merit closer surveillance following surgical intervention.

Assessment of Spinal Metastases Surgery Risk Stratification Tools in Breast Cancer by Molecular Subtype.

BACKGROUND: Breast cancer molecular features and modern therapies are not included in spine metastasis prediction algorithms. OBJECTIVE: To examine molecular differences and the impact of postoperative systemic therapy to improve prognosis prediction for spinal metastases surgery and aid surgical decision making. METHODS: This is a retrospective multi-institutional study of patients who underwent spine surgery for symptomatic breast cancer spine metastases from 2008 to 2021 at the Massachusetts General Hospital and Brigham and Women's Hospital. We studied overall survival, stratified by breast cancer molecular subtype, and calculated hazard ratios (HRs) adjusting for demographics, tumor characteristics, treatments, and laboratory values. We tested the performance of established models (Tokuhashi, Bauer, Skeletal Oncology Research Group, New England Spinal Metastases Score) to predict and compare all-cause. RESULTS: A total of 98 patients surgically treated for breast cancer spine metastases were identified (100% female sex; median age, 56 years [IQR, 36-84 years]). The 1-year probabilities of survival for hormone receptor positive, hormone receptor positive/human epidermal growth factor receptor 2+, human epidermal growth factor receptor 2+, and triple-negative breast cancer were 63% (45 of 71), 83% (10 of 12), 0% (0 of 3), and 12% (1 of 8), respectively ( P < .001). Patients with triple-negative breast cancer had a higher proportion of visceral metastases, brain metastases, and poor physical activity at baseline. Postoperative chemotherapy and endocrine therapy were associated with prolonged survival. The Skeletal Oncology Research Group prognostic model had the highest discrimination (area under the receiver operating characteristic, 0.77 [95% CI, 0.73-0.81]). The performance of all prognostic scores improved when preoperative molecular data and postoperative systemic treatment plans was considered. CONCLUSION: Spine metastases risk tools were able to predict prognosis at a significantly higher degree after accounting for molecular features which guide treatment response.

Effects of rod diameter on kinematics of posterior cervical spine instrumented constructs: an ex vivo study.

OBJECTIVE: Posterior cervical spine fixation is a robust strategy for stabilizing the spine for a wide range of spinal disorders. With the evolution of spinal implant technology, posterior fixation with lateral mass screws in the subaxial spine is now common. Despite interest in variable rod diameters to meet a wide range of clinical needs such as trauma, revision, and deformity surgery, indications for use of posterior cervical spine fixation are not clear. This laboratory investigation evaluates the mechanical stability and kinematic properties of lateral mass fixation with various commercially available rod diameters. METHODS: The authors conducted an ex vivo experiment using 13 fresh-frozen human cervical spine specimens, instrumented from C3 to C6 with lateral mass screws, to evaluate the effects of titanium rod diameter on kinematic stability. Each intact spine was tested using a kinematic profiling machine with an optoelectrical camera and infrared sensors applying 1.5-Nm bending moments to the cranial vertebra (C2) simulating flexion-extension, lateral bending, and axial rotation anatomical motions. A compressive follower preload of 150 N was applied in flexion-extension prior to application of a bending moment. Instrumented spines were then tested with rod diameters of 3.5, 4.0, and 4.5 mm. The kinematic data between intact and surgical cases were studied using a nonparametric Wilcoxon signed-rank test. A multivariable, multilevel linear regression model was built to identify the relationship between segmental motion and rod diameter. RESULTS: Instrumentation resulted in significant reduction in range of motion in all three rod constructs versus intact specimens in flexion-extension, lateral bending, and axial rotation (p < 0.05). The maximum reductions in segmental ROM versus intact spines in 3.5-, 4.0-, and 4.5-mm rod constructs were 61%, 71%, and 81% in flexion-extension; 70%, 76%, and 81% in lateral bending; and 50%, 60%, and 75% in axial rotation, respectively. Segmental motion at the adjacent segments (C2-3 and C6-7) increased significantly (p < 0.05) with increasing rod diameter. The 4.5-mm rod construct had the greatest increase in motion compared to the intact spine. CONCLUSIONS: With increasing rod diameters from 3.5 to 4.0 mm, flexion-extension, lateral bending, and axial rotation across C3-6 were significantly reduced (p < 0.05). Similar trends were observed with a statistically significant reduction in motion in all anatomical planes when the rod diameter was increased to 4.5 mm. Although the increase in rod diameter resulted in a more rigid construct, it also created an increase (p < 0.05) in the kinematics of the adjacent segments (C2-3 and C6-7). Whether this increase translates into adverse long-term clinical effects in vivo requires further investigation and clinical assessment.

Machine Learning Applications of Surgical Imaging for the Diagnosis and Treatment of Spine Disorders: Current State of the Art.

Recent developments in machine learning (ML) methods demonstrate unparalleled potential for application in the spine. The ability for ML to provide diagnostic faculty, produce novel insights from existing capabilities, and augment or accelerate elements of surgical planning and decision making at levels equivalent or superior to humans will tremendously benefit spine surgeons and patients alike. In this review, we aim to provide a clinically relevant outline of ML-based technology in the contexts of spinal deformity, degeneration, and trauma, as well as an overview of commercial-level and precommercial-level surgical assist systems and decisional support tools. Furthermore, we briefly discuss potential applications of generative networks before highlighting some of the limitations of ML applications. We conclude that ML in spine imaging represents a significant addition to the neurosurgeon's armamentarium-it has the capacity to directly address and manifest clinical needs and improve diagnostic and procedural quality and safety-but is yet subject to challenges that must be addressed before widespread implementation.

Evaluating frailty, mortality, and complications associated with metastatic spine tumor surgery using machine learning-derived body composition analysis.

OBJECTIVE: Cancer patients with spinal metastases may undergo surgery without clear assessments of prognosis, thereby impacting the optimal palliative strategy. Because the morbidity of surgery may adversely impact recovery and initiation of adjuvant therapies, evaluation of risk factors associated with mortality risk and complications is critical. Evaluation of body composition of cancer patients as a surrogate for frailty is an emerging area of study for improving preoperative risk stratification. METHODS: To examine the associations of muscle characteristics and adiposity with postoperative complications, length of stay, and mortality in patients with spinal metastases, the authors designed an observational study of 484 cancer patients who received surgical treatment for spinal metastases between 2010 and 2019. Sarcopenia, muscle radiodensity, visceral adiposity, and subcutaneous adiposity were assessed on routinely available 3-month preoperative CT images by using a validated deep learning methodology. The authors used k-means clustering analysis to identify patients with similar body composition characteristics. Regression models were used to examine the associations of sarcopenia, frailty, and clusters with the outcomes of interest. RESULTS: Of 484 patients enrolled, 303 had evaluable CT data on muscle and adiposity (mean age 62.00 ± 11.91 years; 57.8% male). The authors identified 2 clusters with significantly different body composition characteristics and mortality risks after spine metastases surgery. Patients in cluster 2 (high-risk cluster) had lower muscle mass index (mean ± SD 41.16 ± 7.99 vs 50.13 ± 10.45 cm2/m2), lower subcutaneous fat area (147.62 ± 57.80 vs 289.83 ± 109.31 cm2), lower visceral fat area (82.28 ± 48.96 vs 239.26 ± 98.40 cm2), higher muscle radiodensity (35.67 ± 9.94 vs 31.13 ± 9.07 Hounsfield units [HU]), and significantly higher risk of 1-year mortality (adjusted HR 1.45, 95% CI 1.05-2.01, p = 0.02) than individuals in cluster 1 (low-risk cluster). Decreased muscle mass, muscle radiodensity, and adiposity were not associated with a higher rate of complications after surgery. Prolonged length of stay (> 7 days) was associated with low muscle radiodensity (mean 30.87 vs 35.23 HU, 95% CI 1.98-6.73, p < 0.001). CONCLUSIONS: Body composition analysis shows promise for better risk stratification of patients with spinal metastases under consideration for surgery. Those with lower muscle mass and subcutaneous and visceral adiposity are at greater risk for inferior outcomes.

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.

Biomechanical analysis of stand-alone lumbar interbody cages versus 360° constructs: an in vitro and finite element investigation.

OBJECTIVE: Low fusion rates and cage subsidence are limitations of lumbar fixation with stand-alone interbody cages. Various approaches to interbody cage placement exist, yet the need for supplemental posterior fixation is not clear from clinical studies. Therefore, as prospective clinical studies are lacking, a comparison of segmental kinematics, cage properties, and load sharing on vertebral endplates is needed. This laboratory investigation evaluates the mechanical stability and biomechanical properties of various interbody fixation techniques by performing cadaveric and finite element (FE) modeling studies. METHODS: An in vitro experiment using 7 fresh-frozen human cadavers was designed to test intact spines with 1) stand-alone lateral interbody cage constructs (lateral interbody fusion, LIF) and 2) LIF supplemented with posterior pedicle screw-rod fixation (360° constructs). FE and kinematic data were used to validate a ligamentous FE model of the lumbopelvic spine. The validated model was then used to evaluate the stability of stand-alone LIF, transforaminal lumbar interbody fusion (TLIF), and anterior lumbar interbody fusion (ALIF) cages with and without supplemental posterior fixation at the L4-5 level. The FE models of intact and instrumented cases were subjected to a 400-N compressive preload followed by an 8-Nm bending moment to simulate physiological flexion, extension, bending, and axial rotation. Segmental kinematics and load sharing at the inferior endplate were compared. RESULTS: The FE kinematic predictions were consistent with cadaveric data. The range of motion (ROM) in LIF was significantly lower than intact spines for both stand-alone and 360° constructs. The calculated reduction in motion with respect to intact spines for stand-alone constructs ranged from 43% to 66% for TLIF, 67%-82% for LIF, and 69%-86% for ALIF in flexion, extension, lateral bending, and axial rotation. In flexion and extension, the maximum reduction in motion was 70% for ALIF versus 81% in LIF for stand-alone cases. When supplemented with posterior fixation, the corresponding reduction in ROM was 76%-87% for TLIF, 86%-91% for LIF, and 90%-92% for ALIF. The addition of posterior instrumentation resulted in a significant reduction in peak stress at the superior endplate of the inferior segment in all scenarios. CONCLUSIONS: Stand-alone ALIF and LIF cages are most effective in providing stability in lateral bending and axial rotation and less so in flexion and extension. Supplemental posterior instrumentation improves stability for all interbody techniques. Comparative clinical data are needed to further define the indications for stand-alone cages in lumbar fusion surgery.

The effectiveness of systemic therapies after surgery for metastatic renal cell carcinoma to the spine: a propensity analysis controlling for sarcopenia, frailty, and nutrition.

OBJECTIVE: The effectiveness of starting systemic therapies after surgery for spinal metastases from renal cell carcinoma (RCC) has not been evaluated in randomized controlled trials. Agents that target tyrosine kinases, mammalian target of rapamycin signaling, and immune checkpoints are now commonly used. Variables like sarcopenia, nutritional status, and frailty may impact recovery from spine surgery and are considered when evaluating a patient's candidacy for such treatments. A better understanding of the significance of these variables may help improve patient selection for available treatment options after surgery. The authors used comparative effectiveness methods to study the treatment effect of postoperative systemic therapies (PSTs) on survival. METHODS: Univariable and multivariable Cox regression analyses were performed to determine factors associated with overall survival (OS) in a retrospective cohort of adult patients who underwent spine surgery for metastatic RCC between 2010 and 2019. Propensity score-matched (PSM) analysis and inverse probability weighting (IPW) were performed to determine the treatment effect of PST on OS. To address confounding and minimize bias in estimations, PSM and IPW were adjusted for covariates, including age, sex, frailty, sarcopenia, nutrition, visceral metastases, International Metastatic RCC Database Consortium (IMDC) risk score, and performance status. RESULTS: In total, 88 patients (73.9% male; median age 62 years, range 29-84 years) were identified; 49 patients (55.7%) had an intermediate IMDC risk, and 29 (33.0%) had a poor IMDC risk. The median follow-up was 17 months (range 1-104 months) during which 57 patients (64.7%) died. Poor IMDC risk (HR 3.2 [95% CI 1.08-9.3]), baseline performance status (Eastern Cooperative Oncology Group score 3 or 4; HR 2.7 [95% CI 1.5-4.7]), and nutrition (prognostic nutritional index [PNI] first tertile, PNI < 40.74; HR 2.69 [95% CI 1.42-5.1]) were associated with worse OS. Sarcopenia and frailty were not significantly associated with poor survival. PST was associated with prolonged OS, demonstrated by similar effects from multivariable Cox analysis (HR 0.55 [95% CI 0.30-1.00]), PSM (HR 0.53 [95% CI 0.29-0.93]), IPW (HR 0.47 [95% CI 0.24-0.94]), and comparable confidence intervals. The median survival for those receiving PST was 28 (95% CI 19-43) months versus 12 (95% CI 4-37) months for those who only had surgery (log-rank p = 0.027). CONCLUSIONS: This comparative analysis demonstrated that PST is associated with improved survival in specific cohorts with metastatic spinal RCC after adjusting for frailty, sarcopenia, and malnutrition. The marked differences in survival should be taken into consideration when planning for surgery.