A 3-Year Study Investigating the Utility of Patient-Reported Outcomes Measurement Information System-29 for Long-Term Follow-Up in Adult Spinal Deformity.

BACKGROUND: Adult spinal deformity (ASD) significantly impacts the quality of life due to three-dimensional spinal abnormalities. Patient-reported outcome measures, such as the Patient-Reported Outcomes Measurement Information System (PROMIS-29), play a crucial role in assessing postoperative outcomes. This study aims to investigate trends in PROMIS-29 scores over 36 months in patients undergoing long-segment thoracolumbar fusion for ASD and provide insights into its long-term utility. METHODS: A retrospective study including 163 ASD patients undergoing long-segment thoracolumbar fusion was conducted. PROMIS-29 scores were collected at baseline and at postoperative (0-), 3-, 6-, 12-, 18-, 24-, 30-, and 36-month follow-ups. Statistical analyses was performed to assess significant score changes from baseline and in consecutive recordings. RESULTS: Significant improvements in all PROMIS-29 categories were observed at 36 months, with the greatest changes in pain intensity (-35.19%, P < 0.001), physical function (+29.13%, P < 0.001), and pain interference (-28.8%, P < 0.001). Between the 0 and 3 month mark, the greatest significant changes were recorded in pain intensity (-26.5%, P < 0.001), physical function (+24.3%, P < 0.001), and anxiety (-16.9%, P < 0.018). However, scores plateaued after the 3-month mark, with zero categories showing significant changes with subsequent consecutive recordings. CONCLUSIONS: PROMIS-29 scores demonstrated notable improvements in ASD patients particularly in pain intensity, pain interference, and physical function. However, scores plateaued beyond the 3-month mark, suggesting PROMIS-29's limited sensitivity to nuanced changes in long-term patient recovery. Future investigations exploring optimal combinations of patient reported outcome measures for comprehensive short- and long-term outcome assessments in ASD surgery would be beneficial.

Clinical relevance of intracranial hemorrhage after thrombectomy versus medical management for large core infarct: a secondary analysis of the SELECT2 randomized trial.

BACKGROUND: The incidence of intracerebral hemorrhage (ICH) and its effect on the outcomes after endovascular thrombectomy (EVT) for patients with large core infarcts have not been well-characterized. METHODS: SELECT2 trial follow-up imaging was evaluated using the Heidelberg Bleeding Classification (HBC) to define hemorrhage grade. The association of ICH with clinical outcomes and treatment effect was examined. RESULTS: Of 351 included patients, 194 (55%) and 189 (54%) demonstrated intracranial and intracerebral hemorrhage, respectively, with a higher incidence in EVT (134 (75%) and 130 (73%)) versus medical management (MM) (60 (35%) and 59 (34%), both P<0.001). Hemorrhagic infarction type 1 (HBC=1a) and type 2 (HBC=1b) accounted for 93% of all hemorrhages. Parenchymal hematoma (PH) type 1 (HBC=1c) and type 2 (HBC=2) were observed in 1 (0.6%) EVT-treated and 4 (2.2%) MM patients. Symptomatic ICH (sICH) (SITS-MOST definition) was seen in 0.6% EVT patients and 1.2% MM patients. No trend for ICH with core volumes (P=0.10) or Alberta Stroke Program Early CT Score (ASPECTS) (P=0.74) was observed. Among EVT patients, the presence of any ICH did not worsen clinical outcome (modified Rankin Scale (mRS) at 90 days: 4 (3-6) vs 4 (3-6); adjusted generalized OR 1.00, 95% CI 0.68 to 1.47, P>0.99) or modify EVT treatment effect (Pinteraction=0.77). CONCLUSIONS: ICH was present in 75% of the EVT population, but PH or sICH were infrequent. The presence of any ICH did not worsen functional outcomes or modify EVT treatment effect at 90-day follow-up. The high rate of hemorrhages overall still represents an opportunity for adjunctive therapies in EVT patients with a large ischemic core.

Endovascular Thrombectomy for Large Ischemic Stroke Across Ischemic Injury and Penumbra Profiles.

Importance: Whether endovascular thrombectomy (EVT) efficacy for patients with acute ischemic stroke and large cores varies depending on the extent of ischemic injury is uncertain. Objective: To describe the relationship between imaging estimates of irreversibly injured brain (core) and at-risk regions (mismatch) and clinical outcomes and EVT treatment effect. Design, Setting, and Participants: An exploratory analysis of the SELECT2 trial, which randomized 352 adults (18-85 years) with acute ischemic stroke due to occlusion of the internal carotid or middle cerebral artery (M1 segment) and large ischemic core to EVT vs medical management (MM), across 31 global centers between October 2019 and September 2022. Intervention: EVT vs MM. Main Outcomes and Measures: Primary outcome was functional outcome-90-day mRS score (0, no symptoms, to 6, death) assessed by adjusted generalized OR (aGenOR; values >1 represent more favorable outcomes). Benefit of EVT vs MM was assessed across levels of ischemic injury defined by noncontrast CT using ASPECTS score and by the volume of brain with severely reduced blood flow on CT perfusion or restricted diffusion on MRI. Results: Among 352 patients randomized, 336 were analyzed (median age, 67 years; 139 [41.4%] female); of these, 168 (50%) were randomized to EVT, and 2 additional crossover MM patients received EVT. In an ordinal analysis of mRS at 90 days, EVT improved functional outcomes compared with MM within ASPECTS categories of 3 (aGenOR, 1.71 [95% CI, 1.04-2.81]), 4 (aGenOR, 2.01 [95% CI, 1.19-3.40]), and 5 (aGenOR, 1.85 [95% CI, 1.22-2.79]). Across strata for CT perfusion/MRI ischemic core volumes, aGenOR for EVT vs MM was 1.63 (95% CI, 1.23-2.16) for volumes ≥70 mL, 1.41 (95% CI, 0.99-2.02) for ≥100 mL, and 1.47 (95% CI, 0.84-2.56) for ≥150 mL. In the EVT group, outcomes worsened as ASPECTS decreased (aGenOR, 0.91 [95% CI, 0.82-1.00] per 1-point decrease) and as CT perfusion/MRI ischemic core volume increased (aGenOR, 0.92 [95% CI, 0.89-0.95] per 10-mL increase). No heterogeneity of EVT treatment effect was observed with or without mismatch, although few patients without mismatch were enrolled. Conclusion and Relevance: In this exploratory analysis of a randomized clinical trial of patients with extensive ischemic stroke, EVT improved clinical outcomes across a wide spectrum of infarct volumes, although enrollment of patients with minimal penumbra volume was low. In EVT-treated patients, clinical outcomes worsened as presenting ischemic injury estimates increased. Trial Registration: ClinicalTrials.gov Identifier: NCT03876457.

Endovascular thrombectomy plus medical care versus medical care alone for large ischaemic stroke: 1-year outcomes of the SELECT2 trial.

BACKGROUND: Multiple randomised trials have shown efficacy and safety of endovascular thrombectomy in patients with large ischaemic stroke. The aim of this study was to evaluate long-term (ie, at 1 year) evidence of benefit of thrombectomy for these patients. METHODS: SELECT2 was a phase 3, open-label, international, randomised controlled trial with blinded endpoint assessment, conducted at 31 hospitals in the USA, Canada, Spain, Switzerland, Australia, and New Zealand. Patients aged 18-85 years with ischaemic stroke due to proximal occlusion of the internal carotid artery or of the first segment of the middle cerebral artery, showing large ischaemic core on non-contrast CT (Alberta Stroke Program Early Computed Tomographic Score of 3-5 [range 0-10, with lower values indicating larger infarctions]) or measuring 50 mL or more on CT perfusion and MRI, were randomly assigned, within 24 h of ischaemic stroke onset, to thrombectomy plus medical care or to medical care alone. The primary outcome for this analysis was the ordinal modified Rankin Scale (range 0-6, with higher scores indicating greater disability) at 1-year follow-up in an intention-to-treat population. The trial is registered at ClinicalTrials.gov (NCT03876457) and is completed. FINDINGS: The trial was terminated early for efficacy at the 90-day follow-up after 352 patients had been randomly assigned (178 to thrombectomy and 174 to medical care only) between Oct 11, 2019, and Sept 9, 2022. Thrombectomy significantly improved the 1-year modified Rankin Scale score distribution versus medical care alone (Wilcoxon-Mann-Whitney probability of superiority 0·59 [95% CI 0·53-0·64]; p=0·0019; generalised odds ratio 1·43 [95% CI 1·14-1·78]). At the 1-year follow-up, 77 (45%) of 170 patients receiving thrombectomy had died, compared with 83 (52%) of 159 patients receiving medical care only (1-year mortality relative risk 0·89 [95% CI 0·71-1·11]). INTERPRETATION: In patients with ischaemic stroke due to a proximal occlusion and large core, thrombectomy plus medical care provided a significant functional outcome benefit compared with medical care alone at 1-year follow-up. FUNDING: Stryker Neurovascular.

Endovascular Thrombectomy Treatment Effect in Direct vs Transferred Patients With Large Ischemic Strokes: A Prespecified Analysis of the SELECT2 Trial.

Importance: Patients with large ischemic core stroke have poor clinical outcomes and are frequently not considered for interfacility transfer for endovascular thrombectomy (EVT). Objective: To assess EVT treatment effects in transferred vs directly presenting patients and to evaluate the association between transfer times and neuroimaging changes with EVT clinical outcomes. Design, Setting, and Participants: This prespecified secondary analysis of the SELECT2 trial, which evaluated EVT vs medical management (MM) in patients with large ischemic stroke, evaluated adults aged 18 to 85 years with acute ischemic stroke due to occlusion of the internal carotid or middle cerebral artery (M1 segment) as well as an Alberta Stroke Program Early CT Score (ASPECTS) of 3 to 5, core of 50 mL or greater on imaging, or both. Patients were enrolled between October 2019 and September 2022 from 31 EVT-capable centers in the US, Canada, Europe, Australia, and New Zealand. Data were analyzed from August 2023 to January 2024. Interventions: EVT vs MM. Main Outcomes and Measures: Functional outcome, defined as modified Rankin Scale (mRS) score at 90 days with blinded adjudication. Results: A total of 958 patients were screened and 606 patients were excluded. Of 352 enrolled patients, 145 (41.2%) were female, and the median (IQR) age was 66.5 (58-75) years. A total of 211 patients (59.9%) were transfers, while 141 (40.1%) presented directly. The median (IQR) transfer time was 178 (136-230) minutes. The median (IQR) ASPECTS decreased from the referring hospital (5 [4-7]) to an EVT-capable center (4 [3-5]). Thrombectomy treatment effect was observed in both directly presenting patients (adjusted generalized odds ratio [OR], 2.01; 95% CI, 1.42-2.86) and transferred patients (adjusted generalized OR, 1.50; 95% CI, 1.11-2.03) without heterogeneity (P for interaction = .14). Treatment effect point estimates favored EVT among 82 transferred patients with a referral hospital ASPECTS of 5 or less (44 received EVT; adjusted generalized OR, 1.52; 95% CI, 0.89-2.58). ASPECTS loss was associated with numerically worse EVT outcomes (adjusted generalized OR per 1-ASPECTS point loss, 0.89; 95% CI, 0.77-1.02). EVT treatment effect estimates were lower in patients with transfer times of 3 hours or more (adjusted generalized OR, 1.15; 95% CI, 0.73-1.80). Conclusions and Relevance: Both directly presenting and transferred patients with large ischemic stroke in the SELECT2 trial benefited from EVT, including those with low ASPECTS at referring hospitals. However, the association of EVT with better functional outcomes was numerically better in patients presenting directly to EVT-capable centers. Prolonged transfer times and evolution of ischemic change were associated with worse EVT outcomes. These findings emphasize the need for rapid identification of patients suitable for transfer and expedited transport. Trial Registration: ClinicalTrials.gov Identifier: NCT03876457.

Matched three-dimensional organoids and two-dimensional cell lines of melanoma brain metastases mirror response to targeted molecular therapy.

Purpose: Despite significant advances in the treatment paradigm for patients with metastatic melanoma, melanoma brain metastasis (MBM) continues to represent a significant treatment challenge. The study of MBM is limited, in part, by shortcomings in existing preclinical models. Surgically eXplanted Organoids (SXOs) are ex vivo, three-dimensional cultures prepared from primary tissue samples with minimal processing that recapitulate genotypic and phenotypic features of parent tumors and are grown without artificial extracellular scaffolding. We aimed to develop the first matched patient-derived SXO and cell line models of MBM to investigate responses to targeted therapy. Methods: MBM SXOs were created by a novel protocol incorporating techniques for establishing glioma and cutaneous melanoma organoids. A BRAFV600K-mutant and BRAF-wildtype MBM sample were collected directly from the operating room for downstream experiments. Organoids were cultured in an optimized culture medium without an artificial extracellular scaffold. Concurrently, matched patient-derived cell lines were created. Drug screens were conducted to assess treatment response in SXOs and cell lines. Results: Organoid growth was observed within 3-4 weeks, and MBM SXOs retained histological features of the parent tissue, including pleomorphic epithelioid cells with abundant cytoplasm, large nuclei, focal melanin accumulation, and strong SOX10 positivity. After sufficient growth, organoids could be manually parcellated to increase the number of replicates. Matched SXOs and cell lines demonstrated sensitivity to BRAF and MEK inhibitors. Conclusion: Here, we describe the creation of a scaffold-free organoid model of MBM. Further study using SXOs may improve the translational relevance of preclinical studies and enable the study of the metastatic melanoma tumor microenvironment.

Trends of the Oswestry Disability Index in Adult Spinal Deformity Patients: A 3-Year Study.

BACKGROUND: Patients with adult spinal deformity (ASD) undergoing operative treatment may have varying degrees of improvement in patient-reported outcomes. The Oswestry Disability Index (ODI) assesses improvement in quality of life. We aim to measure longitudinal outcomes of ODI scores over 3 years to determine if early ODI scores predict late ODI scores and to analyze longitudinal changes in ODI scores. METHODS: Two hundred thirty-five patients above the age of 18 who underwent surgical correction of ASD at a single institution from 2016 to 2021 and completed ODI questionnaires at follow-up appointments met inclusion criteria. ODI scores were included from follow-up visits at 0 months (immediately postoperative) and within ±1 month of 3, 6, 12, 18, 24, 30, and 36 months. Percent change in ODI from 0 months was calculated, and unpaired t tests were conducted. RESULTS: ODI scores increased by 8.8% immediately postoperatively, and the percent change from preoperative ODI scores at each subsequent visit were as follows: -11.1% at 3 months, -21.4% at 6 months, -25.4% at 12 months, -28% at 18 months, -31.3% at 24 months, -25.7% at 30 months, and -36.5% at 36 months. ODI scores at each follow-up visit showed significant improvement from baseline (P < 0.001). There was an improvement in scores from 3 to 6 months (P = 0.04), but no significant difference in 6-month interval visits following 6 months. CONCLUSIONS: Our results demonstrate a significant and sustained improvement in ODI scores over 3 years following surgical correction of ASD. ODI scores were stable after 6 months, indicating that ODI scores at 6 months may be predictive of scores out to 3 years postoperatively. Examining individual components of ODI sub-scores and comparing ODI results to other PROMs are critical to better assess long-term outcomes in ASD.

Identifying Correlation Among Patient-Reported Outcome Measures: A Study of PROMIS-29, ODI, and VAS in Adult Spinal Deformity Patients.

BACKGROUND: Adult spinal deformity (ASD) is becoming increasingly common in aging populations. Patient-reported outcome measures (PROMs) are self-reported patient surveys administered pre- and postoperatively that provide insight into patient improvement. We aim to compare 3 of the most utilized PROMs: PROMIS-29, Oswestry Disability Index (ODI), and Visual Analogue Scale (VAS), to investigate whether they provide unique and independent assessments of patient outcomes when assessed longitudinally. METHODS: We retrospectively reviewed a database of ASD at UT Southwestern Medical Center between 2016 and 2021. Adult patients (>18 years old) were included if they underwent long-segment (>4 levels) thoracolumbar fusion. PROMIS-29, ODI, and VAS scores were collected preoperatively and at 3-, 6-, 12-, 18-, 24-, 30-, and 36-month follow-ups. Scores were recorded ±1 month of the time points. Pearson correlation coefficients for each PROM were then calculated in a pairwise fashion. RESULTS: A total of 163 patients were included in our analysis. ODI and VAS showed significant covariance, with VAS Neck and VAS Back having Pearson coefficients of 0.95 and 0.94, respectively. ODI and PROMIS-29 also showed significant covariance, with Physical Function and ODI showing a Pearson coefficient of 0.95. PROMIS-29 and VAS demonstrated less correlation regarding Pain and Physical Function; however, they showed a significantly high Pearson coefficient when comparing VAS Back with PROMIS-29 Sleep and Pain Intensity (r = 0.97 and r = 0.96, respectively). CONCLUSIONS: All 3 PROMs demonstrated significant correlation over 36 months, indicating that simultaneous administration of each during follow-up is redundant. The measure that provided the least unique information was ODI, as both VAS and PROMIS-29 demonstrated similar progression and assessed additional metrics. PROMIS-29 provided the same information as VAS and ODI, with extra facets of patient-reported outcomes, indicating that it may be a more comprehensive measure of longitudinal patient improvement.

A case series on treatment of central and branch retinal artery occlusion with intravenous tenecteplase: Tenecteplase for retinal artery occlusions.

OBJECTIVES: Central and branch retinal artery occlusions are disabling ischemic strokes of the retina for which established acute treatments are lacking. This is the first published report of the use of intravenous tenecteplase (TNK) for retinal artery occlusion, in which we describe the clinical course of four patients with central retinal artery occlusion (CRAO) and one patient with branch retinal artery occlusion (BRAO). MATERIALS AND METHODS: Patients were retrospectively recruited to the study from two stroke centers. Clinical course was determined from review of electronic medical records. The primary outcomes of interest were short and long term complications as well as visual acuity at presentation and at any subsequent follow up. RESULTS: There were no hemorrhagic complications. None of the four patients with CRAO experienced functional visual recovery (defined as improvement to 20/100 or better). The patient with BRAO had functional visual recovery. CONCLUSIONS: Intravenous TNK may be a safe and reasonable treatment for CRAO and BRAO.

Can the UK meet the World Health Organization PM2.5 interim target of 10 µg m-3 by 2030?

The recent United Kingdom (UK) Environment Act consultation had the intention of setting two targets for PM2.5 (particles with an aerodynamic diameter less than 2.5 µm), one related to meeting an annual average concentration and the second to reducing population exposure. As part of the consultation, predictions of PM2.5 concentrations in 2030 were made by combining European Union (EU) and UK government's emissions forecasts, with the Climate Change Committee's (CCC) Net Zero vehicle forecasts, and in London with the addition of local policies based on the London Environment Strategy (LES). Predictions in 2018 showed 6.4% of the UK's area and 82.6% of London's area had PM2.5 concentrations above the World Health Organization (WHO) interim target of 10 µg m-3, but by 2030, over 99% of the UK's area was predicted to be below it. However, kerbside concentrations in London and other major cities were still at risk of exceeding 10 µg m-3. With local action on PM2.5 in London, population weighted concentrations showed full compliance with the WHO interim target of 10 µg m-3 in 2030. However, predicting future PM2.5 concentrations and interpreting the results will always be difficult and uncertain for many reasons, such as imperfect models and the difficulty in estimating future emissions. To help understand the sensitivity of the model's PM2.5 predictions in 2030, current uncertainty was quantified using PM2.5 measurements and showed large areas in the UK that were still at risk of exceeding the WHO interim target despite the model predictions being below 10 µg m-3. Our results do however point to the benefits that policy at EU, UK and city level can have on achieving the WHO interim target of 10 µg m-3. These results were submitted to the UK Environment Act consultation. Nevertheless, the issues addressed here could be applicable to other European cities.

Retropharyngeal Blastomycosis Abscess Causing Osteomyelitis, Discitis, Cervical Deformity, and Cervical Epidural Abscess: A Case Report.

Blastomycosis infection is caused by the inhalation of the spores of the dimorphic Blastomyces sp.fungus. While more commonly a self-limited infection of the lungs, extrapulmonary manifestations arise from hematogenous or contiguous spread. Disseminated infection most often includes skin lesions and osteomyelitis; however, central nervous system (CNS) involvement is infrequently reported in the literature. Herein, we present a case of a retropharyngeal blastomycosis abscess leading to cervical spine osteonecrosis with retropulsion, deformity, and a spinal epidural abscess, and we discuss the relevant literature. The patient was successfully treated with cervical traction, followed by a combined anterior-posterior cervical approach, including abscess drainage, corpectomies, and instrumented fixation. Postoperatively, the patient completed 12 months of voriconazole and had near resolution of preoperative symptoms. Expediting neurosurgical intervention, such as the utilization of decompression, the clearance of infectious burden, and the correction of alignment, is critical for preventing downstream complications. Retropharyngeal blastomycosis abscesses are rare, and we report one of the rare instances of dissemination to and the degeneration of the cervical spine.

Properties of Packed Bed Structures Formed during Filtration: A Two and Three-Dimensional Model.

Agglomeration is an issue that causes many problems during secondary processing for pharmaceutical companies, causing material to need further processing and costing additional time and resources to ensure a satisfactory outcome. A potential source of agglomeration arises from the particle contacts established during filtration that lead to robust agglomerates forming during drying, so that a necessary first step toward understanding agglomeration is to study the packing properties of filtration beds. Here, we present two and three-dimensional models simulating the formation of packed bed structures during filtration. The models use circular and spherical particles of different sizes, mimicking the bimodal particle size distributions sometimes encountered in industrial practice. The statistics of packing and void formation, along with the distribution of interparticle contacts and percolation structures, are presented and discussed in the context of filtration, drying, and agglomeration. The model paves the way for predictive capabilities that can lead to the rational design of processes to minimize the impact of agglomeration.

Quantifying the change of brake wear particulate matter emissions through powertrain electrification in passenger vehicles.

With vehicle fleets transitioning from internal combustion engines (ICE) to electric powertrains, we have used friction brake power simulations, for different vehicle classes and driving styles, to predict the impact of regenerative braking systems (RBS) on brake wear particulate matter emissions (PM10 and PM2.5). Under the same powertrain, subcompact (SC) vehicles were predicted to require between 38 and 68% less friction brake power than heavier sports utility vehicles (L-SUV). However, despite electric and hybrid vehicles being heavier than ICE vehicles, the results show that RBS would reduce brake wear by between 64 and 95%. The study highlights the effect of aggressive braking on the amount of friction brake power required, with electric powertrains more likely to require friction braking to perform short, but aggressive braking compared with longer, slower braking events. Brake wear reductions varied under different driving conditions, as the level of mitigation depends on the complex interaction of several variables, including: vehicle speed, deceleration rate, regenerative braking technology and vehicle mass. Urban brake wear emission factors for electric powertrains ranged from 3.9 to 5.5 mg PM10/km and 1.5-2.1 mg PM2.5/km, providing an average reduction in PM emission factors of 68%. Rural and motorway driving conditions had lower brake wear emission factors, with plug-in hybrid electric vehicles (PHEV) and battery electric vehicles (BEV) emitting negligible PM10 and PM2.5 brake wear. Although electric powertrain uptake, vehicle mileage driven and driving styles are dependent upon national policies and strategies, by 2035, we project that total UK brake wear PM emissions would reduce by up to 39% compared with 2020 levels. This analysis supports the transition towards electric and hybrid vehicle fleets to reduce brake wear emissions, however increases in tyre wear, road wear, and resuspension due to increased vehicle mass may offset these benefits.

Human plasma-like medium facilitates metabolic tracing and enables upregulation of immune signaling pathways in glioblastoma explants.

Purpose: Metabolism within the tumor microenvironment (TME) represents an increasing area of interest to understand glioma initiation and progression. Stable isotope tracing is a technique critical to the study of tumor metabolism. Cell culture models of this disease are not routinely cultured under physiologically relevant nutrient conditions and do not retain cellular heterogeneity present in the parental TME. Moreover, in vivo, stable isotope tracing in intracranial glioma xenografts, the gold standard for metabolic investigation, is time consuming and technically challenging. To provide insights into glioma metabolism in the presence of an intact TME, we performed stable isotope tracing analysis of patient-derived, heterocellular Surgically eXplanted Organoid (SXO) glioma models in human plasma-like medium (HPLM). Methods: Glioma SXOs were established and cultured in conventional media or transitioned to HPLM. We evaluated SXO cytoarchitecture and histology, then performed spatial transcriptomic profiling to identify cellular populations and differential gene expression patterns. We performed stable isotope tracing with 15N2-glutamine to evaluate intracellular metabolite labeling patterns. Results: Glioma SXOs cultured in HPLM retain cytoarchitecture and cellular constituents. Immune cells in HPLM-cultured SXOs demonstrated increased transcription of immune-related signatures, including innate immune, adaptive immune, and cytokine signaling programs. 15N isotope enrichment from glutamine was observed in metabolites from diverse pathways, and labeling patterns were stable over time. Conclusion: To enable ex vivo, tractable investigations of whole tumor metabolism, we developed an approach to conduct stable isotope tracing in glioma SXOs cultured under physiologically relevant nutrient conditions. Under these conditions, SXOs maintained viability, composition, and metabolic activity while exhibiting increased immune-related transcriptional programs.

Evaluating risk of recurrence in patients with meningioma.

OBJECTIVE: Meningioma prognostication and treatment continues to evolve with an increasing understanding of tumor biology. In this study, the authors aimed to test conventional predictors of meningioma recurrence, histopathology variables for which there exists some controversy (brain invasion), as well as a novel molecular-based location paradigm. METHODS: This is a retrospective study of a consecutive series of patients with WHO grade I-III meningioma resected at The University of Texas Southwestern Medical Center between 1994 and 2015. Time to meningioma recurrence (i.e., recurrence-free survival [RFS]) was the primary endpoint measured. Kaplan-Meier curves were constructed and compared using log-rank tests. Cox univariate and multivariate analyses were performed to identify predictors of RFS. RESULTS: A total of 703 consecutive patients with meningioma underwent resection at The University of Texas Southwestern Medical Center between the years 1994 and 2015. A total of 158 patients were excluded for insufficient follow-up (< 3 months). The median age of the cohort was 55 years (range 16-88 years) and 69.5% (n = 379) were female. The median follow-up was 48 months (range 3-289 months). There was not a significantly increased risk of recurrence in patients with evidence of brain invasion, in patients with otherwise WHO grade I meningioma (Cox univariate HR 0.92, 95% CI 0.44-1.91, p = 0.82, power 4.4%). Adjuvant radiosurgery to subtotally resected WHO grade I meningiomas did not prolong the time to recurrence (n = 52, Cox univariate HR 0.21, 95% CI 0.03-1.61, p = 0.13, power 71.6%). Location (midline skull base, lateral skull base, and paravenous) was significantly associated with RFS (p < 0.01, log-rank test). In patients with high-grade meningiomas (WHO grade II or III), location was predictive of RFS (p = 0.03, log-rank test), with paravenous meningiomas exhibiting the highest rates of recurrence. Location was not significant on multivariate analysis. CONCLUSIONS: The data suggest that brain invasion does not increase the risk of recurrence in otherwise WHO grade I meningioma. Adjuvant radiosurgery to subtotally resected WHO grade I meningiomas did not prolong the time to recurrence. Location categorized by distinct molecular signatures did not predict RFS in a multivariate model. Larger studies are needed to confirm these findings.

Trial of Endovascular Thrombectomy for Large Ischemic Strokes.

BACKGROUND: Trials of the efficacy and safety of endovascular thrombectomy in patients with large ischemic strokes have been carried out in limited populations. METHODS: We performed a prospective, randomized, open-label, adaptive, international trial involving patients with stroke due to occlusion of the internal carotid artery or the first segment of the middle cerebral artery to assess endovascular thrombectomy within 24 hours after onset. Patients had a large ischemic-core volume, defined as an Alberta Stroke Program Early Computed Tomography Score of 3 to 5 (range, 0 to 10, with lower scores indicating larger infarction) or a core volume of at least 50 ml on computed tomography perfusion or diffusion-weighted magnetic resonance imaging. Patients were assigned in a 1:1 ratio to endovascular thrombectomy plus medical care or to medical care alone. The primary outcome was the modified Rankin scale score at 90 days (range, 0 to 6, with higher scores indicating greater disability). Functional independence was a secondary outcome. RESULTS: The trial was stopped early for efficacy; 178 patients had been assigned to the thrombectomy group and 174 to the medical-care group. The generalized odds ratio for a shift in the distribution of modified Rankin scale scores toward better outcomes in favor of thrombectomy was 1.51 (95% confidence interval [CI], 1.20 to 1.89; P<0.001). A total of 20% of the patients in the thrombectomy group and 7% in the medical-care group had functional independence (relative risk, 2.97; 95% CI, 1.60 to 5.51). Mortality was similar in the two groups. In the thrombectomy group, arterial access-site complications occurred in 5 patients, dissection in 10, cerebral-vessel perforation in 7, and transient vasospasm in 11. Symptomatic intracranial hemorrhage occurred in 1 patient in the thrombectomy group and in 2 in the medical-care group. CONCLUSIONS: Among patients with large ischemic strokes, endovascular thrombectomy resulted in better functional outcomes than medical care but was associated with vascular complications. Cerebral hemorrhages were infrequent in both groups. (Funded by Stryker Neurovascular; SELECT2 ClinicalTrials.gov number, NCT03876457.).

Mediation of Successful Reperfusion Effect through Infarct Growth and Cerebral Edema: A Pooled, Patient-Level Analysis of EXTEND-IA Trials and SELECT Prospective Cohort.

OBJECTIVE: Reperfusion therapy is highly beneficial for ischemic stroke. Reduction in both infarct growth and edema are plausible mediators of clinical benefit with reperfusion. We aimed to quantify these mediators and their interrelationship. METHODS: In a pooled, patient-level analysis of the EXTEND-IA trials and SELECT study, we used a mediation analysis framework to quantify infarct growth and cerebral edema (midline shift) mediation effect on successful reperfusion (modified Treatment in Cerebral Ischemia ≥ 2b) association with functional outcome (modified Rankin Scale distribution). Furthermore, we evaluated an additional pathway to the original hypothesis, where infarct growth mediated successful reperfusion effect on midline shift. RESULTS: A total 542 of 665 (81.5%) eligible patients achieved successful reperfusion. Baseline clinical and imaging characteristics were largely similar between those achieving successful versus unsuccessful reperfusion. Median infarct growth was 12.3ml (interquartile range [IQR] = 1.8-48.4), and median midline shift was 0mm (IQR = 0-2.2). Of 249 (37%) demonstrating a midline shift of ≥1mm, median shift was 2.75mm (IQR = 1.89-4.21). Successful reperfusion was associated with reductions in both predefined mediators, infarct growth (ß = -1.19, 95% confidence interval [CI] = -1.51 to -0.88, p < 0.001) and midline shift (adjusted odds ratio = 0.36, 95% CI = 0.23-0.57, p < 0.001). Successful reperfusion association with improved functional outcome (adjusted common odds ratio [acOR] = 2.68, 95% CI = 1.86-3.88, p < 0.001) became insignificant (acOR = 1.39, 95% CI = 0.95-2.04, p = 0.094) when infarct growth and midline shift were added to the regression model. Infarct growth and midline shift explained 45% and 34% of successful reperfusion effect, respectively. Analysis considering an alternative hypothesis demonstrated consistent results. INTERPRETATION: In this mediation analysis from a pooled, patient-level cohort, a significant proportion (~80%) of successful reperfusion effect on functional outcome was mediated through reduction in infarct growth and cerebral edema. Further studies are required to confirm our findings, detect additional mediators to explain successful reperfusion residual effect, and identify novel therapeutic targets to further enhance reperfusion benefits. ANN NEUROL 2023;93:793-804.

Thrombectomy Outcomes With General vs Nongeneral Anesthesia: A Pooled Patient-Level Analysis From the EXTEND-IA Trials and SELECT Study.

BACKGROUND AND OBJECTIVES: The effect of anesthesia choice on endovascular thrombectomy (EVT) outcomes is unclear. Collateral status on perfusion imaging may help identify the optimal anesthesia choice. METHODS: In a pooled patient-level analysis of EXTEND-IA, EXTEND-IA TNK, EXTEND-IA TNK part II, and SELECT, EVT functional outcomes (modified Rankin Scale score distribution) were compared between general anesthesia (GA) vs non-GA in a propensity-matched sample. Furthermore, we evaluated the association of collateral flow on perfusion imaging, assessed by hypoperfusion intensity ratio (HIR) - Tmax > 10 seconds/Tmax > 6 seconds (good collaterals - HIR < 0.4, poor collaterals - HIR ≥ 0.4) on the association between anesthesia type and EVT outcomes. RESULTS: Of 725 treated with EVT, 299 (41%) received GA and 426 (59%) non-GA. The baseline characteristics differed in presentation National Institutes of Health Stroke Scale score (median [interquartile range] GA: 18 [13-22], non-GA: 16 [11-20], p < 0.001) and ischemic core volume (GA: 15.0 mL [3.2-38.0] vs non-GA: 9.0 mL [0.0-31.0], p < 0.001). In addition, GA was associated with longer last known well to arterial access (203 minutes [157-267] vs 186 minutes [138-252], p = 0.002), but similar procedural time (35.5 minutes [23-59] vs 34 minutes [22-54], p = 0.51). Of 182 matched pairs using propensity scores, baseline characteristics were similar. In the propensity score-matched pairs, GA was independently associated with worse functional outcomes (adjusted common odds ratio [adj. cOR]: 0.64, 95% CI: 0.44-0.93, p = 0.021) and higher neurologic worsening (GA: 14.9% vs non-GA: 8.9%, aOR: 2.10, 95% CI: 1.02-4.33, p = 0.045). Patients with poor collaterals had worse functional outcomes with GA (adj. cOR: 0.47, 95% CI: 0.29-0.76, p = 0.002), whereas no difference was observed in those with good collaterals (adj. cOR: 0.93, 95% CI: 0.50-1.74, p = 0.82), p interaction: 0.07. No difference was observed in infarct growth overall and in patients with good collaterals, whereas patients with poor collaterals demonstrated larger infarct growth with GA with a significant interaction between collaterals and anesthesia type on infarct growth rate (p interaction: 0.020). DISCUSSION: GA was associated with worse functional outcomes after EVT, particularly in patients with poor collaterals in a propensity score-matched analysis from a pooled patient-level cohort from 3 randomized trials and 1 prospective cohort study. The confounding by indication may persist despite the doubly robust nature of the analysis. These findings have implications for randomized trials of GA vs non-GA and may be of utility for clinicians when making anesthesia type choice. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that use of GA is associated with worse functional outcome in patients undergoing EVT. TRIAL REGISTRATION INFORMATION: EXTEND-IA: ClinicalTrials.gov (NCT01492725); EXTEND-IA TNK: ClinicalTrials.gov (NCT02388061); EXTEND-IA TNK part II: ClinicalTrials.gov (NCT03340493); and SELECT: ClinicalTrials.gov (NCT02446587).

Psoas Muscle Index as a Predictor of Perioperative Outcomes in Geriatric Patients Undergoing Spine Surgery.

STUDY DESIGN: Single-center retrospective study. OBJECTIVE: The objective of this study was to evaluate the association of psoas muscle mass defined sarcopenia with perioperative outcomes in geriatric patients undergoing elective spine surgery. METHODS: We included geriatric patients undergoing thoracolumbar spinal surgery. Total psoas surface area (TPA) was measured on preoperative axial computerized tomography or magnetic resonance imaging at the L3 vertebra and normalized to the L3 vertebral body area. Patients were divided into quartiles by normalized TPA, and the fourth quartile (Q4) was compared to quartiles 1-3 (Q1-3). Outcomes included perioperative transfusions, length of stay (LOS), delirium, pseudoarthrosis, readmission, discharge disposition, revision surgery, and mortality. RESULTS: Of the patients who met inclusion criteria (n = 196), the average age was 73.4 y, with 48 patients in Q4 and 148 patients in Q1-3. Q4 normalized TPA cut-off was <1.05. Differences in Q4 preoperative characteristics included significantly lower body mass index, baseline creatinine, and a greater proportion of females (Table 1). Q4 patients received significantly more postoperative red blood cell and platelet transfusions and had longer ICU LOS (P < .05; Table 2). There was no difference in intraoperative transfusion volumes, delirium, initiation of walking, discharge disposition, readmission, pseudoarthrosis, or revision surgery (Tables 2 and 3). Mortality during follow-up was higher in Q4 but was not statistically significant (P = .075). CONCLUSION: Preoperative TPA in geriatric patients undergoing elective spine surgery is associated with increased need for intensive care and postoperative blood transfusion. Preoperative normalized TPA is a convenient measurement and could be included in geriatric preoperative risk assessment algorithms.