Diagnostic accuracy of arterial spin labeling MR imaging in detecting cerebral arteriovenous malformations: a systematic review and meta-analysis.

Diagnostic accuracy of arteriovenous malformations (AVMs) is imperative for delineating management. The current standard is digital subtraction angiography (DSA). Arterial spin labeling (ASL) is an understudied noninvasive, non-contrast technique that allows angioarchitecture visualization and additionally quantifies cortical and AVM cerebral blood flow and hemodynamics. This meta-analysis aims to compare ASL and DSA imaging in detecting and characterizing cerebral AVMs. EMBASE, Medline, Scopus, and Cochrane databases were queried from inception to July 2022 for reports of AVMs evaluated by DSA and ASL imaging. Fourteen studies with 278 patients evaluated using DSA and ASL imaging prior to intervention were included; pCASL in 11 studies (n = 239, 85.37%) and PASL in three studies (n = 41, 14.64%). The overall AVM detection rate on ASL was 99% (CI 97-100%); subgroup analysis revealed no difference between pCASL vs. PASL (99%; CI 96-100% vs. 100%; CI 95-100% respectively, p = 0.42). The correlation value comparing ASL and DSA nidus size was 0.99. DSA and ASL intermodality agreement Cohen's k factor for Spetzler Martin Grading (SMG) was reported at a median of 0.98 (IQR 0.73-0.1), with a 1.0 agreement on SMG classification. A median of 25 arteries were detected by DSA (IQR 14.5-27), vs. 25 by ASL (IQR 14.5-27.5) at a median 0.92 k factor. ASL provides angioarchitectural visualization noninferior to DSA and additionally quantifies CBF. Our study suggests that ASL should be considered in the detection of AVMs, especially in patients with contrast contraindications or apprehension towards an invasive assessment.

Robust prediction of nonhome discharge following elective anterior cervical discectomy and fusion using explainable machine learning.

PURPOSE: Predict nonhome discharge (NHD) following elective anterior cervical discectomy and fusion (ACDF) using an explainable machine learning model. METHODS: 2227 patients undergoing elective ACDF from 2008 to 2019 were identified from a single institutional database. A machine learning model was trained on preoperative variables, including demographics, comorbidity indices, and levels fused. The validation technique was repeated stratified K-Fold cross validation with the area under the receiver operating curve (AUROC) statistic as the performance metric. Shapley Additive Explanation (SHAP) values were calculated to provide further explainability regarding the model's decision making. RESULTS: The preoperative model performed with an AUROC of 0.83 ± 0.05. SHAP scores revealed the most pertinent risk factors to be age, medicare insurance, and American Society of Anesthesiology (ASA) score. Interaction analysis demonstrated that female patients over 65 with greater fusion levels were more likely to undergo NHD. Likewise, ASA demonstrated positive interaction effects with female sex, levels fused and BMI. CONCLUSION: We validated an explainable machine learning model for the prediction of NHD using common preoperative variables. Adding transparency is a key step towards clinical application because it demonstrates that our model's "thinking" aligns with clinical reasoning. Interactive analysis demonstrated that those of age over 65, female sex, higher ASA score, and greater fusion levels were more predisposed to NHD. Age and ASA score were similar in their predictive ability. Machine learning may be used to predict NHD, and can assist surgeons with patient counseling or early discharge planning.

Inhibitors of Protein Methyltransferases and Demethylases.

Post-translational modifications of histones by protein methyltransferases (PMTs) and histone demethylases (KDMs) play an important role in the regulation of gene expression and transcription and are implicated in cancer and many other diseases. Many of these enzymes also target various nonhistone proteins impacting numerous crucial biological pathways. Given their key biological functions and implications in human diseases, there has been a growing interest in assessing these enzymes as potential therapeutic targets. Consequently, discovering and developing inhibitors of these enzymes has become a very active and fast-growing research area over the past decade. In this review, we cover the discovery, characterization, and biological application of inhibitors of PMTs and KDMs with emphasis on key advancements in the field. We also discuss challenges, opportunities, and future directions in this emerging, exciting research field.

Characterizing the risk and outcome profiles of lumbar fusion procedures in patients with opioid use disorders: a step toward improving enhanced recovery protocols for a unique patient population.

OBJECTIVEThe authors set out to conduct the first national-level study assessing the risks and outcomes for different lumbar fusion procedures in patients with opioid use disorders (OUDs) to help guide the future development of targeted enhanced recovery after surgery (ERAS) protocols for this unique population.METHODSData for patients with or without OUDs who underwent an anterior lumbar interbody fusion (ALIF), posterior lumbar interbody fusion (PLIF), or lateral transverse lumbar interbody fusion (LLIF) for lumbar disc degeneration (LDD) were collected from the 2013-2014 National (Nationwide) Inpatient Sample database. Multivariable logistic regression was implemented to analyze how OUD status impacted in-hospital complications, length of hospital stay, discharge disposition, and total charges by procedure type.RESULTSA total of 139,995 patients with LDD were identified, with 1280 patients (0.91%) also having a concurrent OUD diagnosis. Overall complication rates were higher in OUD patients (48.44% vs 31.01%, p < 0.0001). OUD patients had higher odds of pulmonary (p = 0.0006), infectious (p < 0.0001), and hematological (p = 0.0009) complications. Multivariate regression modeling of outcomes by procedure type showed that after ALIF, OUD patients had higher odds of nonhome discharge (p = 0.0007), extended hospitalization (p = 0.0002), and greater total charges (p = 0.0054). This analysis also revealed that OUD patients faced higher odds of complication (p = 0.0149 and p = 0.0471), extended hospitalization (p = 0.0439 and p = 0.0001), and higher total charges (p < 0.0001 and p < 0.0001) after PLIF and LLIF procedures, respectively.CONCLUSIONSObtaining a better understanding of the risks and outcomes that OUD patients face perioperatively is a necessary step toward developing more effective ERAS protocols for this vulnerable population. This study, which sought to characterize the outcome profiles for lumbar fusion procedures in OUD patients on a national level, found that this population tended to experience increased odds of complications, extended hospitalization, nonhome discharge, and higher total costs. Results from this study warrant future prospective studies to better the understanding of these associations and to further the development of better ERAS programs that may improve patient care and reduce cost burden.

Neural processing of audiovisual and painful analogue trauma and its relationship with subsequent audiovisual and pain intrusions.

Background: Posttraumatic stress disorder and medically unexplained pain frequently co-occur. While pain is common during traumatic events, the processing of pain during trauma and its relation to audiovisual and pain intrusions is poorly understood.Objective: Here we investigate neural activations during painful analogue trauma, focusing on areas that have been related to threat and pain processing, and how they predict intrusion formation. We also examine the moderating role of cumulative lifetime adversity.Methods: Sixty-five healthy women were assessed using functional magnetic resonance imaging. An analogue trauma was induced by an adaptation of the trauma-film paradigm extended by painful electrical stimulation in a 2 (film: aversive, neutral) x 2 (pain: pain, no-pain) design, followed by 7-day audiovisual and pain intrusion assessment using event-based ecological momentary assessment. Intrusions were fitted with Bayesian multilevel regression and a hurdle lognormal distribution.Results: Conjunction analysis confirmed a wide network including anterior insula (AI) and dorsal anterior cingulate cortex (dACC) being active both, during aversive films and pain. Pain resulted in activation in areas amongst posterior insula and deactivation in a network around ventromedial prefrontal cortex (VMPFC). Higher AI and dACC activity during aversive>neutral film predicted greater audiovisual intrusion probability over time and predicted greater audiovisual intrusion frequency particularly for participants with high lifetime adversity. Lower AI, dACC, hippocampus, and VMPFC activity during pain>no-pain predicted greater pain intrusion probability particularly for participants with high lifetime adversity. Weak regulatory VMPFC activation was associated with both increased audiovisual and pain intrusion frequency.Conclusions: Enhanced AI and dACC processing during aversive films, poor pain vs. no-pain discrimination in AI and dACC, as well as weak regulatory VMPFC processing may be driving factors for intrusion formation, particularly in combination with high lifetime adversity. Results shed light on a potential path for the etiology of PTSD and medically unexplained pain.

AI and dACC play a common role for both trauma- and pain-processing.In combination with high lifetime adversity, higher AI and dACC aversive film processing was associated with higher audiovisual intrusion frequency, whereas weaker AI and dACC pain discrimination enhanced the chance for pain intrusions.Weak regulatory VMPFC activity in aversive situations increased both audiovisual and pain intrusion formation.

Angiographic cross-filling between inferior petrosal sinuses and alteration of adrenocorticotropic hormone sampling results for tumor localization in Cushing disease.

OBJECTIVE: Inferior petrosal sinus (IPS) sampling (IPSS) is a diagnostic procedure used to guide diagnostic localization of imaging-negative adrenocorticotropic hormone (ACTH)-secreting pituitary microadenomas. However, the efficacy of IPSS has been suboptimal at accurately lateralizing the adenoma, reducing surgical cure rates and leading to unintended pituitary dysfunction due to the added exploration. One rationale for the occasional imprecision is the existence of additional petrosal sinus collateral channels that connect the IPS bilaterally, which may lead to false localization results during sampling. The aim of this study was to explore a potential connection between normal anatomical variation in the angioarchitecture of the IPSs and the ACTH results obtained in subsequent IPSS tests. METHODS: A retrospective review was performed on all cases between 1998 and 2013 involving patients at a single institution who underwent IPSS for radiographically equivocal pituitary microadenomas. Cases were reviewed for tumor laterality noted on either operative or pathology reports, as well as the presence of angiographic evidence of cross-filling between the sinuses. In addition, ACTH levels from the right and left IPSs were documented at baseline and at 2, 5, and 10 minutes after corticotropin-releasing hormone (CRH) administration. A ratio of the change in ACTH levels measured at the time of maximal response (10 minutes) versus the levels measured at the initial response (2 minutes) was computed for each patient and compared between patients by their angiographic cross-filling status. RESULTS: There were 41 patients with a histopathologically confirmed right- or left-sided ACTH-secreting pituitary microadenoma who underwent preoperative IPSS. Among these patients, 28 (68%) showed angiographic evidence of cross-filling between the IPSs, and 13 showed no cross-filling. On average, ACTH levels increased by a factor of 3.91 ± 0.77 in the contralateral IPS in patients with angiographic cross-filling, compared with a factor increase of only 1.80 ± 0.27 in patients without cross-filling (p = 0.014). In comparison, ACTH levels increased by a factor of 2.01 ± 0.57 in the ipsilateral IPS in patients with cross-filling, and by 8.78 ± 7.30 in those without cross-filling (p = 0.373). CONCLUSIONS: The presence of angiographic cross-filling, suggestive of a greater degree of vascular channel networking between the right and left IPS, is a significant factor influencing the measured rates of change of ACTH in IPSS and may impact the specificity of this test to accurately determine microadenoma laterality in the preoperative setting.

The Predictors of Incidental Durotomy in Patients Undergoing Pedicle Subtraction Osteotomy for the Correction of Adult Spinal Deformity.

Background: Pedicle subtraction osteotomy (PSO) is a powerful tool for sagittal plane correction in patients with rigid adult spinal deformity (ASD); however, it is associated with high intraoperative blood loss and the increased risk of durotomy. The objective of the present study was to identify intraoperative techniques and baseline patient factors capable of predicting intraoperative durotomy. Methods: A tri-institutional database was retrospectively queried for all patients who underwent PSO for ASD. Data on baseline comorbidities, surgical history, surgeon characteristics and intraoperative maneuvers were gathered. PSO aggressiveness was defined as conventional (Schwab 3 PSO) or an extended PSO (Schwab type 4). The primary outcome of the study was the occurrence of durotomy intraoperatively. Univariable analyses were performed with Mann-Whitney U tests, Chi-squared analyses, and Fisher's exact tests. Statistical significance was defined by p < 0.05. Results: One hundred and sixteen patients were identified (mean age 61.9 ± 12.6 yr; 44.8% male), of whom 51 (44.0%) experienced intraoperative durotomy. There were no significant differences in baseline comorbidities between those who did and did not experience durotomy, with the exception that baseline weight and body mass index were higher in patients who did not suffer durotomy. Prior surgery (OR 2.73; 95% CI [1.13, 6.58]; p = 0.03) and, more specifically, prior decompression at the PSO level (OR 4.23; 95% CI [1.92, 9.34]; p < 0.001) was predictive of durotomy. A comparison of surgeon training showed no statistically significant difference in durotomy rate between fellowship and non-fellowship trained surgeons, or between orthopedic surgeons and neurosurgeons. The PSO level, PSO aggressiveness, the presence of stenosis at the PSO level, nor the surgical instrument used predicted the odds of durotomy occurrence. Those experiencing durotomy had similar hospitalization durations, rates of reoperation and rates of nonroutine discharge. Conclusions: In this large multisite series, a history of prior decompression at the PSO level was associated with a four-fold increase in intraoperative durotomy risk. Notably the use of extended (versus) standard PSO, surgical technique, nor baseline patient characteristics predicted durotomy. Durotomies occurred in 44% of patients and may prolong operative times. Additional prospective investigations are merited.

Reduced Bone Density Based on Hounsfield Units After Long-Segment Spinal Fusion with Harrington Rods.

BACKGROUND: Long-segment instrumentation, such as Harrington rods, offloads vertebrae within the construct, which may result in significant stress shielding of the fused segments. The present study aimed to determine the effects of spinal fusion on bone density by measuring Hounsfield units (HUs) throughout the spine in patients with a history of Harrington rod fusion. METHODS: Patients with a history of Harrington rod fusion treated at a single academic institution were identified. Mean HUs were calculated at 5 spinal segments for each patient: cranial adjacent mobile segment, cranial fused segment, midconstruct fused segment, caudal fused segment, and caudal adjacent mobile segment. Mean HUs for each level were compared using a paired-sample t test, with statistical significance defined by P < 0.05. Hierarchic multiple regression, including age, gender, body mass index, and time since original fusion, was used to determine predictors of midfused segment HUs. RESULTS: One hundred patients were included (mean age, 55 ± 12 years; 62% female). Mean HUs for the midconstruct fused segment (110; 95% confidence interval [CI], 100-121) were significantly lower than both the cranial and caudal fused segments (150 and 118, respectively; both P < 0.05), as well as both the cranial and caudal adjacent mobile segments (210 and 130, respectively; both P < 0.001). Multivariable regression showed midconstruct HUs were predicted only by patient age (-2.6 HU/year; 95% CI, -3.4 to -1.9; P < 0.001) and time since original surgery (-1.4 HU/year; 95% CI, -2.6 to -0.2; P = 0.02). CONCLUSIONS: HUs were significantly decreased in the middle of previous long-segment fusion constructs, suggesting that multilevel fusion constructs lead to vertebral bone density loss within the construct, potentially from stress shielding.

Bone Quality as Measured by Hounsfield Units More Accurately Predicts Proximal Junctional Kyphosis than Vertebral Bone Quality Following Long-Segment Thoracolumbar Fusion.

OBJECTIVE: To compare the prognostic power of Hounsfield units (HU) and Vertebral Bone Quality (VBQ) score for predicting proximal junctional kyphosis (PJK) following long-segment thoracolumbar fusion to the upper thoracic spine (T1-T6). METHODS: Vertebral bone quality around the upper instrumented vertebrae (UIV) was measured using HU on preoperative CT and VBQ on preoperative MRI. Spinopelvic parameters were also categorized according to the Scoliosis Research Society-Schwab classification. Univariable analysis to identify predictors of the occurrence of PJK and survival analyses with Kaplan-Meier method and Cox regression were performed to identify predictors of time to PJK (defined as ≥10° change in Cobb angle of UIV+2 and UIV). Sensitivity analyses showed thresholds of HU < 164 and VBQ > 2.7 to be most predictive for PJK. RESULTS: Seventy-six patients (mean age 66.0 ± 7.0 years; 27.6% male) were identified, of whom 15 suffered PJK. Significant predictors of PJK were high postoperative pelvic tilt (P = 0.038), high postoperative T1-pelvic angle (P = 0.041), and high postoperative PI-LL mismatch (P = 0.028). On survival analyses, bone quality, as assessed by the average HU of the UIV and UIV+1 was the only significant predictor of time to PJK (odds ratio [OR] 3.053; 95% CI 1.032-9.032; P = 0.044). VBQ measured using the UIV, UIV+1, UIV+2, and UIV-1 vertebrae approached, but did not reach significance (OR 2.913; 95% CI 0.797-10.646; P = 0.106). CONCLUSIONS: In larger cohorts, VBQ may prove to be a significant predictor of PJK following long-segment thoracolumbar fusion. However, Hounsfield units on CT have greater predictive power, suggesting preoperative workup for long-segment thoracolumbar fusion benefits from computed tomography versus magnetic resonance imaging alone to identify those at increased risk of PJK.

Significant Reduction in Bone Density as Measured by Hounsfield Units in Patients with Ankylosing Spondylitis or Diffuse Idiopathic Skeletal Hyperostosis.

Background: Multisegmental pathologic autofusion occurs in patients with ankylosing spondylitis (AS) and diffuse idiopathic skeletal hyperostosis (DISH). It may lead to reduced vertebral bone density due to stress shielding. Methods: This study aimed to determine the effects of autofusion on bone density by measuring Hounsfield units (HU) in the mobile and immobile spinal segments of patients with AS and DISH treated at a tertiary care center. The mean HU was calculated for five distinct regions-cranial adjacent mobile segment, cranial fused segment, mid-construct fused segment, caudal fused segment, and caudal adjacent mobile segment. Means for each region were compared using paired-sample t-tests. Multivariable regression was used to determine independent predictors of mid-fused segment HUs. Results: One hundred patients were included (mean age 76 ± 11 years, 74% male). The mean HU for the mid-construct fused segment (100, 95% CI [86, 113]) was significantly lower than both cranial and caudal fused segments (174 and 108, respectively; both p < 0.001), and cranial and caudal adjacent mobile segments (195 and 115, respectively; both p < 0.001). Multivariable regression showed the mid-construct HUs were predicted by history of smoking (-30 HU, p = 0.009). Conclusions: HUs were significantly reduced in the middle of long-segment autofusion, which was consistent with stress shielding. Such shielding may contribute to the diminution of vertebral bone integrity in AS/DISH patients and potentially increased fracture risk.

Reliable Prediction of Discharge Disposition Following Cervical Spine Surgery With Ensemble Machine Learning and Validation on a National Cohort.

STUDY DESIGN: A retrospective cohort study. OBJECTIVE: The purpose of this study is to develop a machine learning algorithm to predict nonhome discharge after cervical spine surgery that is validated and usable on a national scale to ensure generalizability and elucidate candidate drivers for prediction. SUMMARY OF BACKGROUND DATA: Excessive length of hospital stay can be attributed to delays in postoperative referrals to intermediate care rehabilitation centers or skilled nursing facilities. Accurate preoperative prediction of patients who may require access to these resources can facilitate a more efficient referral and discharge process, thereby reducing hospital and patient costs in addition to minimizing the risk of hospital-acquired complications. METHODS: Electronic medical records were retrospectively reviewed from a single-center data warehouse (SCDW) to identify patients undergoing cervical spine surgeries between 2008 and 2019 for machine learning algorithm development and internal validation. The National Inpatient Sample (NIS) database was queried to identify cervical spine fusion surgeries between 2009 and 2017 for external validation of algorithm performance. Gradient-boosted trees were constructed to predict nonhome discharge across patient cohorts. The area under the receiver operating characteristic curve (AUROC) was used to measure model performance. SHAP values were used to identify nonlinear risk factors for nonhome discharge and to interpret algorithm predictions. RESULTS: A total of 3523 cases of cervical spine fusion surgeries were included from the SCDW data set, and 311,582 cases were isolated from NIS. The model demonstrated robust prediction of nonhome discharge across all cohorts, achieving an area under the receiver operating characteristic curve of 0.87 (SD=0.01) on both the SCDW and nationwide NIS test sets. Anterior approach only, age, elective admission status, Medicare insurance status, and total Elixhauser Comorbidity Index score were the most important predictors of discharge destination. CONCLUSIONS: Machine learning algorithms reliably predict nonhome discharge across single-center and national cohorts and identify preoperative features of importance following cervical spine fusion surgery.

Comparison of Hounsfield units and vertebral bone quality score for the prediction of time to pathologic fracture in mobile spine metastases treated with radiotherapy.

OBJECTIVE: Spine metastases are commonly treated with radiotherapy for local tumor control; pathologic fracture is a potential complication of spinal radiotherapy. Both Hounsfield units (HUs) on CT and vertebral bone quality (VBQ) on MRI have been argued to predict stability as measured by odds of pathologic fracture, although it is unclear if there is a difference in the predictive power between the two methodologies. The objective of the present study was to examine whether one methodology is a better predictor of pathologic fracture following radiotherapy for mobile spine metastases. METHODS: Patients who underwent radiotherapy (conventional external-beam radiation therapy, stereotactic body radiation therapy, or intensity-modulated radiation therapy) for mobile spine (C1-L5) metastases at a tertiary care center were retrospectively identified. Details regarding underlying pathology, patient demographics, and tumor morphology were collected. Vertebral involvement was assessed using the Weinstein-Boriani-Biagini (WBB) system. Bone quality of the non-tumor-involved bone was assessed on both pretreatment CT and MRI. Univariable analyses were conducted to identify independent predictors of fracture, and Kaplan-Meier analyses were used to identify significant predictors of time to pathologic fracture. Stepwise Cox regression analysis was used to determine independent predictors of time to fracture. RESULTS: One hundred patients were included (mean age 62.7 ± 11.9 years; 61% male), of whom 35 experienced postradiotherapy pathologic fractures. The most common histologies were lung (22%), prostate (21%), breast (14%), and renal cell (13%). On univariable analysis, the mean HUs of the vertebrae adjacent to the fractured vertebra were significantly lower among those experiencing fracture; VBQ was not significantly associated with fracture odds. Survival analysis showed that average HUs ≤ 132, nonprostate pathology, involvement of ≥ 3 vertebral body segments on the WBB system, Spine Instability Neoplastic Score (SINS) ≥ 7, and the presence of axial pain all predicted increased odds of fracture (all p < 0.001). Cox regression found that HUs ≤ 132 (OR 2.533, 95% CI 1.257-5.103; p = 0.009), ≥ 3 WBB vertebral body segments involved (OR 2.376, 95% CI 1.132-4.987; p = 0.022), and axial pain (OR 2.036, 95% CI 0.916-4.526; p = 0.081) predicted increased fracture odds, while prostate pathology predicted decreased odds (OR 0.076, 95% CI 0.009-0.613; p = 0.016). Sensitivity analysis suggested that an HU threshold of ≤ 132 and a SINS of ≥ 7 identified patients at increased risk of fracture. CONCLUSIONS: The present results suggest that bone density surrogates as measured on CT, but not MRI, can be used to predict the risk of pathologic fracture following radiotherapy for mobile spine metastases. More extensive vertebral body involvement and the presence of mechanical axial pain additionally predict increased fracture odds.

Change in spinal bone mineral density as estimated by Hounsfield units following osteoporosis treatment with romosozumab, teriparatide, denosumab, and alendronate: an analysis of 318 patients.

OBJECTIVE: The purpose of this study was to determine the effect of osteoporosis medications on opportunistic CT-based Hounsfield units (HU). METHODS: Spine and nonspine surgery patients were retrospectively identified who had been treated with romosozumab for 3 to 12 months, teriparatide for 3 to 12 months, teriparatide for > 12 months, denosumab for > 12 months, or alendronate for > 12 months. HU were measured in the L1-4 vertebral bodies. One-way ANOVA was used to compare the mean change in HU among the five treatment regimens. RESULTS: In total, 318 patients (70% women) were included, with a mean age of 69 years and mean BMI of 27 kg/m2. There was a significant difference in mean HU improvement (p < 0.001) following treatment with romosozumab for 3 to 12 months (n = 32), teriparatide for 3 to 12 months (n = 30), teriparatide for > 12 months (n = 44), denosumab for > 12 months (n = 123), and alendronate for > 12 months (n = 100). Treatment with romosozumab for a mean of 10.5 months significantly increased the mean HU by 26%, from a baseline of 85 to 107 (p = 0.012). Patients treated with teriparatide for > 12 months (mean 23 months) experienced a mean HU improvement of 25%, from 106 to 132 (p = 0.039). Compared with the mean baseline HU, there was no significant difference after treatment with teriparatide for 3 to 12 months (110 to 119, p = 0.48), denosumab for > 12 months (105 to 107, p = 0.68), or alendronate for > 12 months (111 to 113, p = 0.80). CONCLUSIONS: Patients treated with romosozumab for a mean of 10.5 months and teriparatide for a mean of 23 months experienced improved spinal bone mineral density as estimated by CT-based opportunistic HU. Given the shorter duration of effective treatment, romosozumab may be the preferred medication for optimization of osteoporotic patients in preparation for elective spine fusion surgery.

Trends in Immunotherapy Clinical Trials to Treat Glioblastoma: A Look at Progress and Challenges.

PURPOSE: We aimed to catalog past and present clinical trials on immunotherapy treatments for glioblastoma (GBM) and discover relevant trends in this field. METHODS: Former and ongoing clinical trials involving the use of immunotherapy to treat GBM were queried in July 2022 within the clinicaltrials.gov registry (https://clinicaltrials.gov/). Pertinent trials were categorized by variables including immunotherapy classification, tumor type (newly diagnosed versus recurrent), country of origin, start date, clinical phase, study completion status, estimated subject enrollment, design, publication status, and funding source. RESULTS: A list of 173 trials was identified in total. The number of immunotherapy clinical trials to treat GBM has increased over time. The largest proportion of trials were gene therapies (97 studies; 56.1%) and viral therapies (37 studies; 21.4%). Studies were designated as a biologic (45.1%), drug (43.9%), genetic (2.3%), or procedure (1.2%). Trials spanned 19 countries; China, the second largest contributor (5.8%) after the United States (70.0%), has increased clinical trial development in the past years. The average time to completion was 52.3 months. Trials were primarily funded by academic centers; however, one-fourth of the trials were funded by industry and 2 were funded by foundations. One-t of the trials were active and over one-third were linked to publications. CONCLUSIONS: Our findings provide a comprehensive summary of the state of immunotherapy clinical trials for GBM, highlighting the evolving nature and growing scope of this field.

Impact of preoperative spinal injections within 30 days of lumbar decompression on surgical outcomes: a matched institutional study.

OBJECTIVE: The authors sought to determine how the temporal proximity of lumbar epidural spinal injection prior to surgery impacts clinical outcomes (e.g., 30-day readmission, postoperative complications, CSF leak) in patients undergoing lumbar decompression without fusion. METHODS: The authors queried their institutional registry to identify patients who underwent elective lumbar decompression for spondylotic pathology between January 2019 and March 2022 at multiple centers within the same hospital network. Patients were divided into groups based on the time between their surgical date and the most recent preoperative spinal injection: group 1, patients with duration < 1 month; group 2, 1-3 months; and group 3, no spinal injection within 3 months. Primary outcomes of interest were the length of hospital stay, postoperative complications, rate of intraoperative CSF leak, and rates of reoperation and hospital readmission. For patients in groups 1 and 2, the authors also recorded the number of injections within 12 months prior to surgery to better understand the effect of multiple recent injections. The independent Student t-test and Pearson's chi-square test were mainly performed for univariate analyses of the continuous and categorical variables, respectively. RESULTS: A total of 121 and 283 patients received a spinal injection at < 1 month and 1-3 months prior to surgery, respectively, and were separately matched in a 3:1 ratio with 2562 patients with no history of preoperative spinal injection within 3 months before surgery. Among the matched cohorts, patients who received spinal injections < 1 month before lumbar decompression had significantly higher risks of 30-day complication (7.4% vs 0.8%, OR 9.6, p < 0.001), 30-day readmission (5.8% vs 2.2%, OR 3.5, p = 0.049), and 90-day readmission (9.1% vs 2.8%, OR 3.5, p = 0.003) than patients with no history of spinal injection. However, compared with patients with no history of spinal injection, the patients who received spinal injections 1-3 months before surgery were not at higher risk for postoperative complications or readmission. The CSF leak rates were significantly different between the three patient cohorts (10.7% vs 6.7% vs 4.9% for the < 1 month, 1-3 months, and no injection cohorts, respectively; p = 0.02). CONCLUSIONS: Lumbar decompression within 1 month of preoperative spinal injection was associated with higher risks of readmission and postoperative complications, including CSF leak. However, with the exception of CSF leak, these risks were no longer observed when spinal injection occurred 1-3 months prior to lumbar decompression.

Dopamine-Depleted Dopamine Transporter Knockout (DDD) Mice: Dyskinesia with L-DOPA and Dopamine D1 Agonists.

L-DOPA is the mainstay of treatment for Parkinson's disease (PD). However, over time this drug can produce dyskinesia. A useful acute PD model for screening novel compounds for anti-parkinsonian and L-DOPA-induced dyskinesia (LID) are dopamine-depleted dopamine-transporter KO (DDD) mice. Treatment with α-methyl-para-tyrosine rapidly depletes their brain stores of DA and renders them akinetic. During sensitization in the open field (OF), their locomotion declines as vertical activities increase and upon encountering a wall they stand on one leg or tail and engage in climbing behavior termed "three-paw dyskinesia". We have hypothesized that L-DOPA induces a stereotypic activation of locomotion in DDD mice, where they are unable to alter the course of their locomotion, and upon encountering walls engage in "three-paw dyskinesia" as reflected in vertical counts or beam-breaks. The purpose of our studies was to identify a valid index of LID in DDD mice that met three criteria: (a) sensitization with repeated L-DOPA administration, (b) insensitivity to a change in the test context, and (c) stimulatory or inhibitory responses to dopamine D1 receptor agonists (5 mg/kg SKF81297; 5 and 10 mg/kg MLM55-38, a novel compound) and amantadine (45 mg/kg), respectively. Responses were compared between the OF and a circular maze (CM) that did not hinder locomotion. We found vertical counts and climbing were specific for testing in the OF, while oral stereotypies were sensitized to L-DOPA in both the OF and CM and responded to D1R agonists and amantadine. Hence, in DDD mice oral stereotypies should be used as an index of LID in screening compounds for PD.

A Nationwide Study Characterizing the Risk and Outcome Profiles of Multilevel Fusion Procedures in Neuromuscular Scoliosis Patients with Neurofibromatosis Type 1.

BACKGROUND: Spine abnormalities are a common manifestation of Neurofibromatosis Type 1 (NF1); however, the outcomes of surgical treatment for NF1-associated spinal deformity are not well explored. The purpose of this study was to investigate the outcome and risk profiles of multilevel fusion surgery for NF1 patients. METHODS: The National Inpatient Sample was queried for NF1 and non-NF1 patient populations with neuromuscular scoliosis who underwent multilevel fusion surgery involving eight or more vertebral levels between 2004 and 2017. Multivariate regression modeling was used to explore the relationship between perioperative variables and pertinent outcomes. RESULTS: Of the 55,485 patients with scoliosis, 533 patients (0.96%) had NF1. Patients with NF1 were more likely to have comorbid solid tumors (P < 0.0001), clinical depression (P < 0.0001), peripheral vascular disease (P < 0.0001), and hypertension (P < 0.001). Following surgery, NF1 patients had a higher incidence of hydrocephalus (0.6% vs. 1.9% P = 0.002), seizures (4.9% vs. 5.7% P = 0.006), and accidental vessel laceration (0.3% vs.1.9% P = 0.011). Although there were no differences in overall complication rates or in-hospital mortality, multivariate regression revealed NF1 patients had an increased probability of pulmonary (OR 0.5, 95%CI 0.3-0.8, P = 0.004) complications. There were no significant differences in utilization, including nonhome discharge or extended hospitalization; however, patients with NF1 had higher total hospital charges (mean -$18739, SE 3384, P < 0.0001). CONCLUSIONS: These findings indicate that NF1 is associated with certain complications following multilevel fusion surgery but does not appear to be associated with differences in quality or cost outcomes. These results provide some guidance to surgeons and other healthcare professionals in their perioperative decision making by raising awareness about risk factors for NF1 patients undergoing multilevel fusion surgery. We intend for this study to set the national baseline for complications after multilevel fusion in the NF1 population.

Opportunistic CT-Based Hounsfield Units Strongly Correlate with Biomechanical CT Measurements in the Thoracolumbar Spine.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: Hounsfield units (HUs) are known to correlate with clinical outcomes, no study has evaluated how they correlate with BCT and DXA measurements. SUMMARY OF BACKGROUND: Low bone mineral density (BMD) represents a major risk factor for fracture and poor outcomes following spine surgery. Dual-energy x-ray absorptiometry (DXA) can provide regional BMD measurements but has limitations. Opportunistic HUs provide targeted BMD estimates; however, they are not formally accepted for diagnosing osteoporosis in current guidelines. More recently, biomechanical computed tomography (BCT) analysis has emerged as a new modality endorsed by the International Society for Clinical Densitometry (ISCD) for assessing bone strength. METHODS: Consecutive cases from 2017-2022 at a single institution were reviewed for patients who underwent BCT in the thoracolumbar spine. BCT-measured vertebral strength, trabecular BMD, and the corresponding American College of Radiology (ACR) Classification were recorded. DXA studies within three months of the BCT were reviewed. Pearson Correlation Coefficients were calculated, and receiver-operating characteristic curves were constructed to assess the predictive capacity of HUs. Threshold analysis was performed to identify optimal HU values for identifying osteoporosis and low BMD. RESULTS: Correlation analysis of 114 cases revealed a strong relationship between HUs and BCT vertebral strength (r=0.69; P<0.0001; R2=0.47) and trabecular BMD (r=0.76; P<0.0001; R2=0.58). However, DXA poorly correlated with opportunistic HUs and BCT measurements. HUs accurately predicted osteoporosis and low BMD (Osteoporosis: C=0.95, 95% CI 0.89-1.00; Low BMD: C=0.87, 95% CI 0.79-0.96). Threshold analysis revealed that 106 and 122 HUs represent optimal thresholds for detecting osteoporosis and low BMD. CONCLUSION: Opportunistic HUs strongly correlated with BCT-based measures, while neither correlated strongly with DXA-based BMD measures in the thoracolumbar spine. HUs are easy to perform at no additional cost and provide accurate BMD estimates at non-instrumented vertebral levels across all ACR-designated BMD categories.

Comparative Analysis of Early Outcomes and Complications of PSO Among Neurosurgeons and Orthopedic Surgeons.

STUDY DESIGN: Retrospective comparative cohort study using the National Surgical Quality Improvement Program. OBJECTIVE: The aim of this study was to evaluate trends in the annual number of PSOs performed, describe the patient populations associated with each cohort, and compare outcomes between specialties.Summary of Background Data:Pedicle subtraction osteotomies (PSO) are complex and advanced spine deformity surgical procedures performed by neurosurgeons and orthopedic surgeons. Though both sets of surgeons can be equally qualified and credentialed to perform a PSO, it is possible that differences in training and exposure could translate into differences in patient management and outcomes. METHODS: Patients that underwent lumbar PSO from 2005 to 2014 in the American College of Surgeons-National Surgical Quality Improvement Program registry were identified. Relevant demographic, preoperative comorbidity, and postoperative 30-day complications were queried and analyzed. The data was divided into 2 cohorts consisting of those patients who were treated by neurosurgeons versus orthopedic surgeons. Additional data from the Scoliosis Research Society Morbidity and Mortality database was queried and analyzed for comparison. RESULTS: Demographic and comorbidity factors were similar between the neurosurgery and orthopedic surgery cohorts, except there were higher rates of hypertension among orthopedic surgeon-performed PSOs (65.66% vs. 48.67%, P =0.004). Except for 2012, in every year queried, orthopedic surgeons reported more PSOs than neurosurgeons. In patients who underwent lumbar fusion surgery, there was a higher rate of PSOs if the surgery was performed by an orthopedic surgeon (OR 1.7824, 95% CI: 1.4017-2.2665). The incidence of deep vein thrombosis after PSOs was higher for neurosurgery compared with orthopedic surgery (8.85% vs. 1.20%, P =0.004). However, besides deep vein thrombosis, there were no salient differences in surgical complication rates between neurosurgeon-performed PSOs and orthopedic surgeon-performed PSOs. CONCLUSIONS: The number of PSO procedures performed by neurosurgeons and orthopedic surgeons has increased annually. Differences in outcomes between neurosurgeons and orthopedic surgeons suggest an opportunity for wider assessment and alignment of adult spinal deformity surgery exposure and training across specialties.

Characterizing the Current Clinical Trial Landscape in Spinal Deformity: A Retrospective Analysis of Trends in the ClinicalTrials.gov Registry.

BACKGROUND: The management of adult spinal deformity (ASD) relies upon retrospective data, but there have been calls for prospective trials to improve the evidentiary base. This study sought to define the state of the spinal deformity clinical trials and highlight trends to guide future research. METHODS: The ClinicalTrials.gov database was queried for all ASD trials initiated since 2008. ASD was defined as adults (>18 years) and defined by the trial. All identified trials were categorized by enrollment status, study design, funding source, start and completion dates, country, outcomes examined, among many other study characteristics. RESULTS: Sixty trials were included, of which 33(55.0%) started within the past 5 years of the query date. Most trials were sponsored by academic centers (60.0%) followed by industry (48.3%). Notably, 16 (27%) trials had multiple funding sources, all included collaboration with an industry entity. Only one trial had funding from a government agency. There were 30 (50%) interventional and 30 (50%) observational studies. The average time to completion was 50.8 ± 49.1 months. A total of 23 (38.3%) studies investigated a new procedural innovation, while 17 (28.3%) studies examined the safety or efficacy of a device. Study publications were associated with 17 (28.3%) trials in the registry. CONCLUSIONS: The number of trials has increased significantly over the past 5 years, with the bulk of trials being funded by academic centers and industry and a notably lack by government agencies. Most trials focused on device or procedural investigation. Despite growing interest in ASD clinical trials, there remain many points for improvement in the current evidentiary base.