bluuebunny/crossref_metadata_2025 huggingface dataset:
407 Anterior Cervical Discectomy and Fusion in Ambulatory Surgery Center Versus Hospital Setting: One-Year Cost Utility and Cost Benefit Analysis
Authors: Hani Ummey , Monk Steve Hubert , Pfortmiller Deborah , Adamson Tim E. , Bohl Michael , Kim Paul Keetae , Holland Christopher Michael , McGirt Matthew J.
Published: March 2023

INTRODUCTION:

Outpatient anterior cervical discectomy and fusion (ACDF) has recently gained popularity due to improved care and reduced costs. Cost-utility studies for ambulatory vs. inpatient ACDF are largely limited to small series, precluding an accurate assessment of cost-effectiveness.

METHODS:

A 6,504, ASA 1-3, patient sample (520 ASC, 5,984 inpatient) was used to propensity-match 748 patients (374/cohort) undergoing 1-2-level ACDF. Data was queried from the National Quality Outcomes Database (QOD). Medical resource utilization, missed work, and quality adjusted life years (QALYs) were assessed. Direct cost (one-year resource use x unit costs based on Medicare national allowable payment amounts) and indirect cost (missed workdays x average US daily wage) were recorded and incremental cost-effectiveness ratio was calculated.

RESULTS:

Estimated blood loss, length of surgery, and hospitalization were less for ASC vs. inpatient ACDF (p < 0.001). ASC vs. inpatient ACDF demonstrated similar improvement in patient reported outcomes. ASC vs. inpatient ACDF was associated with lower total one-year cost of $5,879.46 for Medicare patients and $12,873.97 for private payers (p < 0.001), with similar QALYs gained. Hospital vs ASC had a highly cost ineffective ICER of $3,674,662.50/QALY-gained and $8,046,231.25/QALY for Medicare and private payer patients, respectively.

CONCLUSIONS:

1-2-level ACDF in the hospital vs ASC is associated with increased mean costs, without a QALY, safety, or outcome benefit. Hence, health economics strongly favor the ASC setting to the hospital for ACDF.
411 The Cost of a Single Sport-Related Concussion in Adolescent Athletes
Authors: Liles David Campbell , Tang Alan Ruigang , Williams Kristen , Yengo-Kahn Aaron Michael , Zuckerman Scott L. , Terry Douglas
Published: March 2023

INTRODUCTION:

Despite the ubiquity of sport-related concussions (SRC), the healthcare costs incurred by a single SRC are unknown.

METHODS:

We conducted a retrospective cohort study examining concussed athletes ages 12-23 who presented to a multi-disciplinary concussion center between 11/2017-10/2020. Athletes presenting for treatment more than 10 days post-injury and those sustaining >1 concussion during the study period were excluded. The primary outcome was the direct cost of the concussion care episode, derived by matching visit and imaging dates with institution inflation-adjusted cost data. A multivariable linear regression examined predictors of total concussion care costs. Independent variables included relevant demographics, medical/family medical history, injury characteristics, and initial Post-Concussion Symptom Scale (PCSS) score.

RESULTS:

In total, 710 athletes were included. Median age was 16.1 years (IQR = 15.1-17.2; 66.5% male). Median initial PCSS was 26 (IQR = 6-39). Sports with the highest prevalence of SRC were football (n = 261, 36.8%), soccer (n = 102, 14.4%) and basketball (n = 97, 13.7%). The mean cost of an SRC care episode was $822 (SD = $1,233). The mean costs associated with a softball-related concussion were highest (M = $2,372, SD = $4,707), followed by basketball (M = $1,012 SD = $1,863), lacrosse (M = $924, SD = $1,101), and football (M = $814, SD = $993). A multivariable linear regression showed that higher initial PCSS (b = 4.87, 95% CI = 1.32-8.42, p = .007), number of prior concussions (b = 118.79, 95% CI = 42.71-194.88, p = .002), and having an emergency department/urgent care visit (b = 670.20, 95% CI = 497.66-842.74) were significant predictors of greater cost.

CONCLUSIONS:

With a mean value of $822 per SRC, healthcare costs associated with this common injury total over $3 billion annually in the U.S. Greater costs were associated with higher initial symptom burden, prior concussion history, and emergency department/urgent care utilization. A nuanced understanding of cost-driving factors associated with SRC is a prerequisite to understanding cost-effectiveness of prevention and treatment.
412 A Protocol for Reducing Intensive Care Utilization After Craniotomy: A Three-Year Assessment
Authors: Colon Gabriela Ruiz , Ohkuma Rika , Pendharkar Arjun Vivek , Heifets Boris , Li Gordon , Lu Amy , Gephart Melanie Hayden , Ratliff John K.
Published: March 2023

INTRODUCTION:

Craniotomy patients have traditionally received intensive care unit (ICU) care postoperatively. Our institution developed the “Non-Intensive CarE” (NICE) protocol to identify craniotomy patients that did not require postoperative ICU care.

METHODS:

Our institution’s electronic medical record (EMR) was queried to identify craniotomies prior to protocol deployment (May 2014-May 2018), and after deployment (May 2018-December 2021). Patients are considered for the protocol if they are having an elective craniotomy for select procedures (e.g. microvascular decompressions, extra-axial tumor resection), are under age of 65, have no history of coagulopathy, and have no other medical contraindications. Reason for readmission or reoperation among NICE protocol patients was collected via chart review. The primary endpoints were average POLS and ICU utilization; secondary endpoints included readmission, reoperation, and postoperative complications rates. Endpoints were compared among pre- and post-protocol cohorts.

RESULTS:

4,837 craniotomies were performed from May 2014-December 2021 (2,302 pre-protocol, 2,535 post-protocol). 21% percent of post-protocol craniotomies were enrolled in the NICE protocol. After protocol deployment, overall POLS decreased from 4.0 to 3.5 days (p = 0.0031), which was driven by deceased POLS among protocol patients (average 2.4 days).ICU utilization decreased from 57% of patients to 42% (p < 0.0001), generating ∼$760,000 in savings. Return to the ICU and complications decreased after protocol deployment. 5.8% of protocol patients had a readmission within thirty days; none could have been prevented through ICU stay.

CONCLUSIONS:

The NICE protocol is an effective, sustainable method to increase ICU bed availability and decrease costs without changing outcomes. To our knowledge, this study features the largest series of patients enrolling in an ICU utilization reduction protocol. Careful patient selection is a requirement for the success of this approach.
420 Coaching for Success: An Athlete-Centered Approach to Optimizing Performance and Protecting Wellbeing in Neurosurgery Residents
Authors: Chennareddy Susmita , Kalagara Roshini , Schupper Alexander J. , Carr Matthew Thomas , Philbrick Brandon , Turner Dan , Kellner Christopher Paul
Published: March 2023

INTRODUCTION:

Medicine has long attracted high-performing individuals. In particular, neurosurgical residents are faced with challenging conditions, including long workdays, demanding caseloads, and complex relationships, which rival those of the world’s greatest athletes. Unlike athletes, however, who have personalized programs that optimize performance and protect wellbeing, neurosurgical residents typically have a less-developed support network.

METHODS:

In collaboration with a human performance specialist, we conducted interviews, team exercises, and questionnaires with residents at our institution over six weeks. Qualitative data were analyzed using domain-classification, sentiment analysis, word association and proprietary algorithms, to identify themes of wellbeing, performance, and culture.

RESULTS:

Ten residents participated in the sessions; the highest and lowest scoring domains are reported. Five key findings were highlighted on domain analysis: (1) Residents noted meaningful workplace relationships and felt respected by peers; (2) Considerable variation existed in residents’ perceived ability to maintain their work level and in their preferences around sleep, exercise, nutrition, and free time; (3) Major sources of stress included sleep loss, work pace, uncertainty, where to focus wellbeing efforts, and mild performance anxiety; (4) Most residents underutilized relaxation techniques, noting frequent changes in motivation/self-worth; (5) Nearly all residents reported a deep sense of fulfillment/satisfaction.

CONCLUSIONS:

The neurosurgery residency environment requires sustained high performance. Here, we highlight opportunities for neurosurgery resident wellbeing and performance optimization, including strengthening communication under pressure, strategic decision-making promoting work-life balance/self-preservation, and encouraging a culture prioritizing wellbeing and performance. Importantly, inter-resident diversity accentuates the need for individualized resident support. Based on these findings, several programs were deployed, including a 12-month coaching program, an operating room feedback tool, and a digital advisor providing rapid, personalized guidance on performance and wellbeing.
426 Utility of the Fried Phenotype as a Frailty Assessment Tool in Predicting Post-Operative Outcomes in Lumbar Degenerative Spine Surgery Patients
Authors: Yan Sandra C. , Porche Ken Michael , Hoh Daniel J. , Garvan Cynthia , Mohamed Basma
Published: March 2023

INTRODUCTION:

Frailty is a syndrome of physiological decline that can predispose surgical patients to increased peri-operative morbidity. The Fried phenotype is a clinical measure of frailty and categorizes patients’ frailty based on grip strength, walking speed, unintentional weight loss, low physical activity, and exhaustion. It has been validated in non-spine surgical populations and has been shown to be correlated with poor postoperative outcomes and longer hospital lengths of stay (LOS); it has not yet been validated in patients undergoing spine surgery. Other assessment tools, including the Modified Frailty Index-11 (mFI-11) and Charlson Comorbidity Index (CCI), are calculated based on comorbidities. The mFI-11 has previously been studied in spine patients - a higher mFI-11 score has been associated with a higher risk of post-operative morbidity and mortality.

METHODS:

Patients >65 years of age who underwent elective lumbar spine surgery for degenerative disease since 2015 were included. Data for the Fried phenotype, mFI-11, CCI, and outcomes were gathered for each patient. ROC curves were generated, and multivariate analyses were performed.

RESULTS:

248 patients (128 females; 120 males) with an average age of 71.8 years were included. The median Fried score was 1, median CCI was 1, and median mFI-11 was 0.18. The median LOS was 4 days, with 11 30-day re-admissions. Fried phenotype was found to be the best predictor of an extended LOS and of a non-home discharge.

CONCLUSIONS:

The Fried phenotype is now shown to be a validated measure of frailty in the spine population. Because it relies on categories that are impacted by the patient's functional condition (instead of the comorbidity burden), it has profound implications for optimizing patients through pre-habilitation prior to elective surgery.
428 Accomplishing Realignment Goals Withstands the Test of Time: The Outcomes of a Prospective Consecutively Enrolled Single-Center Adult Cervical Deformity Series With Minimum 5-Year Follow-Up
Authors: Passias Peter G. , Williamson Tyler K. , Joujon-Roche Rachel , Imbo Bailey , Krol Oscar , Tretiakov Peter S. , Bennett-Caso Claudia , Owusu-Sarpong Stephane , Lebovic Jordan
Published: March 2023

INTRODUCTION:

Adult cervical deformity(CD) realignment has shown promising short-term and two-year clinical results, but longer-term outcomes of CD surgery remain unclear.

METHODS:

Operative CD patients>18 years eligible for 5-year (5Y) follow-up were included. Optimal thresholds for C2 Slope and T1 Slope by Passfall et al were assessed. Student’s t-test, paired t-test, binary and multivariable logistic regression analyses were used to evaluate the clinical, radiographic, and complications outcomes of the five-year eligible cohort.

RESULTS:

58 patients were enrolled from 2012 to 2017(54.5±10.3 years,57% female, BMI: 30.0 ± 7.3 kg/m2, 16% osteoporosis), and underwent surgical correction (levels fused: 5.2 ± 2.6, EBL: 772 ± 672 mL, operative time: 372 ± 139 min, LOS: 5.9 ± 8.1 days). By surgical approach, 13.8% anterior-only, 51.7% posterior-only, 34.5% combined. 53% had previous cervical surgery, 41% a fusion. The most common UIV was C3, LIV was T1. By three months (3M), patients improved in cervical lordosis, C2-C7 SVA (cSVA), and T1 Slope(all p <.02), but not C2 Slope or TS-CL (both p>.5). The cohort significantly improved from baseline (BL) to 2Y in NDI, NRS-Neck, and EQ-5D(all P<.02). From 2Y to last follow-up, patients did not improve in mJOA or NDI, but did in EQ-5D (0.441 to 0.509) and NRS-Neck (5.9 to 5.0, both p<.05). There were 14(24.1%) cases of DJK, 6 were distal junctional failure (10.3%), and 17(29.3%) underwent reoperation. Patients corrected below the T1 Slope threshold of 26.5° and maintained at last follow-up experienced DJK less often(OR: 0.1,[0.02-0.74]). Patients corrected below the C2 Slope threshold of 10° and maintained at last follow-up experienced no DJK, DJF or reoperations.

CONCLUSIONS:

Although complications including distal junctional failure and reoperation remain prevalent, correction of cervical deformity and achievement of realignment targets results in notable clinical and radiographic improvement with most patients achieving favorable outcomes by two years, with further improvement seen until last follow-up.
432 Enhanced Surgical Recovery for Thoracolumbar Spine Surgery is Associated With Decreased Opioid Consumption, Length of Hospital Stay, and Hospital Readmissions: Evaluation of 51,236 Cases
Authors: Good Christopher , Bess Shay , Orosz Lindsay , Scibelli Stephen Scott , Line Breton G. , Remington Gina , Roman Cecile , Luckett Daniel , Jazini Ehsan
Published: March 2023

INTRODUCTION:

Evidence-based enhanced surgical recovery (ESR) programs integrate a multidimensional approach to optimize patients during the pre-, intra-, and post-operative phases of surgery. Smaller studies suggest benefits of ESR in spine surgery, but large-scale evidence is lacking.

METHODS:

In this retrospective case-control study of a healthcare system ESR program, data from thoracolumbar (TL) fusions were extracted from electronic medical records. Patients were divided into two cohorts, ESR or non-ESR, based upon enrollment into an ESR program defined by (1) preoperative patient education, (2) multimodal analgesia, (3) intraoperative fluid optimization, (4) opioid-sparing anesthesia, and (5) early postoperative nutrition and ambulation. Exclusion criteria were: unknown ESR status, age <18 yrs, and surgery for tumor, infection, or trauma. Impact of ESR upon postoperative daily morphine milligram equivalents (MME), length of hospital stay (LOS), and 30-day hospital readmission rates (READMIT) was evaluated for single-level TL fusions, multi-level TL fusions, and all TL fusions using regression models.

RESULTS:

51,236 TL fusion cases were identified from 2018 to 2021: 24,391 participated in an ESR program and 26,845 did not. ESR and non-ESR groups were demographically similar. For single level TL fusions, ESR was associated with decreased MME (β= -8.76, p < 0.001), LOS (β= -8.85, p < 0.001), and READMIT (OR = 0.77, 95% CI: 0.67-0.88). For multi-level TL fusions, ESR was associated with decreased MME (β = -7.32, p < 0.001) and LOS (β= -12.14, p < 0.001), and for all TL fusions, ESR was associated with decreased MME (β= -7.94, p<0.001), LOS (β = -10.54, p < 0.001), and READMIT (OR = 0.91, 95% CI: 0.84-0.98).

CONCLUSIONS:

This national healthcare system analysis of 51,236 TL fusion cases by 1,352 surgeons at 138 centers confirms that ESR adoption is associated with decreased MME, LOS, and READMIT. Surgeons should consider adoption of ESR programs to improve patient care.
437 Percutaneous Juxtapedicular Cement Salvage of Failed Pedicle Screws: A Cadaveric Biomechanical Study
Authors: Kurland David B. , Lendhey Matin , Delavari Nader , Winfield Jalen , Mahoney Jonathan , Bucklen Brandon , Frempong-Boadu Anthony
Published: March 2023

INTRODUCTION:

Posterior spinal fixation with pedicle screw-based constructs is the gold standard for stabilizing the thoracolumbar spine; however, these constructs sometimes fail due to fatigue loading, necessitating revision surgery. A common hardware revision strategy involves open surgery for screw upsizing, with or without cement augmentation, and extension of fusion. Others have described good clinical outcomes following percutaneous juxtapedicular cement salvage of failing pedicle screws. The relative biomechanical properties of these various approaches has not been evaluated.

METHODS:

Thirty-two fresh, un-embalmed vertebrae from four cadaveric thoracolumbar spines were used for the study. The study was conducted in two phases. The first phase involved primary pedicle screw insertions and pullout strength testing to model critical pedicle screw failure. The second phase involved revision of failed pedicle screws followed by pullout testing. The four revision cohorts were: 1) Screw Upsizing, 2) Vertebroplasty (cement augmentation with replacement of primary screw), 3) Fenestrated Screws with cement augmentation, and 4) Juxtapedicular Cement Salvage.

RESULTS:

There was no statistically significant difference in primary fixation strength between the cohorts. The Screw Upsizing cohort exhibited inferior pullout strength compared to the other groups which involved cement augmentation. There was no significant difference in pullout strength between Vertebroplasty, Fenestrated Screws, or Juxtapedicular Cement Salvage cohorts.

CONCLUSIONS:

Cement augmentation confers superior pullout strength compared to screw upsizing only. The key finding of this study is that the technique of percutaneous juxtapedicular cement salvage is biomechanically non-inferior to other revision strategies that require an open procedure to perform.
438 Benefits of Short- Versus Long-segment Fixation for the Treatment of Thoracolumbar Chance Fractures: A Comparison of Perioperative and Radiological Outcomes
Authors: Vaca Silvia , Carmichael Marc , Miao Jingya , Singh Harminder
Published: March 2023

INTRODUCTION:

Discussion continues regarding optimal surgical management of thoracolumbar fractures. Some have indicated long-segment posterior fixation (LSPF) is favorable when evaluating implant stability, kyphotic deformity, and pain. However, most studies either included multiple fracture subtypes or focused on burst fractures. Short-segment fixation (SSPF) may be similarly effective for a subset of patients while minimizing surgical time and length of stay (LOS). This study reviews inpatient and follow-up outcomes of chance fractures managed with SSPF versus LSPF.

METHODS:

Retrospective review of 50 consecutive patients with thoracolumbar distraction injuries (AO B1 and B2) at a single center over a five-year period. Patients underwent pedicle fixation one level (SSPF) or two to three levels (LSPF) above and below the fracture. Patient demographics, preoperative characteristics, and perioperative outcomes were compared between groups. Radiological outcomes were assessed by measuring Cobb angles immediately postoperatively and up to 12 months postoperatively.

RESULTS:

There was a 31% reduction in mean surgical time for SSPF patients vs LSPF (134 vs 195 minutes, independent samples t test, p = 0.037) without a significant difference in ICU LOS (4.6 vs 4.8 days, independent samples t test, p = 0.947), hospital LOS (15 vs 14 days, independent samples t test, p = 0.865) or complication rates (2 of 35 vs 2 of 15 patients, Fisher’s Exact, p = 0.574). Longitudinal assessment of kyphosis by measuring Cobb angles immediately postoperatively and 2 - 4, 6, 8 - 12, and > 12 months postoperatively showed no significant differences in radiological outcomes between groups. There was a trend toward an increased likelihood of discharge to home (Likelihood ratio = 5.299, ꭓ2 test, p = 0.032) with SSPF.

CONCLUSIONS:

SSPF is non-inferior to LSPF for thoracolumbar chance fractures while offering reduced surgery time. Our results additionally suggest SSPF may offer increased likelihood of discharge home.
441 The Role of Preoperative MRI Imaging in Assessing Neurovascular Compression Prior to Microvascular Decompression in Trigeminal Neuralgia
Authors: Xu Risheng , Nair Sumil , Raj Divyaansh , Materi Joshua , Gujar Sachin , Huang Judy , Blitz Ari M. , Lim Michael , Sair Haris , Bettegowda Chetan
Published: March 2023

INTRODUCTION:

Preoperative MRI is a standard component of the preoperative clinical workup for patients prior to microvascular decompression (MVD). However, its ability to accurately exclude neurovascular compression of the trigeminal nerve is not well understood.

METHODS:

We retrospectively reviewed 1020 patients with available preoperative MRI data prior to microvascular decompression. General patient demographics and clinical characteristics were collected for each case. We recorded both evidence of neurovascular conflict on preoperative MRI radiology notes and intraoperative compression from operative notes. Sensitivity, specificity, positive predictive value, and negative predictive value was determined for general MRI, high-resolution MRI, and non-high resolution.

RESULTS:

Overall, preoperative MRI prior to MVD demonstrated a sensitivity of 75.8%, specificity of 65.8%, positive predictive value of 92.4%, and negative predictive value of 33.3% in predicting neurovascular compression of the trigeminal nerve. In particular, MRI was unable to identify 21.0% cases of sole arterial compression, 42.5% cases of sole venous compression, and combined arterial and venous compression in 18.5% of cases. 958 (93.9%) patients underwent high-resolution preoperative MRI with skull base sequences. This exhibited a sensitivity of 75.6%, specificity of 66.9%, positive predictive value of 92.5% and a negative predictive value of 33.4% in predicting trigeminal nerve neurovascular compression. Finally, non-high resolution MRI showed a sensitivity of 78.8%, specificity of 50.0%, positive predictive value of 89.1%, and negative predictive value of 31.3%. Importantly, the negative predictive values of general, high resolution, and non-high resolution MRIs were all below 50%.

CONCLUSIONS:

Preoperative MRI may offer a high predictive value for neurovascular conflict and should be part of the standard preoperative care workup for trigeminal neuralgia patients. However, lack of neurovascular conflict on preoperative imaging is not sufficient to exclude patients from undergoing MVD.
443 Bilateral Facial Pain With Simultaneous Onset in Trigeminal Neuralgia
Authors: Materi Joshua , Xu Risheng , Nair Sumil , Wang Dorothy , Kalluri Anita , Raj Divyaansh , Xia Yuanxuan , Huang Judy , Lim Michael , Bettegowda Chetan
Published: March 2023

INTRODUCTION:

Bilateral TN (BTN) represents a non-negligible disease burden. BTN is often sequential in nature, meaning pain develops on one side before developing on the contralateral side. The few cases of simultaneous onset BTN are often indiscriminately considered or not specified from sequential onset BTN cases.

METHODS:

A retrospective analysis was conducted to identify patients with simultaneous onset of bilateral TN. Demographic characteristics and comorbidities were assessed. Treatment plans and modalities were recorded, and procedural outcomes and treatment durability was assessed by determining median time pain recurrence in patients with at least 30 days of follow-up. Pharmacotherapy treatment and Barrow Neurological Institute pain intensity scores were compared at last follow-up with index treatment.

RESULTS:

Between 1996 and 2021, 17 out of 1723 patients with trigeminal neuralgia presented with simultaneous onset of bilateral trigeminal orofacial pain which underwent bilateral surgical intervention. Patients were followed for 3 to 148 months, during which 63 procedures were performed: 20 glycerin rhizotomies, 25 glycerin-radiofrequency rhizotomies, and 18 microvascular decompressions. 16 of 17 patients experienced pain recurrence after undergoing treatment: 12 with bilateral pain and 4 with unilateral recurrence. Glycerin-radiofrequency rhizotomy provided the greatest recurrence free interval (median = 15.4 months) compared to glycerin rhizotomy (median = 0.9 months; p = 0.02) and microvascular decompression (median = 7.8 months; p = 0.25). Over the course of treatment, the number of pharmacotherapy agents increased from 2 to 3 (p = 0.05). Overall facial pain scores improved from a median of 6 to 4 bilaterally.

CONCLUSIONS:

Patients with simultaneous bilateral trigeminal neuralgia represent a rare disease population who tend to have early pain recurrence after surgical treatment. Nevertheless, many experience overall pain improvement with re-treatment.
451 Posterior Cingulate Theta Power as a Novel Biomarker of Mood
Authors: Hacker Carl , Brunner Peter , Willie Jon Timothy , Leuthardt Eric C.
Published: March 2023

INTRODUCTION:

One third of patients with major depressive disorder (MDD) are refractory to standard therapies. Progress in therapeutic neuromodulation for depression has been challenging because of the widespread, network basis of mood and lack of neurophysiologic biomarkers. Neuroimaging studies of depression demonstrate increased connectivity within the default mode network (DMN), which subserves internal processes such as self-reflection, mind wandering, and memory. Invasive electrophysiology in the resting state has demonstrated that DMN connectivity corresponds to correlations in theta-band power. DMN activity is anti-correlated with the dorsal attention network (DAN) which, in contrast, subserves externally oriented cognition (i.e., top-down attention), and demonstrates alpha-specific resting-state correlations.

METHODS:

We used hourly, self-reported measures of mood and video facial affect recognition to estimate mood valence in six epilepsy patients undergoing invasive stereotactic electroencephalography monitoring. We analyzed power spectra and functional connectivity (band-limited power correlations) in epochs corresponding to mood estimates. Patients without substantial inpatient mood variability (n=3) were excluded.

RESULTS:

Depressed mood was correlated with increased theta power. This was most significant in electrodes within posterior cingulate cortex (DMN region; r = -0.58; p = 0.0007). Conversely, alpha power was increased during elevated mood, most significantly in the intraparietal sulcus (DAN region; r = 0.55, p = 0.0013). Theta connectivity was correlated with depressed mood (r = -0.53, p = 0.003) whereas alpha connectivity was correlated with elevated mood (r = 0.56, p = 0.002).

CONCLUSIONS:

Our results recapitulate the frequency specificity of resting-state physiology and encourage a network-based perspective of depression neurophysiology. Theta and alpha power within DMN and DAN networks, respectively, represent important biomarkers of mood and may guide neuromodulatory therapies. Posterior cingulate/precuneus cortex is a major DMN hub and should be sampled in future studies of neural correlates of mood.
456 CD39 T Cells With Low PD-1 Expression are Markers for Durable Immunotherapy Response to Anti-PD-1 in Murine Glioblastoma
Authors: Choi John , Pant Ayush , Kim Young-Hoon , Routkevitch Denis , Jackson Christopher Mitchell , Jackson Christina , Kim Lily H. , Lim Michael
Published: March 2023

INTRODUCTION:

Clinical trials investigating anti-PD-1 therapy for glioblastoma (GBM) have failed to demonstrate increased overall survival, unlike in other cancers such as non-small cell lung cancer (NSCLC). Despite the immunosuppressive characteristics of GBM, a small subset of patients in these trials have shown durable anti-PD-1 response. Recently, CD39+ T cells have been implicated as infiltrating lymphocytes that, once activated, demonstrate robust anti-tumor activity. Understanding the unique immunosuppressive milieu of GBM including this cell population may help elucidate why some patients show treatment response.

METHODS:

Mice orthotopically implanted with GL261 had blood collection prior to anti-PD-1 exposure with t-SNE mapping of T cells. The molecular profiles of mice with long-term survival were compared with those that did not. Due to a lack of GBM patient samples that have shown immunotherapy response, we examined whether these molecular patterns recapitulated in the blood of NSCLC patients responded to anti-PD-1.

RESULTS:

The blood of long-term survivor mice implanted with GBM demonstrated a significantly greater proportion of CD39+ CD8 T cells with low PD-1 expression (PD-1lo) with subsequent increased representation of this population in the tumor as well (P < 0.05). This CD39+ CD8+ PD-1lo population was also highly represented in the blood of treatment-naÏve NSCLC patients who responded to anti-PD-1 (P < 0.05). Furthermore, once exposed to anti-PD-1 in vivo, this CD39+ CD8+ PD-1lo population showed high immune activity with robust IFN-y expression (P < 0.05).

CONCLUSIONS:

Mice with CD39+ CD8+ PD-1lo T cells are strongly associated with anti-PD-1 response. This has implications for exploring this cell population as a blood biomarker and an active anti-tumor population that may be mobilized with adoptive cell transfer and CAR-T cell strategies.
460 MP-Pt(IV): A Platinum (IV)-Based Prodrug for Treating DIPG With Selective Mitochondrial Chemotherapy
Authors: Baskin David S. , Raghavan Sudhir , Sharpe Martyn , Manalo Jeanne , Bailey Callie A.
Published: March 2023

INTRODUCTION:

Diffuse intrinsic pontine glioma (DIPG) is a universally fatal childhood cancer of the brain. Despite conventional chemotherapy and radiotherapy, improvements in survival have been marginal and long-term survivorship is uncommon. We previously developed MP-Pt(IV), a platinum (IV) based prodrug that is selectively accumulates in GBM mitochondria upon oxidation by the overexpressed enzyme monoamine oxidase B (MAOB), and is then reduced to the chemotherapeutic cisplatin. Expression levels of MAOB in DIPG is high.

METHODS:

In-vitro cell growth inhibition studies were conducted on DIPG cells using MP-Pt(IV). Labeling studies were carried out with Mitosox, Mitotraker, and H2DCF. Oxygen consumption studies were performed to show mitochondrial targeting. Clonogenic survival assay and scratch assay were performed.

RESULTS:

MP-Pt(IV) shows potent growth inhibition of DIPG in cell culture studies. Mechanistic studies indicate mitochondrial targeting of the prodrug. Significant increases in cellular ROS and hydrogen peroxide levels are observed upon MP-Pt(IV) treatment. Oxygen consumption studies confirm mitochondrial targeting of MP-Pt(IV). MP-Pt(IV) strongly inhibits clonogenic survival and cell migration in treated cells.

CONCLUSIONS:

We demonstrate that MP-Pt(IV) is highly effective in DIPG in vitro, and is a good candidate for testing in an in-vivo mouse intracranial DIPG model, and for further development.
461 Intracranial Tumors Hijack the Meningeal Venolymphatic Network Through VEGFR-2 Signaling
Authors: Ampie Leonel , McGavern Dorian
Published: March 2023

INTRODUCTION:

Glioblastoma and other intracranial neoplasms have been associated with breakdown of the blood brain barrier. Other protective CNS barriers have sparsely been studied in brain tumors. Here, we identify the ability of intracranial neoplasms to hijack the meningeal venolymphatic network, which is driven through VEGFR-2/VEGF-A signaling.

METHODS:

C57BL/6J mice were stereotactically injected with syngeneic SB28 (glioblastoma) cell lines. Mice were treated with either isotype control or a VEGFR-2 inhibitor. Two-photon microscopy was used to visualize vascular cytoarchitecture and dynamics in vivo. Meningeal whole mounts, brains and spleens were also collected and analyzed by confocal microscopy and high parameter flow cytometry. Similar experiments were conducted with a PECAM-1 inhibitor to assess the role of endothelial cell crosstalk in venolymphatic expansion. Human dura mater from glioblastoma patients underwent multiplex immunohistochemistry to confirm the translatability of our findings.

RESULTS:

Our imaging studies revealed that glioblastomas can generate an extensive de novo network of meningeal blood vessels and lymphatics both in mice and humans. Lymphatic vessels were often observed developing in parallel to the newly formed vasculature. Intravital two-photon microscopy further revealed that the peritumoral vascular bed in the meninges of mice was leaky, dysfunctional, and generated a hypoxic microenvironment. Importantly, inhibition of VEGFR signaling impeded formation of this faulty venolymphatic network, which slowed tumor growth, reduced peritumoral hypoxia, enhanced immune infiltration, and increased survival. PECAM-1 (CD31) inhibition had a similar effect on the tumor microenvironment, suggesting that endothelial cell crosstalk is required for glioblastomas to optimally invade the meninges.

CONCLUSIONS:

Our results demonstrate that glioblastomas can invade the meninges and hijack the venolymphatic network through VEGFR-2 and PECAM-1 signaling. While VEGFR-2 is associated with angiogenesis, our data suggest that it may also have an important role in regulating the simultaneous development of de novo meningeal venous and lymphatic drainage during glioblastoma.
463 Tandem CAR T Cells Targeting EGFRvIII and IL-13R⍺2 are Effective Against Heterogeneous Glioblastoma
Authors: Schmidts Andrea , Srivastava Ambike , Ramapriyan Rishab , Cahill Daniel P. , Carter Bob S. , Curry William T. , Dunn Gavin P. , Ghannam Jack , Nahed Brian V. , Sun Jing , Wakimoto Hiroaki , Maus Marcela V. , Choi Bryan D.
Published: March 2023

INTRODUCTION:

Chimeric antigen receptor (CAR) T cells have achieved remarkable responses in patients with hematological malignancies; however, the potential of this therapeutic platform for solid tumors like glioblastoma (GBM) has been limited, due in large part to the targeting of single antigens in a heterogenous disease. Strategies that allow CAR T cells to engage multiple antigens concomitantly may broaden therapeutic responses and mitigate the effects of immune escape.

METHODS:

We generated a TanCART construct with dual specificity consisting of both the humanized anti-EGFRvIII scFv and IL-13 zetakine translated in tandem separated by a flexible glycine-serine linker. We also employed two monospecific CAR T cells, CART-EGFRvIII and CART-IL-13Rɑ2 as controls. We used both standard immunological assays and multiple orthotopic preclinical models including patient-derived xenograft to demonstrate efficacy of this approach against heterogenous tumors.

RESULTS:

Tandem CAR T cells displayed enhanced cytotoxicity in vitro against heterogeneous GBM populations, including patient-derived brain tumor cultures (P < 0.05). Compared to CAR T cells targeting single antigens, dual antigen engagement through the tandem construct was necessary to achieve long-term, complete and durable responses in orthotopic murine models of heterogeneous GBM, including patient-derived xenografts (P < 0.05).

CONCLUSIONS:

We demonstrate that TanCART is effective against heterogenous tumors in the brain. To our knowledge, this is the first report of a tandem CAR T cell targeting EGFRvIII and IL-13Rɑ2 simultaneously. These data lend further credence to the development of multi-specific CAR T cells in the treatment of GBM and other cancers.
466 Robust Model of Microglia Replacement With Circulation-Derived Microglia-Like Cells (CDMCs) in CNS Malignancies
Authors: Rodrigues Adrian , Mader Marius , Chernikova Sophia , Li Guan , Wang Yuelong , Wong Sam , Petritsch Claudia , Wernig Marius , Gephart Melanie Hayden
Published: March 2023

INTRODUCTION:

Tumor-associated microglia and macrophages (TAMs) represent a main cell type of brain malignancies and demonstrate complex interactions with cancerous cells and the tumor microenvironment. These interactions have important implications for the progression and treatment of malignant central nervous system (CNS) tumors. TAMs have therefore emerged as therapeutic targets, though their potential to date has been unfulfilled.

METHODS:

C57BL/6 mice were preconditioned for BMT with retroorbital busulfan injections (25 mg/kg), and native microglia were depleted via PLX5622 (1200 mg/kg, chow). Following transplantation, animals underwent intracranial stereotactic injection of syngeneic cell lines of either high-grade glioma (GL261) or breast cancer metastasis (E0771). Following animal sacrifice, we used single cell RNA sequencing of CD45-positive cells to profile the transcriptomic identity of glioma tumor-associated CDMCs (TA-CDMCs).

RESULTS:

Lineage tracing proved high intra- and peri-tumoral chimerism of BMT-graft derived cells among CNS myeloid cells in both models two weeks after tumor cell injection, demonstrating a robust ability to modify the tumor-immune microenvironment in animal models. TA-CDMCs showed a similarly activated morphology as naÏve TAMs under immunohistochemistry. Pathway enrichment analysis revealed an upregulation of immune response pathways in TA-CDMCs compared to regular TAMs, including the overexpression of genes relevant for the regulation of T cell activation, suggesting possible modification of the glioma immune-environment following CDMC repopulation.

CONCLUSIONS:

The present study offered a robust proof-of-concept that highly efficient TAM replacement could be achieved in orthotopic murine brain tumor models. Additionally, it appears that replaced CDMCs retain unique transcriptional patterns in the tumor-immune microenvironment, with the upregulation of several key immune response pathways. These efforts may represent a novel route of tumor-directed immunotherapy and offer exciting opportunities for ex-vivo CDMC manipulation to specifically target neoplastic cells.
467 Stimulator of Interferon Genes Protein (STING) Agonist Incited Sustained Antitumor Immunity in Murine Models of Glioblastoma
Authors: Huntoon Kristin , Lee DaeYong , Lu Yifei , Jiang Wen , Curran Michael , Kim Betty Y.S.
Published: March 2023

INTRODUCTION:

Introduction: Stimulator of interferon genes (STING) is an innate pattern recognition receptor natively localized to the endoplasmic reticulum that detects both exogenous and endogenous pathogenic or damage-associated cytosolic cyclic dinucleotides (CDNs), activating IRF3 (interferon regulatory factor 3), NF-κB (nuclear factor κB), and STAT6 (signal transducer and activator of transcription 6) signaling pathways to induce a potent type I interferon and proinflammatory cytokine responses. Activation of the STING pathway has been recognized as a critical component of the innate immune sensing of tumors that is required for optimal cytotoxic T-cell priming against tumor antigens. Recently a highly potent cyclic dinucleotide STING agonist, IACS-8803, showed robust activation of the STING pathway resulting in systemic anti-tumor response in the B16 murine model of melanoma. Additionally, the STING agonists have been shown to achieve robust tumor regression at both injected and distal lesions and are reported to facilitate generation of long-lived immunologic memory.

METHODS:

Methods: We established murine gliomas with stereotactic implantation of GL261, a murine glioma cell line. Mice were assessed with luciferase imaging to ensure baseline tumor size and then randomized into treatment arms (IgG, IACS-8803, CD47, PD-1 and combinations thereof). Treatment was initiated one week after the tumor implantation.

RESULTS:

Results: All mice that received IACS-8803 had no detectable luciferase activity. Tumor regression was additionally verified via MR Imaging. Utilization of IACS-8803 led to long-term tumor-free survival (p < 0.01). Re-challenge with GL261 tumors ensured long term memory was sustained with a single dose of agonist.

CONCLUSIONS:

Conclusion: Engaging the STING pathway may be an ideal targeting strategy for GBM. Ongoing studies are delineating the mechanisms of activating this pathway with specific attention being paid to reprogramming and education of innate immunity.
471 Automated Detection and Analysis of Cerebral Aneurysms With the Viz.ai ANX Algorithm
Authors: Colasurdo Marco , Shalev Daphna , Robledo Ariadna , Vasandani Viren , Luna Zean Aaron , Rao Abhijit , Garcia Roberto , Edhayan Gautam , Srinivasan Visish M. , Sheth Sunil , Avni Naama , Bibas Orin , Donner Yoni , Limzider Nicole , Shaltoni Hashem , Kan Peter
Published: March 2023

INTRODUCTION:

Machine learning algorithms have shown groundbreaking results in neuroimaging. We evaluate the performance of a convolutional neural network (CNN) to detect and analyze intracranial aneurysms (IAs) from computed tomography angiography (CTA).

METHODS:

Consecutive patients CTA were identified from a single center between January 2015 and July 2021. The ground truth determination of cerebral aneurysm presence or absence was made by the neuroradiology report. The primary outcome was performance of the CNN at detecting IAs in an external validation set, measured using area-under-the-curve (AUC) receiver-operator curve statistics. Secondary outcomes included accuracy for location and size measurement.

RESULTS:

Among 400 patients with CTA, 150 (37.5%) were male, median age was 39 years (SD 21), and 195 were diagnosed with IAs on neuroradiologist evaluation. Median IAs maximum diameter was 4.6 mm [IQR 2 mm]. In the independent validation imaging dataset, the CNN performed well with 87.6% sensitivity (95%-CI [0.81, 0.92]), 94.0% specificity (95%-CI [0.90, 0.97]) and positive predictive value of 90.9% (95%-CI [0.84, 0.95]) in the subgroup with diameter >=3 mm.

CONCLUSIONS:

The described Viz.ai ANX CNN performed exceptionally well at identifying presence or absence of intracranial aneurysms in an independent validation imaging set.
475 Local Conditional Induction of Brain Arteriovenous Malformations in Alk1-Inducible Knock-Out Mice
Authors: Scherschinski Lea , Han Chul , Winkler Ethan A. , Vajkoczy Peter , Lawton Michael T. , Oh S. Paul
Published: March 2023

INTRODUCTION:

Current mouse models of familial brain arteriovenous malformations (AVMs) have limitations in long-term survival. These drawbacks are mainly attributed to systemic and ubiquitous genetic recombinations with development of AVMs in peripheral organs that result in hemorrhagic conditions.

METHODS:

Transgenic mice with ubiquitous CreER expression were used (ROSA26CreER;Alk1f/f; Alk1-iKO). 4-hydroxytamoxifen (4-OHTM) was stereotactically delivered into the striatum, parietal cortex, or cerebellum of neonatal mice at postnatal day 1. Mice were evaluated for brain AVMs with systemic latex dye perfusion and 3D time-of-flight magnetic resonance angiography.

RESULTS:

Alk1-iKO mice injected stereotactically with 4-OHTM developed brain AVMs with 68% (21/31) frequency in the striatum, 72% (13/18) in the parietal cortex, and 44% (4/9) in the cerebellum. Brain AVMs formed in or near the injection site with 95% accuracy (36/38). A subset of mice (8%, [3/38]) presented with a communicating hydrocephalus from CSF malabsorption. The formation of AVMs in these Alk1-iKO mice was restricted to the brain, without AVMs developing in peripheral organs (n = 38). The hemoglobin levels were not significantly different between mutant and control Alk1-iKO mice after stereotactic, intracerebral 4-OHTM injection (p = 0.27). The 4-week mortality was 5% (2/38). Longitudinally monitored mice demonstrated good survival at 3 months of age (86%, [6/7]).

CONCLUSIONS:

We present the first experimental mouse model with local, CreER-mediated induction of brain AVMs. The model is advantageous in generating brain AVMs with high efficiency, along with an improved long-term survival and reduced early lethality of mice. Collectively, these features may serve as a framework to accelerate the ongoing investigations of brain AVM pathogenesis, rupture, and preclinical testing of novel therapeutics.
477 Stereotactic Radiosurgery With Versus Without Prior Onyx Embolization for Brain Arteriovenous Malformations
Authors: Chen Ching-Jen , Ding Dale , Lee Cheng-chia , Kearns Kathryn , Pomeraniec Isaac Jonathan , Cifarelli Christopher Paul , Liscak Roman , May Jaromir , Williams Brian Jeremy , Ironside Natasha , Burke Rebecca M. , Warnick Ronald E. , Trifiletti Daniel M. , Mathieu David , Kondziolka Douglas , Feliciano Caleb E. , Rodriguez-Mercado Rafael , Cockroft Kevin M. , Simon Scott Douglas , Lee John Y.K. , Sheehan Jason P.
Published: March 2023

INTRODUCTION:

Investigations of the combined effects of neoadjuvant Onyx embolization and stereotactic radiosurgery (SRS) on brain arteriovenous malformations (AVM) have not accounted for initial angioarchitectural features prior to neuroendovascular intervention.

METHODS:

The International Radiosurgery Research Foundation AVM databases from 1987–2018 were retrospectively reviewed. Patients were categorized, based on AVM treatment approach, into Onyx embolization and SRS (OE+ SRS) or SRS alone (SRS-only) cohorts and then propensity score-matched in a 1:1 ratio. Primary outcome was AVM obliteration. Secondary outcomes were post-SRS hemorrhage, all-cause mortality, radiologic and symptomatic radiation-induced changes (RIC), and cyst formation. Comparisons were analyzed using crude rates and cumulative probabilities adjusted for competing risk of death.

RESULTS:

The matched OE + SRS and SRS-only cohorts each comprised 53 patients. Crude rates (37.7% vs. 47.2% for OE + SRS vs. SRS-only cohorts, respectively; OR = 0.679, p = 0.327) and cumulative probabilities at 3, 4, 5, and 6 years (33.7%, 44.1%, 57.5%, and 65.7% for OE + SRS cohort vs. 34.8%, 45.5%, 59.0%, and 67.1% for SRS-only cohort, respectively; SHR = 0.961, p = 0.896) of obliteration were similar between the matched cohorts. The secondary outcomes of the matched cohorts were also similar. Asymptomatic and symptomatic embolization-related complication rates in the matched OE + SRS cohort were 18.9% and 9.4%, respectively.

CONCLUSIONS:

Pre-SRS AVM embolization with Onyx does not appear to negatively influence outcomes after SRS. Our analyses, based on de novo nidal characteristics, thereby refute previous studies that found detrimental effects of Onyx embolization on SRS-induced AVM obliteration. However, given the risks incurred by nidal embolization using Onyx, this neoadjuvant intervention should be employed judiciously in multimodal treatment strategies involving SRS for appropriately selected large-volume or angioarchitecturally high-risk AVMs.
478 Microsurgical Outcome of Unruptured Middle Cerebral Artery Aneurysms
Authors: Krisht Ali F. , Pravdenkova Svetlana , Cai Li
Published: March 2023

INTRODUCTION:

Recently introduced endovascular techniques for treating middle cerebral aneurysms (MCA) has to achieve results superior to surgical outcomes before it becomes the established treatment modality. We present our surgical outcomes in 403 unruptured aneurysms.

METHODS:

Data of 403 MCAs were prospectively collected and retrospectively analyzed. Modified pterional approach with linear dural opening over the Sylvian fissure (Limited brain exposure) was used. Outcome evaluated with Modified Rankin scale (mRS at DC and one year.

RESULTS:

403 unruptured MCA aneurysms were clipped in 354 pts. 48 aneurysms (42 pts) had a ruptured aneurysm of different location and were excluded from analysis leaving 355 aneurysms in 312 patients. M/F ratio-1/2.9 Average age-59.34+ 12.22 and median age-60.109 pts had clipping of single MCA aneurysm during surgery and 203 had multiple aneurysms. Location: MCA bifurcation = 227 (64%), M1 = 101 (28%), M2 = 27 (8%) MCA. Size: Giant = 3 (1%); Large = 32 (9%); Medium = 85 (24%); Small = 235(66%), Outcome- MRs 0-2 at DC = 90%. MRs 0-2 at 3mo-1 year = 98.5%; Mortality = 0.64 % (1- sepsis, comfort care; 1- Massive heart attack); Residual = 0.84% (3/355); Ischemic event - 0.96% (3/312)

CONCLUSIONS:

Recently introduced endovascular techniques for treating middle cerebral aneurysms (MCA) cannot be pushed to become an established modality before at least it matches the present excellent results achieved with microsurgery. Maybe the future should focus on the high level microsurgery.