bluuebunny/crossref_metadata_2025 huggingface dataset:
368 Intravenous Lidocaine for Analgesia in Spine Surgery: A Meta-Analysis of Randomized Controlled Trials
Authors: Musa Arif , Haratian Aryan , Field Ryan , Farhan Saif , Bennett Collin , Rajalingam Karan , Cooke Christopher , Patel Rakesh , Aleem Ilyas , Eichler Martin , Lee Carlin , Bederman S. Samuel
Published: March 2022

INTRODUCTION:

Spine surgeons face numerous challenges when managing postoperative pain. Although opioid-based management remains the gold standard for the treatment of postoperative pain, opioid consumption is associated with respiratory depression, sedation, pruritus, ileus, nausea, vomiting, and other complications. Lidocaine, a commonly used local anesthetic, also has documented anti-inflammatory, analgesic, and anti-emetic properties. However, its potential as an adjunctive analgesic to minimize reliance on opioid-based therapy remains controversial.

METHODS:

We conducted a meta-analysis of randomized controlled trials (RCTs) comparing adjunctive intravenous lidocaine to placebo control for pain management after spine surgery. The following databases were searched: PubMed, Clinicaltrials.gov, Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, Clarivate Analytics Web of Science, and World Health Organization International Clinical Trial Register Platform. Postoperative morphine equivalent consumption was compared using standardized mean difference (SMD) and 95% confidence interval (CI). Complications such as nausea, vomiting, pneumonia, delirium, and wound infection were compared using odds ratios (OR) and 95% CI. A p-value < 0.05 was considered statistically significant.

RESULTS:

A total of three RCTs were included in quantitative synthesis, comprising 235 patients. Cumulative morphine equivalent consumption was not significantly different between lidocaine and control groups (SMD = -1.69, 95% CI: -3.65 to 0.27, p = 0.09) at 48 hours postoperatively. There was no statistical significance between groups in terms of the following adverse events: nausea (OR = 1.40, 95% CI: 0.73 to 2.71, p = 0.31), vomiting (OR = 1.59, 95% CI: 0.76 to 3.34, p = 0.22), pneumonia (OR = 0.31, 95% CI: 0.76 to 3.34, p = 0.48), delirium (OR = 3.00, 95% CI: 0.12 to 76.24, p = 0.51), or surgical site infection (OR = 3.05, 95% CI: 0.12 to 76.54, p = 0.50).

CONCLUSION:

There was no significant difference between the average cumulative morphine equivalent consumption of patients in the lidocaine and control groups at 48 hours after surgery. The addition of lidocaine did not significantly increase the rates of postoperative complications such as nausea, vomiting, pneumonia, delirium, or surgical site infections.
400 Safety and Efficacy of the Off-label Use of Pipeline Embolization Device Based on the 2018 FDA Approved Indications for Intracranial Aneurysms: A Single Center Retrospective Cohort Study
Authors: Enriquez-Marulanda Alejandro , Penumaka Anirudh , Ogilvy Christopher S. , Thomas Ajith J. , Moore Justin M.
Published: March 2022

INTRODUCTION:

The Pipeline embolization device (PED) has proven to be safe and effective for treating selected intracranial aneurysms. The versatility and the popularity of this device have driven increased interest in expanding the latest 2018 FDA-approved indications.

METHODS:

Retrospective analysis of aneurysms treated with PED at a single center from 2013-2019 was performed. Comparisons were made based on the compliance to the 2018 FDA-approved indications. Univariate comparisons and longitudinal analysis were performed.

RESULTS:

A total of 492 treated aneurysms were included, from which 65.2% were considered on-label and 34.8% off-label. Aneurysm complete and near-complete occlusion rate was non-significantly lower in the off-label group (80.9% vs 85.7%; p=0.19). Off-label treatment had higher rate of poor functional outcomes defined as modified Rankin scale > 2 (10.3% vs 3.5%; p=0.002). Although baseline pre-treatment mRS was already higher in the off-label group (10.3% vs 3.5%; p<0.001). There were no differences in retreatment, thromboembolic complications, intracranial hemorrhagic complications, and mortality rates.

CONCLUSION:

Off-label treatment with PED may be considered for select aneurysms, which are challenging to treat with other techniques (clipping, coiling, etc.). These cases have similar complete and near-complete occlusion rates compared to on-label cases. There are, however, potential higher risks of poor functional outcomes.
403 Saccular Aneurysms in the Post–Barrow Ruptured Aneurysm Trial Era
Authors: Catapano Joshua , Labib Mohamed , Srinivasan Visish M. , Nguyen Candice , Rumalla Kavelin , Rahmani Redi , Cole Tyler S. , Baranoski Jacob F. , Rutledge Caleb , Chapple Kristina , Ducruet Andrew F. , Albuquerque Felipe , Zabramski Joseph M. , Lawton Michael T.
Published: March 2022

INTRODUCTION:

The Barrow Ruptured Aneurysm Trial (BRAT) was a single-center trial that compared endovascular coiling to microsurgical clipping in patients treated for aneurysmal subarachnoid hemorrhage (aSAH). However, because patients in the BRAT were treated more than 15 years ago, and because there have been advances since then—particularly in endovascular techniques—the relevance of the BRAT remains controversial.

METHODS:

All patients with a confirmed saccular aSAH treated at a single quaternary center from August 1, 2007, to July 31, 2019, were retrospectively reviewed. Patients were separated into two groups for analyses: microsurgery or endovascular intervention. The primary outcome analyzed for comparison was a poor neurological outcome, defined as a modified Rankin Scale (mRS) score >2. The secondary outcomes that were compared included retreatment rates for both therapies.

RESULTS:

Of the 1014 patients with aSAH during the study period, 798 (79%) were confirmed to have saccular aneurysms. Neurologic outcomes at =1-year follow-up did not differ between patients treated with microsurgery and those who received endovascular treatment (P=0.51). The number of retreatments was significantly higher among patients treated endovascularly (32/347, 9%) than among patients treated microsurgically (6/451, 1%) (P<0.001). The retreatment rate after endovascular treatment was lower in the PBRAT (9%) than in the BRAT (18%).

CONCLUSION:

Similar to results from the BRAT, results from the PBRAT era showed equivalent neurologic outcomes and increased rates of retreatment among patients undergoing endovascular embolization compared with microsurgery. However, the rate of retreatment after endovascular intervention was much lower in the PBRAT than in the BRAT.
411 Treatment Results of Arteriovenous Fistulas at the Craniocervical Junction: A Multicenter Cohort Study of 108 Patients
Authors: Endo Toshiki , Takai Keisuke , Inoue Tomoo , Seki Toshitaka
Published: March 2022

INTRODUCTION:

No standard treatment has been established for the arteriovenous fistulas (AVFs) at the craniocervical junction (CCJ).

METHODS:

A total of 103 consecutive patients with the CCJ AVFs were collected from 29 centers that are members of Neurospinal society of Japan. Angiographic findings and the clinical characteristics of the CCJ AVFs were evaluated.

RESULTS:

Among 103 cases, dural AVF (59 cases), radicular AVF (12 cases), epidural AVF (16 cases), and perimedullary AVF (5 cases) were included. There were 11 cases in which combinations of the pathologies occurred in one case. 51 and 7 patients presented with subarachnoid hemorrhage (SAH) and intramedullary hemorrhage, respectively. 28 cases presented with congestive myelopathy, while there were 17 asymptomatic cases. Overall, 78 cases (76%) and 19 cases (18 %) underwent primary surgical or endovascular treatments, respectively. 4 cases (4%) underwent combined treatments. 14 cases (14%) required second treatments. The rate of initial treatment failure or recurrence was 2.6% after the surgical treatments (Surgery Group), while it was 63% of the endovascular treatment group (Endovascular Group). In multivariate analysis, endovascular treatment was the independent risk factor with significantly higher odds of initial treatment failure or recurrence (odds ratio [OR], 59; 95% confidence interval [CI], 11-324). Treatments related complications occurred in 28 cases (27 %). The rates of complications were 21% in the Surgery Group. While, it was 42% in the Endovascular Group. Complications included medulla/spinal/cerebellar infarction (12 cases), the cerebrospinal fluid leak (3 cases), and postoperative hematomas (3 cases).Post-operatively, an improvement of 1 or more in modified Rankin Scale (mRS), was observed in 60% and 37% of Surgery and Endovascular Groups, respectively with a median follow-up of 23.0 months.

CONCLUSION:

Based on the largest and latest multicenter cohort, this study showed that primary microsurgery was superior to endovascular treatment to achieve complete obliteration of the CCJ AVF in a single procedure.
413 ABO Blood Type and Thromboembolic Complications After Intracerebral Hemorrhage
Authors: Ironside Natasha , Chen Ching-Jen , Connolly E. Sander , Roh David
Published: March 2022

INTRODUCTION:

Thromboembolic complications (TECs) are preventable causes of morbidity and mortality in patients with intracerebral hemorrhage (ICH).

METHODS:

Consecutive adult ICH patients enrolled in the Intracerebral Hemorrhage Outcomes Project with available ABO blood type data were included. The primary analysis dichotomized patients by O blood type status (O versus non-O cohorts). The primary outcome was TEC, comprising pulmonary embolism, deep venous thrombosis, ischemic stroke, and myocardial infarction, during the hospital stay. Outcomes were compared between cohorts using multivariable regression and propensity score-matched analyses. A secondary analysis compared outcomes between individual non-type O (i.e., A, B, and AB) and type O blood phenotypes.

RESULTS:

Type O and non-type O cohorts comprised 269 and 244 patients, respectively. TECs were more common in the type O cohort compared to non-type O cohort (15.2% vs. 9.4%; OR = 1.728 [1.004-2.974], p = 0.048). In the propensity score-matched analysis, comprising 126 patients in each cohort, TEC rates were comparable between the two matched cohorts (13.5% vs. 11.1%; OR = 1.248 [0.586-2.654], p = 0.566). TEC rates were also comparable between individual non-type O and type O blood phenotypes in the secondary analysis. Type A blood phenotype was associated with a lower modified Rankin Scale score at 90 days in shift analysis (OR = 0.654 [0.434-0.985], p = 0.042).

CONCLUSION:

ABO blood phenotype does not appear to be associated with TECs after spontaneous ICH. Type A blood phenotype may be associated with a better 90-day functional outcomes after ICH. A multicenter, multiethnic ICH study capturing genetic and molecular patient data may help elucidate the potential role of blood phenotype in ICH pathophysiology.
416 Low Allele Frequency Somatic Variants in Sporadic Saccular “Berry” Cerebral Aneurysms
Authors: McAvoy Malia , Karasozen Yigit , Parada Carolina , Busald Tina , Osbun Joshua W. , Ruzevick Jacob J. , Emerson Samuel , Nistal Dominic A. , Tyrtova Evgeniya , Eaton Jessica C. , Swaminathan Shreya , Levitt Michael R. , Gonzalez-Cuyar Luis , Hale Christopher , Byers Peter , Kim Louis J. , Dorschner Michael , Ferreira Manuel
Published: March 2022

INTRODUCTION:

The pathogenesis of intracranial aneurysms (IAs) is complex, with both genetic and environmental risk factors. Much effort has been devoted to identifying the molecular mechanisms of IAs to develop new therapies halting the progression of IAs.

METHODS:

Deep whole exome sequencing was performed for 11 anterior circulation, sporadic saccular IAs from 10 unrelated patients. Paired aneurysm-peripheral blood DNA samples were compared to evaluate the somatic saccular aneurysm exome alterations. Variants were validated with deep next generation sequencing methods. The genetic landscape of a validation cohort of 60 aneurysms was analyzed by targeted deep sequencing of a vascular panel of genes.

RESULTS:

Whole exome sequencing revealed somatic variants in 7 of 11 saccular aneurysms. Most coding somatic variants found were missense (68%). Somatic variants in multiple genes were common, all falling into similar allele frequencies (3-18%). Two aneurysms from one patient underwent exome sequencing with differing alterations (Acom with no alterations and MCA with 20 variants with about 8% allele frequencies). Targeted sequencing validation of these in a larger cohort revealed alterations in similar allele fractions. Saccular aneurysms harbored variants in genes falling into several functional categories including angiogenesis (PKD1), DNA repair (SFB3, DCC, MLH1), ECM (COL4A5, MMP8) and cancer genes (ERBb4 and PTCH1). Double variants, predicted to be protein/function altering were found in the following genes: DCC, ATXN1L, CCDC178, GAD2, IARS2, ERBb4, COL4A5, FAM122C, ANK2, SF3B3, ADCY7, ABCB4 and RAB11FIP1.

CONCLUSION:

Anterior circulation saccular IAs harbor somatic low allele fraction variants in coding genes predicted to alter protein function. Allele fractions occurred in a similar range within and between samples suggesting a cell-based population driving the pathogenesis of saccular IAs. Recurrent variants in genes known to be involved in IAs (PKD1 and COL4A5) and novel genes (ERBb4 and FAM122C) are new frontiers for further research.
459 Association Between Vitamin D Deficiency and Surgical Site Infection Following Elective Lumbar Fusions
Authors: Planchard Ryan F. , Alomari Safwan , Azad Tej D. , Feghali James , Sciubba Daniel M. , Witham Timothy F. , Theodore Nicholas , Bydon Ali
Published: March 2022

INTRODUCTION:

Vitamin D deficiency has been associated with higher rates of SSI following a variety of surgical procedures. However, this association has been under-investigated for spinal procedures.

METHODS:

Patients who underwent lumbar fusions between 2011-2014 were reviewed from the HCUP-NIS database. Propensity score matching was utilized to minimize the effect of confounding variables between the 2 groups (normal vitamin D vs vitamin D deficiency).

RESULTS:

A total of 238,875 cases of lumbar fusions met inclusion criteria for analysis. These included posterior/transforaminal lateral interbody fusions (PLIF/TLIF), Anterior lumbar interbody fusion (ALIF) and lateral lumbar interbody fusion (LLIF). 22,454 (9.4%) patients carried the diagnosis of vitamin D deficiency and were significantly more likely to be non-white (26.5% vs. 19.9%) and obese (21.1% vs. 15.4%) as compared to patients without deficiency. Other patient characteristics, socioeconomic factors, and hospital setting were comparable between two groups. SSI rates were compared between matched cohorts (18,350 patients in each). In patients without vitamin D deficiency, there were 202 (1.1%) cases of SSI recorded, while there were 1266 (6.9%) cases of SSI recorded in patients with vitamin D deficiency (P<0.001). Patients with vitamin D deficiency had higher incidence of thromboembolic events (2.6% vs. 0.3%), length of hospital stay (5.7 vs. 3.4 days) as well as increased hospital charges (87,812$ vs. 79,650), (P <0.05).

CONCLUSION:

Optimizing preoperative vitamin D level could be potentially a cost-effective strategy to reduce the rate of SSI, thromboembolic events and prolonged hospital stay in patients undergoing lumbar fusion. Further cost-effectiveness analyses are encouraged to make definitive claims regarding pre-operative vitamin D screening/supplementation in these patients.
465 Analysis of Female Authorship Trends in Neurosurgery Over a 10-year period: 2010–2020
Authors: Shah Darsh , Kohli Vikraant , Shah Aayush , Surapaneni Akhil , Tyler-Kabara Elizabeth C. , Kuo John S.
Published: March 2022

INTRODUCTION:

While women had greater representation in medicine in recent years, neurosurgery continues to rank towards the bottom when it comes to the proportion of women occupying a residency position in the US. Many have inferred a gender gap in the authorship of neurosurgical literature. To our knowledge, no study has analyzed changes in the representation of women among first and principal (last) authors in neurosurgery over a consecutive period.

METHODS:

Using the PUBMED search engine, all articles published from January 1st, 2010, to December 31st, 2020 in 10 prominent general and subspecialty neurosurgery journals were examined. Author gender was inferred using a verified online gender determination tool.

RESULTS:

Among the 49,023 neurosurgery articles analyzed from 2010 to 2020, 8,845 were published by a female first author, while 40,178 were published by a male first author (18.0% vs. 82.0%). Moreover, among articles with at least two authors, 5,542 were published by a female principal author, while 39,682 were published by a male principal author (12.3% vs. 87.7%). The top three publishers in terms of the proportion of female authorship (first or last author) were all subspecialty journals. Over this 10-year period, the proportion of female first authorship increased at a greater rate than female principal authorship. The rate of increase in female first authorship was greater among general neurosurgery literature compared to subspeciality neurosurgery literature. Using binomial logistic regression, articles with a female principal author were 1.72 times more likely to have a female first author than those with a male last author.

CONCLUSION:

In the past decade, woman representation in original neurosurgery literature has varied by time, subspecialty, and principal authorship gender. A gradual rise in woman authorship highlights incremental progress in gender diversity and the need for expanded efforts to achieve equity in neurosurgery research.
470 Blood-based Brain and Global Biomarker Changes Following Combined Hypoxemia and Hemorrhagic Shock in a Rat Model of Penetrating Ballistic-Like Brain Injury
Authors: Pierre Kevin , Li Xue , Yang Zhihui , Nugyen Lynn , Johnson Gabrielle , Venetucci Juliana , Torres Isabel , Lucke-Wold Brandon , Shi Yuan , Boutte Angela , Shear Deborah , Leung Lai Yee , Wang Kevin
Published: March 2022

INTRODUCTION:

Penetrating traumatic brain injury (pTBI) often occurs with systemic insults like hemorrhagic (HS) and hypoxemic (HX) shock.

METHODS:

30 rats were randomly assigned to sham, PBBI, HS+HX, and PBBI+HS+HX groups. PBBI and sham groups underwent craniotomy with and without probe insertion and balloon expansion, respectively. HX and HS was then simulated by blood withdrawal and FiO2 reduction. Biomarker serum concentrations were determined at one (D1) and two (D2) days post-injury with ELISA methods.

RESULTS:

Axonal injury-linked biomarkers pNF-H and NF-L serum levels in PBBI groups were higher than those in sham and HX + HS groups at D1 and D2 post-injury. The same was true for PBBI + HX + HS compared to sham (D2 only for pNF-H) and HX + HS groups. However, pNF-H and NF-L levels in PBBI + HX + HS were not different than their PBBI counterparts. At D1, αII-spectrin levels in the HX + HS and PBBI + HS + HX groups were higher than the sham groups. αII-spectrin levels in the HX + HS group were higher than the PBBI group. This suggests HX + HS as the common insult driving αII-spectrin elevations.

CONCLUSION:

pNF-H and NF-L may serve as specific serum biomarkers of penetrating TBI in the presence or absence of systemic insults. αII-spectrin may be a sensitive acute biomarker in detecting systemic insults occurring alone or with pTBI.
478 Long-term Outcomes of Patients with Complications from Multi-modal Monitoring in Severe Traumatic Brain Injury
Authors: Pease Matthew , Nwachuku Enyinna , Goldschmidt Ezequiel , Jacobs Rachel , Elmer Jonathan , Okonkwo David O.
Published: March 2022

INTRODUCTION:

Insertion of an external ventricular drain or intracranial pressure monitor is one of the most commonly performed neurosurgical procedures. Multi-modal invasive neuromonitoring (IN) is a mainstay of modern management of severe traumatic brain injury (TBI). Complication rates of IN placement are widely reported, but their effects on long-term outcomes following severe TBI are less studied.

METHODS:

We evaluated 599 patients with a severe TBI from November 2002 through December 2018 for IN-associated hemorrhage and infection. Trained neuropsychologists assessed outcomes at 3, 6, 12, and 24 months using the Glasgow Outcome Scale (GOS). We compared GOS between patients with and without IN-associated complications.

RESULTS:

IN-associated hemorrhage occurred in 62 patients out of 535 with post-placement CT scans (12%). Craniotomy was associated with increased risk for hemorrhage after monitor placement (53% vs 28%, p<0.001). Clinical outcomes did not differ in patients with IN-associated hemorrhage compared to those without. IN-associated infection occurred in 34 (7%) of 519 patients with post-IN placement cerebrospinal fluid cultures. Infection was associated with worse outcomes at 3 months (p=0.03), where the proportion of patients with favorable outcomes (p = 0.02) was decreased despite similar mortality (p = 0.24). Patients with an IN-related infection recovered by 6 months, at which point there were no differences in total GOS score or rates of favorable outcomes then or at later time points (p > 0.26). Patients with IN-associated infection trended towards improved outcomes over time with no patients with a GOS 3 or higher at 3 months falling below GOS 3 at a later point. IN-associated infection was associated with increased length of stay (p=0.01), but did not affect rates of shunting (p=0.99).

CONCLUSION:

Complications of IN in severe TBI are associated with delayed recovery but not long-term outcomes.
487 The Human Anti-Ganglioside GM1 Autoantibody Response Following Traumatic and Surgical Central Nervous System Insults
Authors: Roukerd Maryam R. , Schneider Lonnie , Hawryluk Gregory W. J. , Faulkner Jenna , Reichert Ethan , Flis Alexandra , Abou-Al-Shaar Hussam , Rubiano Andres M.
Published: March 2022

INTRODUCTION:

The immune response to central nervous system (CNS) injuries has long been considered a significant contributor to secondary injury following neurotrauma however the autoimmune response to the normal immune-privileged CNS has been insufficiently considered. It has been identified as a possible pathomechanism underlying delayed dementias known to occur after TBI and SCI however the CNS-directed autoantibody response following CNS injury remains poorly understood and the autoimmune response following intra-axial brain surgery is unknown.

METHODS:

Nine serum samples were collected serially from 17 acute severe TBI, 22 acute SCI, and 24 intra-axial brain tumor resection patients for 30 days; 25 healthy subjects served as a control group. An ELISA assay quantitated IgG and IgM autoantibodies to ganglioside GM-1. The maximum autoantibody titers and their correlation with putative predictors such as age, gender, clinical and radiological measurements were investigated.

RESULTS:

Anti-GM1 IgG autoantibody titers were increased following SCI, TBI, and brain tumor resection as compared with baseline values and control patients. By contrast, anti-GM1 IgM autoantibody titers did not significantly change following insult nor show promise as a biomarker. The maximum IgG titers measured in the first 30 days were significantly increased in TBI patients (p<0.01), in SCI patients (p<0.01), and in brain tumor resection patients (p<0.05). The highest IgG titers (or peaks) were most commonly seen at day 14 post-insult in TBI and SCI patients while brain tumor patients did not demonstrate acute increases consistent with a peak. Higher GM1 IgG autoantibodies were associated with more severe insults. The Rotterdam score strongly correlated with increased IgG titers in TBI patients (p<0.05). Age and gender did not correlate with GM1 autoantibody titers in any of the types of insult we studied.

CONCLUSION:

These findings suggest that patients with diverse CNS insults are at risk for CNS-directed autoimmune responses and in particular those with more severe insults. These findings highlight the need to better understand the CNS-directed autoimmune response to insult, its clinical relevance and potential as a therapeutic target.
488 Superiority of Craniotomy Over Supportive Care for Octogenarians and Nonagenarians in Operable Acute Traumatic Subdural Hematoma
Authors: Duehr James , Puccio Ava , Deng Hansen , Hamilton D. Kojo , Okonkwo David O. , Nwachuku Enyinna L.
Published: March 2022

INTRODUCTION:

The neurosurgical evacuation acute subdural hematoma in elderly trauma patients is controversial. We analyzed impact of craniotomy for acute subdural hematoma on survival in patients greater than eighty years of age.

METHODS:

Study population included patients aged 80 years and older who presented with acute traumatic SDHs between September 1, 2015 and January 1, 2020, and had radiographic findings indicating operative eligibility (i.e. midline shift >5mm and/or overall thickness >10mm). 104 patients met inclusion criteria. 35 received craniotomy and 69 were treated with supportive measures due to family/patient wishes or surgeon’s professional decision. Comparative statistics and a Poisson regression adjusted for the influence of covariates were used.

RESULTS:

Of 35 craniotomy patients, 21 (60.00%) were deceased at 2 years of follow-up, compared to 48 (69.57%) deceased out of 69 control patients. No significant demographic differences existed between the two groups, other than age (craniotomy patients were younger; median age 84 vs 86; p < 0.001). In outcomes, the craniotomy cohort survived longer and in higher proportions (p = 0.028; Gehan-Breslow-Wilcoxon test). When adjusting for covariates, this effect became more pronounced: surgical patients died at 41.1% the rate of non-surgical ones. Of all the covariates, only initial GCS had a significant impact on the protective effect of craniotomy. In a logarithmic relationship, each point higher on initial GCS was associated with less benefit from surgery.

CONCLUSION:

The results presented here indicate a surgical benefit for this elderly cohort, consistent with prior findings of benefit in the setting of severe traumatic aSDH. Patients with worse neurologic impairment, i.e. low GCS, had the greatest survival benefit for surgical intervention.
495 5-ALA PDT and Targeting MEK/ERK Signaling Elicits Synergistic Antitumor Effects in Diffuse Midline Glioma
Authors: Price Gabrielle , Rivera Daniel , Bouras Alexandros , Hadjipanayis Constantinos G.
Published: March 2022

INTRODUCTION:

Diffuse midline gliomas are highly invasive, unresectable tumors in children. To date, there is no effective treatment for DMG. Concurrent radiotherapy (RT) and systemic therapies, the standard of care, has only been successful in providing limited disease control. The major obstacle to therapy is the selectively permeable blood brain barrier (BBB) that limits systemic drug delivery. Given the unmet need for penetrant and minimally invasive DMG treatments, photodynamic therapy (PDT), with the precursor photosensitizing agent 5-aminolevulinic acid (5-ALA), is an oncologic treatment that holds promise. 5-ALA PDT of tumors occurs by targeting tumor cells that accumulate the 5-ALA metabolite, protoporphyrin IX (PPIX), with 635 nm light to create deadly reactive oxygen species (ROS).

METHODS:

Growth delay assays were conducted for each individual treatment modality or in combination. FDA-approved MEK/ERK inhibitors were administered to mice with aggressive heterotopic allograft DMGs through intraperitoneal injection. Ex vivo immunofluorescence staining was performed on those mice that received 5-ALA PDT treatment.

RESULTS:

We demonstrated that sub-micromolar levels of 5-ALA PDT and nanomolar levels of MEK inhibitor successfully decrease cell proliferation and induce apoptosis in DMG cell lines. Cell viability assays revealed that drug response differs based on the histone mutation (H3.1 or H3.3) of the line. Mechanisms of decreased cell survival involves the generation of reactive oxygen species that induces programmed cell death. Through the use of a DMG genetically engineered mouse model, we also found 5-ALA PDT to induce apoptosis in vivo.

CONCLUSION:

The synergistic effects of MEK inhibition and 5-ALA PDT in vitro and apoptotic effects of 5-ALA PDT in vivo, highlights the potential therapeutic efficacy of this treatment modality.
498 Assessing Knowledge Silos in the Craniosynostosis Literature
Authors: Motiwala Mustafa , Kumar Rahul , Amro Amro , Himel Sean , Motiwala Ahmed , Kazmi Shehroz , Klimo Paul
Published: March 2022

INTRODUCTION:

The surgical treatment of craniosynostosis has traditionally been a multidisciplinary effort, involving pediatric neurosurgeons and plastic surgeons. Advances in treating this condition may result from collaboration between these two specialties, yet there exists a certain risk of sequestering clinical knowledge between the two which may limit continued progress in this regard.

METHODS:

During September 2020, the Scopus database was queried to identify journal articles related to craniosynostosis. Bibliometric measures were collected for each article, and a database was constructed to assess knowledge sharing between neurosurgeons and plastic surgeons.

RESULTS:

5335 articles were identified. 720 (13.5%) were published in a neurosurgery journal with 499 (9.4%) published by neurosurgeons and 665 (12.5%) by neurosurgeons and plastic surgeons collaborating together. As expected, neurosurgeons published primarily (319, 63.9%) in neurosurgical journals, whereas plastic surgeons published most in plastic surgery journals (990, 65.7%). Collaborations were mostly published in plastic surgery journals (326, 49%). After normalizing for years in press, neurosurgeons were observed to be cited significantly less than plastic surgeons (p <0.0001), and articles published in neurosurgery journals were cited at a lower rate than those published in plastic surgery journals. The differential association of terms used in plastic surgery versus neurosurgery article abstracts illustrates the potential sites of knowledge silo formation in the craniosynostosis literature.

CONCLUSION:

This study demonstrates that a distinct sequestering of knowledge exists between neurosurgeons and plastic surgeons publishing on the topic. Publications by plastic surgeons are more highly cited than by neurosurgeons. While there are certainly specialty-based topics within craniosynostosis, we recommend continued collaboration on all research fronts to avoid sequestration of knowledge and progress.
502 Spy1 as a Novel Cell Cycle Target Against Medulloblastoma
Authors: Habashy Philip , Jassar Samer , Lubanska Dorota , Soliman Mohamed , Porter Lisa
Published: March 2022

INTRODUCTION:

The current treatment strategies for medulloblastoma (MB) are highly aggressive, cytotoxic, and ultimately unsuccessful. One recent therapeutic approach is the use of synthetic cyclin-dependent kinase inhibitors (CKIs). Speedy (Spy1) is a cyclin-like protein that primes its complexes with CDKs insensitive to natural CKIs and promotes uncontrolled cell proliferation by overriding the safety cell cycle checkpoints. Spy1 has been implicated in the expansion of stem-like populations of therapy-resistant tumour initiating cells (TICs) in neural systems.

METHODS:

We established an in vitro neurosphere platform as well as in vivo high-throughput Zebrafish (ZF) xenograft model using ONS-76 and DAOY MB cell lines derived from three patients. Fluorescent Activated Cell Sorting (FACS) was used to enrich for specific CD133+/- or CD15 +/- populations of MB. Spy1 levels were manipulated using lentivirus to obtain overexpression or knockdown of Spy1 protein levels in the derived TICs as well as heterogenous cell populations.

RESULTS:

We found that downregulation of Spy1 levels in the employed cell lines resulted in a decrease in neurospheres formation efficiency as well as significantly lower tumour burden in Zebrafish when compared to control (p<0.001). Spy1 overexpression in CD133 or CD15 negative MB populations resulted in the upregulation of Msi1 mRNA levels. Finally, in vivo treatment of ZF xenografts with R-roscovitine, a synthetic CKI, demonstrated declined migration of Spy1 KD MB cells in comparison to control cells (p<0.05).

CONCLUSION:

This study shows that Spy1 plays a role in the regulation of stemness and aggressive characteristics of TICs in medulloblastoma. The assessed effect on CKI treatment efficacy on the tumours in vivo demonstrated that downregulation of Spy1 may sensitize, at least a subset of MB, to therapy. This work may contribute toward optimizing the design of CKIs and their use in combination therapy for patients with MB.
508 Syngeneic Pair-wise Transcriptomic/Epigenomic Analysis of Sporadic Cushing’s Adenomas and Adjacent Gland Reveals Novel Tumorigenic Pathways
Authors: Asuzu David , Alvarez Reinier , Fletcher Patrick , Mandal Debjani , Chittiboina Prashant
Published: March 2022

INTRODUCTION:

Sporadic pituitary adenomas are found in more than 10% of the general population and are mutationally bland. The normal human pituitary transcriptome is unknown, precluding syngeneic studies on Cushing's disease (CD) pathogenesis.

METHODS:

We surgically annotated adenomas and adjacent normal glands and performed single cell RNAseq (scRNAseq; 10X Genomics Chromium 3’) on 28,724 cells from 6 patients (3 CD and 3 non-CD). We performed bulk RNAseq (Illumina Nextseq) in 7 patients (5 CD and 2 non-CD) and DNA methylation analysis (Illumina Infinium MethylEPIC 850k) in 6 patients (3 CD and 3 non-CD). Transcriptomic/epigenomic data were analyzed using R packages and custom Python pipelines for pairwise differential expression analyses.

RESULTS:

We mapped the post-natal human pituitary gland at single cell resolution and identified canonical resident pituitary cell classes. Corticotrophs were abundant within CD adenomas but rare in the surrounding normal gland, with downregulated POMC expression consistent with repression in the hypercortisolemic state. CD corticotrophs overexpressed signature genes PCSK1, PPP1R17, EGLN, RSPO3 and PMAIP1 compared to surrounding tissues. This gene signature was specific for core adenomas and correlated with anatomic demarcation at the time of surgery. We confirmed overexpression of PCSK1, PPP1R17, RSPO3 and PMAIP1 by independent RNAseq. We identified hypomethylation at the promoters of PMAIP1, PPP1R17 and RSPO3 but not PCSK1 or EGLN1 in CD adenomas.

CONCLUSION:

We mapped the transcriptome of the adult human pituitary gland, identified novel signature genes for CD and highlighted DNA methylation as an epigenetic mechanism of transcriptional activation in a number of Cushing’s adenoma signature genes. We provide novel, targetable mechanistic pathways for therapeutic intervention in Cushing’s disease.
513 Surveilling Cerebrospinal Fluid Protein Biomarkers in Brain Metastasis
Authors: Cheok Stephanie , Arnal-Estape Anna , Wei Wei , Nguyen Don , Chiang Veronica
Published: March 2022

INTRODUCTION:

Cerebrospinal fluid (CSF) is in constant and direct contact with the brain parenchyma, vessels and meninges. The distribution and relative isolation of CSF makes it valuable in the evaluation of central nervous system pathologies. CSF protein profiling has been widely studied in neuro-degenerative and inflammatory diseases. This analysis may also be relevant in patients with brain metastases.

METHODS:

Patients were enrolled between May 2017 and March 2020 under an IRB protocol. CSF and plasma were processed and stored at -80°C. Concentrations of 142 soluble proteins were quantified by Luminex (Eve Technologies).

RESULTS:

Seventy-four patients were included in this study. Of the 60 patients with brain metastases, most had lung cancer (N=29), melanoma (N=10) and breast cancer (N=7). Non-malignant samples included normal pressure hydrocephalus (NPH, N=5), CSF leak (N=9) and radiation necrosis (N=9). Of the 142 soluble proteins profiled, 44 were significantly elevated in patients with LMD compared to intraparenchymal disease. None were more elevated in intraparenchymal disease. This finding was not replicated in the plasma. The CSF profile of patients with LMD and NPH were highly similar.

CONCLUSION:

Soluble CSF proteins are detectable in patients with brain metastases and concentrations differ based on extent of intracranial disease. This difference was not seen in plasma. These findings suggest that patients with LMD have a protein signature, different from those with intraparenchymal brain metastases only, which can help augment current diagnostic standards and reflect the tumor microenvironment. The similarity of LMD and NPH CSF proposes a similar pathogenesis and warrants further exploration. Further analysis of clinical data including survival and treatment response may assist in the management of patients with brain metastases.
517 Metastasis in High-Grade Meningioma: A Systematic Review of Incidence and Risk Factors
Authors: Montgomery Eric , Sundarrajan Chandrasekhar , Pernik Mark N. , Caruso James , Garzon-Muvdi Tomas
Published: March 2022

INTRODUCTION:

Meningioma is the most common primary tumor of the central nervous system and has relatively good outcomes. Rarely, meningiomas metastasize and greatly reduce the likelihood of survival. Due to its infrequency, there is little information available to inform physicians whether a meningioma patient is at-risk for experiencing metastasis.

METHODS:

We searched PubMed, Scopus, Embase, and Ovid for studies with intracranial meningiomas metastasizing to non-CNS locations. Case reports and studies with metastasis to the spinal cord were excluded. Primary tumors were characterized based on location, recurrence, histological grade, patient sex, and overall survival.

RESULTS:

Our database search yielded 1,002 unique articles, of which 5 were included in the final review. The studies yielded a total of 480 patients with high-grade meningioma. Overall, there were 21 patients from this cohort that suffered metastasis of their primary tumor (4.38%). The majority of metastatic patients were female (61.1%), and 18 of the 21 patients experienced recurrence of their primary tumor, along with metastasis (85.7%). Multiple risk factors were individually analyzed by studies, including skull base location, sinus invasion, and molecular characteristics.

CONCLUSION:

Metastatic meningioma is a rare occurrence but greatly reduces the survival of meningioma patients. Due to its infrequent incidence, there is a paucity of literature comparing risk factors for metastasis to guide clinical decision-making. Our study summarizes the current literature available on the overall incidence of metastasis in high-grade meningiomas and highlights multiple risk factors that future studies should characterize to provide a more comprehensive understanding of this rare pathology.
518 Bavituximab Effectively Targets Suppressive Myeloid Cells in Patients with Glioblastoma
Authors: Choi Bryan D. , Richardson Leland G. , Ly K. Ina , Gerstner Elizabeth , Curry William T.
Published: March 2022

INTRODUCTION:

Glioblastoma and tumor endothelial cells express phosphatidylserine, an immunosuppressive membrane phospholipid. Bavituximab – a chimeric monoclonal antibody – competitively binds to the β2-glycoprotein 1-phosphatidylserine complex, resulting in anti-tumor immune activation and anti-angiogenesis. Bavituximab may act in the tumor immune microenvironment (TIME) through myeloid cells.

METHODS:

33 adults with newly diagnosed glioblastoma were enrolled in this phase II trial (NCT03139916). Bavituximab was given weekly, starting week 1 of Stupp. The primary objective was % overall survival at 12 months. We collected peripheral blood mononuclear cells (PBMCs) at enrollment and at regular intervals thereafter. Tumor tissue was banked and analyzed retrospectively. The nCounter Myeloid Innate Immunity Panel, which includes 770 myeloid-associated genes, was used to profile the myeloid transcriptome in both PBMCs and tumor tissue. Multispectral immunofluorescence was used to characterize the intratumoral immune environment.

RESULTS:

In the TIME, bavituximab-treated patients saw a reduction in the number of MDSCs. While the pretreatment RNA profile in PBMCs was not associated with outcome, above-median progression-free and overall survival were associated with significantly enriched expression of myeloid-associated genes in pretreatment tumor tissue.

CONCLUSION:

Bavituximab reduces MDSCs in the glioblastoma microenvironment. Elevated tumor expression of myeloid-associated genes may be a predictive biomarker for response to bavituximab.
810 Aberrant Immune Activation Drives Chronic White Matter Loss After Experimental Traumatic Brain Injury
Authors: Jarrahi Abbas , Braun Molly , Ahluwalia Meenakshi , Ahluwalia Pankaj , Lu Yujiao , Khodadadi Hesam , Salles Evila Lopes , Vaibhav Kumar , Vender John R. , Baban Babak , Vale Fernando L. , Dhandapani Krishnan
Published: March 2022

INTRODUCTION:

Epidemiological studies suggest a single traumatic brain injury (TBI) initiates progressive neurodegeneration, including extensive white matter (WM) injury; yet, the majority of demyelination and WM atrophy occurs in the years following TBI in both rodents and humans. Chronic immune activation correlates with neurological dysfunction after TBI, but the underlying mechanisms remain undefined.

METHODS:

To define the molecular changes associated with focal TBI, unbiased Nanostring arrays were utilized after controlled cortical impact, a pre-clinical model of focal TBI, in adult mice. Immune activation was monitored using flow cytometry and neurodegeneration was assessed at 8 weeks post-TBI, by histology, electron microscopy, and magnetic resonance imaging.

RESULTS:

Genomic profiling revealed acute upregulation of gene classes associated with leukocyte activation, phagocytosis, antigen presentation, lymphocyte activation, and metabolism whereas genes associated with axon/dendrite structure and neural connectivity were downregulated. Infiltrating macrophages, which phagocytosed myelin debris, represented the predominant antigen presenting cells (APCs) within the CNS after TBI. Similarly, a time dependent increase in the number of myelin containing macrophages was observed within cerebrospinal fluid of severe TBI patients. Functionally, APCs stimulated with myelin ex vivo or isolated after TBI increased T-helper (TH) cell proliferation and enhanced pro-inflammatory TH1/TH17 polarization. Myeloid-selective activation of the key metabolic regulator, 5’-adenosine monophosphate-activated protein kinase (AMPK), suppressed myelin reactive T-cells, and reduced neurodegeneration after TBI.

CONCLUSIONS:

The infiltrating myeloid cells after TBI undergo metabolic dysfunction following phagocytosis of myelin debris and orchestrate the generation of myelin autoreactive T-cells resulting in progressive neurodegeneration.
818 Association Between Intraoperative LFP, Lead Location, and Outcomes in Subthalamic Nucleus Deep Brain Stimulation for Parkinson's Disease
Authors: Katlowitz Kalman , Ince Nuri Firat , Tarakad Arjun , Sheth Sameer A. , Viswanathan Ashwin
Published: March 2022

INTRODUCTION:

Imaging-based, LFP-based and empirical programming strategies can be used to determine the optimal therapeutic contact for deep brain stimulation, but the most efficient strategy is unclear.

METHODS:

In this prospective, IRB-approved study, 10 awake patients were implanted with bilateral STN DBS using both an electrophysiologically- and imaged-confirmed technique. Once the DBS lead had been secured, LFP signals were recorded with a Grapevine Neural Amplifier (Ripple Neuro, UT) at 30 KHz and 16-bit A/D resolution, and LFPs were down-sampled to 2 KHz before further processing. Stereotactic CTs acquired two weeks postoperatively were fused to the pre-operative 3T, T2 weighted MRI and processed using the SureTune platform (Medtronic, MN). Therapeutic DBS programming parameters were obtained 6 months post-implantation, along with pre- and post-operative UPDRS Part III scores.

RESULTS:

There was a 54% reduction in the UPDRS score when comparing the preoperative OFF score, to the 6 month postoperative OFF Meds/ON Stimulation Score. 50% of the chosen contacts were in the STN only, 10% in the ZI only, and 35% in both. One lead was found to be outside the segmented STN and ZI; this patient did not experience clinical improvement based on their Part III UPDRS score. Beta (8-30Hz) power was 4.1 times higher for electrodes within the STN versus out, 1.4 times for ZI versus out, and 5.9 times higher for both versus neither. The average beta power was 15% higher in the chosen therapeutic contacts over those contacts not used. Lastly, we found that the number of electrodes within the STN correlated with the decrease in the UPDRS score (r=0.27).

CONCLUSIONS:

There is a strong correlation between image-based electrode localization, LFP characteristics, and clinical outcomes in patients undergoing STN DBS for Parkinson Disease. Focused programming strategies based on either imaging or LFP data can facilitate identification of the optimal therapeutic contact.
819 White Matter Activation Pathways in STN and GPi DBS for Parkinson’s Disease
Authors: DiRisio Aislyn , Avecillas-Chasin Josue Moises , Platt Samantha , Figee Martijn , Jimenez-Shahed Joohi , Mayber,g Helen S. , Choi Ki Sueng , Kopell Brian H.
Published: March 2022

INTRODUCTION:

The subthalamic nucleus (STN) and globus pallidus interna (GPi) are common deep brain stimulation (DBS) targets for Parkinson’s disease (PD). DBS is thought to function by modulating downstream circuits, yet targeting is based on anatomy rather than structural connectivity. While tractography using normative connectomes has been used to study the impact of the hyperdirect pathway, cortical connectivity patterns only account for 20% of the variance in DBS response. Less is known about subcortical and cerebellar connectivity, and patient-specific tractography in DBS for PD.

METHODS:

Preoperative T1-weighted and diffusion-weighted MRI, postoperative CT, and clinical data were acquired for 49 patients (24 STN, 25 GPi) who underwent DBS for PD. After initial programming, the Lead DBS toolbox was used to model VAT based on the individual subject electrode and stimulation parameters. Whole-brain probabilistic tractography was performed from VAT using FSL (FMRIB's Software Library) to estimate activation pathways. Average activation pathways were generated for each target by weighting each subject’s pathways by unilateral MDS-UPDRS-III response to stimulation at initial programming. Comparison tractography was performed using 85-subject PD normative connectome.

RESULTS:

Analysis of weighted activation pathways reveals that STN-DBS strongly activates pathways to the caudate nucleus and bilateral cerebellum. In contrast, GPi-DBS activates pathways to the putamen and the ansa lenticularis. Furthermore, normative connectome tractography shows that the subcortical and cerebellar structural connectivity is not as well appreciated. Lastly,cortical pathways show that GPi DBS has increased premotor connectivity while STN DBS has robust motor connectivity, and confining the seeds to the STN and GPi does not diminish cortical connectivity.

CONCLUSIONS:

Activation pathways from STN and GPi therapeutic contacts have unique subcortical and cerebellar connectivity. White matter connections within the basal ganglia and cerebellum, including ansa lenticularis and regions associated with the DRTT, are connected to the therapeutic contacts, and this connectivity is not as well appreciated using normative connectome data. Activation pathways via the internal capsule alone cannot explain cortical connectivity. Further research to test the utility of defined connections using patient-specific tractography may help better predict DBS response or prospectively inform targeting.