Topical tranexamic acid (TXA) is non-inferior to intravenous TXA in adult spine surgery: a meta-analysis.

Tranexamic acid (TXA) has long been utilized in spine surgery and can be administered through intravenous (IV) and topical routes. Although, topical and IV administration of TXA are both effective in decreasing blood loss during spine surgery, complications like deep vein thrombosis (DVT) and pulmonary embolism have been reported with the use of intravenous TXA (ivTXA). These potential complications may be mitigated through the use of topical TXA (tTXA). To assess optimal dosing protocols and efficacy of topical TXA in spine surgery, Embase, Ovid-MEDLINE, Scopus, Cochrane, and clinicaltrials.gov were queried for original research on the use of tTXA in adult patients undergoing spine surgery. Data parameters analyzed included blood loss, transfusion rate, thromboembolic, and other complications. Data was synthesized and confidence evaluated according to the Grades of Recommendation, Assessment, Development, and Evaluation approach. Nineteen studies were included in the final analysis with 2197 patients. Of the 18 published studies, 9 (50%) displayed high levels of evidence. Topical TXA showed a trend towards a lower risk of transfusion and complications. Protocols that used 1g tTXA showed a significantly reduced risk for transfusion when compared to controls (risk ratio -1.05, 95% CI (-1.62, -0.48); P = 0.94, I2 = 0%). Complications associated with tTXA included DVTs and wound infections. Topical TXA was non-inferior to intravenous TXA with similar efficacy and complication profiles for bleeding control in spine surgery; however, more studies are needed to discern benefits and risks.

Evaluating the state of non-invasive imaging biomarkers for traumatic brain injury.

Non-invasive imaging biomarkers are useful for prognostication in patients with traumatic brain injury (TBI) at high risk for morbidity with invasive procedures. The authors present findings from a scoping review discussing the pertinent biomarkers. Embase, Ovid-MEDLINE, and Scopus were queried for original research on imaging biomarkers for prognostication of TBI in adult patients. Two reviewers independently screened articles, extracted data, and evaluated risk of bias. Data was synthesized and confidence evaluated with the linked evidence according to the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) approach. Our search yielded 3104 unique citations, 44 of which were included in this review. Study populations varied in TBI severity, as defined by Glasgow Coma Scale (GCS), including: mild (n=9), mild and moderate (n=3), moderate and severe (n=7), severe (n=6), and all GCS scores (n=17). Diverse imaging modalities were used for prognostication, predominantly computed tomography (CT) only (n=11), magnetic resonance imaging (MRI) only (n=9), and diffusion tensor imaging (DTI) (N=9). The biomarkers included diffusion coefficient mapping, metabolic characteristics, optic nerve sheath diameter, T1-weighted signal changes, cortical cerebral blood flow, axial versus extra-axial lesions, T2-weighted gradient versus spin echo, translocator protein levels, and trauma imaging of brainstem areas. The majority (93%) of studies identified that the imaging biomarker of interest had a statistically significant prognostic value; however, these are based on a very low to low level of quality of evidence. No study directly compared the effects on specific TBI treatments on the temporal course of imaging biomarkers. The current literature is insufficient to make a strong recommendation about a preferred imaging biomarker for TBI, especially considering GRADE criteria revealing low quality of evidence. Rigorous prospective research of imaging biomarkers of TBI is warranted to improve the understanding of TBI severity.

Risk factors for wound-related complications after microvascular decompression.

Retrosigmoid craniotomy for microvascular decompression (MVD) has been traditionally performed via craniectomy. Various closure techniques have been described, yet factors associated with wound-related complications remain undetermined. Accordingly, herein, we sought to identify risk factors associated with wound-related complications after such procedures. An institutional retrospective case-control study was performed; outcomes of interest were cerebrospinal fluid (CSF) leak, wound dehiscence, wound infection, and pseudomeningocele. Univariate analysis was performed using Wilcoxon rank sum test for non-parametric continuous outcomes and chi-square test for categorical outcomes. Multivariate logistic regression was performed on binomial outcome variables. The study population included 197 patients who underwent MVD for trigeminal neuralgia (83.2%), hemifacial spasm (12.2%), vestibular nerve section (3.0%), and glossopharyngeal neuralgia (1.5%). The overall wound-related complication rate was 14.2% (n = 28), including twelve patients (6.1%) with CSF leak, ten patients (5.1%) with wound infection, ten patients (5.1%) with pseudomeningocele, and nine (4.6%) patients with wound dehiscence. Using multivariate logistic regression, preoperative anemia and current tobacco use were associated with significantly higher rates of complications (OR 6.01 and 4.58, respectively; p < 0.05), including CSF leak (OR 12.83 and 12.40, respectively, p < 0.05). Of note, use of synthetic bone substitute for cranioplasty was associated with a significantly lower rate of complications (OR 0.13, p < 0.01). Preoperative anemia and current tobacco use significantly increased, while synthetic bone substitute cranioplasty significantly decreased, odds of wound-related complications, the need for treatment, and CSF leaks. Additionally, higher BMI, longer operative duration, and prior radiosurgery may increase risk for wound-related complications.

Treatment of pediatric high-grade central nervous system tumors with high-dose methotrexate in combination with multiagent chemotherapy: A single-institution experience.

BACKGROUND: Effective treatment for pediatric embryonal brain tumors includes dose-intensive multiagent chemotherapy (DIMAC) followed by high-dose chemotherapy with stem cell rescue (HDCSCR). Use of repeated cycles of DIMAC including high-dose methotrexate (HDMTX) without HDCSCR has not been described. PROCEDURE: We retrospectively reviewed the responses/toxicities in 13 patients (aged 2-155 months, median 22 months) with central nervous system (CNS) tumors (atypical teratoid rhabdoid tumors, CNS embryonal tumors not otherwise specified, pineoblastoma, embryonal tumor with multilayered rosettes, and CNS sarcoma) treated over a 12-year period with repeated cycles of HDMTX followed by etoposide, cisplatin, cyclophosphamide, and vincristine. RESULTS: Six patients (46.2%) had disseminated disease at presentation and five (38.5%) had gross total resection. A total of 64 courses of therapy were administered with a median of five courses per patient.  Eight patients (61.5%) received radiation therapy (one at relapse). By completion of therapy, 11 patients (84.6%) achieved a response (six complete, five partial).  Six of the 13 patients (46.2%) remain alive with a median follow-up of 48 months (6-146).  Acute toxicities included fever/neutropenia (70.3%), bacteremia (15.6%), and grade 3 mucositis (18.8%).  Long-term complications included learning disability, seizure disorder, and brain necrosis, without treatment-related deaths. CONCLUSIONS: DIMAC with HDMTX without HDCSCR may be an effective treatment option for selected patients with embryonal or high-grade CNS tumors.

Advances in Anterolateral Approaches to the Lumbar Spine: A Focus on Technological Developments.

A historical overview of the evolution of anterolateral approaches to the lumber spine and associated patient outcomes is presented. In addition, the modern incorporation of new technologies is discussed, including interbody cages, intraoperative image guidance, robotics, augmented reality, and machine learning, which have significantly improved the spine surgery safety and efficacy profile. Current challenges and future directions are also covered, emphasizing the need for further research and development, particularly in robotic assistance and machine learning algorithms.

Art and Neurosurgery: The Importance of Medical Illustration.

Art in neurosurgery has been a critical part of the discipline for centuries. Numerous cultures, such as ancient India, China, and Egypt, and more contemporary scientists, such as Leonardo da Vinci, Max Brödel, and Norman Dott, have significantly contributed to medical illustration. Today, advancements in three-dimensional technology have allowed for the creation of detailed neuroanatomy models for surgical planning and education. Medical illustrations are also used for research and outcome documentation as they help visualize anatomy and surgical procedures. Its use in education, surgical planning, and navigation remains integral to the advancement of neurosurgery. This review demonstrates the invaluable contribution of art in neurosurgery and how it has enabled continuous progress in the field.

Strategies for spine surgeons to enhance a clinical practice and research program: stepping stones for practice management.

In this review, the value of patient-reported outcome measures, immersive technology, and patient review systems is discussed, and these strategies are presented as ways to enhance both the research and clinical aspects of a practice. The value of a research team and open access research databases is also discussed. Establishing a research program does not need elaborate resources to sustain efforts. The aforementioned simple yet effective strategies can enhance the clinical and research experience for surgeons in both academic and private practice settings.

Spatial Computing for preoperative planning and postoperative evaluation of single-position lateral approaches in spinal revision surgery.

Spatial computing (SC) in a surgical context offers reconstructed interactive four-dimensional models of radiological imaging. Preoperative and postoperative assessment with SC can offer more insight into personalized surgical approaches. Spine surgery has benefitted from the use of perioperative SC assessment. Herein, we describe the use of SC to perform a perioperative assessment of a revision spinal deformity surgery. A 79-year-old wheelchair-bound male presented to the neurosurgery clinic with a history of chronic lumbar pain associated with bilateral lower extremity weakness. His surgical history is significant for an L2-L5 lumbar decompression with posterior fixation 1 year prior. On examination, there were signs of thoracic myelopathy. Imaging revealed his previous instrumentation, pseudoarthrosis, and cord compression. We perform a two-staged operation to address the thoracic spinal cord compression and myelopathy, pseudoarthrosis, and malalignment with a lack of global spinal harmony. His imaging is driven by a spatial computing and SC environment and offers support for the diagnosis of his L2-3 and L4-5 pseudoarthrosis on the reconstructed SC-based computed tomography scan. SC enabled the assessment of the configuration of the psoas muscle and course of critical neurovascular structures in addition to graft sizing, trajectory and approach, evaluation of the configuration and durability of the anterior longitudinal ligament, and the overlying abdominal viscera. SC increases the familiarity of the patient's specific anatomy and enhances perioperative assessment. As such, SC can be used to preoperatively plan for spinal revision surgery.

Current Trends in Subspecialty Fellowship Training for 1691 Academic Neurological Surgeons.

OBJECTIVE: Neurosurgical subspecialty fellowship training has become increasingly popular in recent decades. However, few studies have evaluated recent trends in postgraduate subspecialty education. This study aims to provide a detailed cross-sectional analysis of subspecialty fellowship training completion trends and demographics among U.S. academic neurosurgeons. METHODS: Academic clinical faculty (M.D. or D.O.) teaching at accredited neurosurgery programs were included. Demographic, career, and fellowship data were collected from departmental physician profiles and the American Association of Neurological Surgeons (AANS) membership database. Relative citation ratio scores were retrieved using the National Institutes of Health iCite tool. RESULTS: This study included 1691 surgeons (1756 fellowships) from 125 institutions. The majority (79.13%) reported fellowship training. Fellowship completion was more common among recent graduates (residency year >2000), as was training in multiple subspecialties (P < 0.0001). Spine was the most popular subspecialty (16.04%), followed by pediatrics (11.18%), and cerebrovascular (9.46%). The least common were trauma/critical care (2.52%) and peripheral nerve (1.26%). Spine, neuroradiology, and endovascular subspecialties grew in popularity over time. Pediatrics and spine were the most popular for females and males, respectively. Epilepsy and cerebrovascular had the most full professors, while endovascular and spine had the most assistant professors. Stereotactic/functional and epilepsy had the most Ph.Ds. Fellowship training correlated with higher weighted, but not mean, relative citation ratio scores among associate (P = 0.002) and full professors (P = 0.005). CONCLUSIONS: There is an emerging proclivity for additional fellowship training among young neurosurgeons, often in multiple subspecialties. These findings are intended to help guide professional decision-making and optimize the delivery of postgraduate education.

Removal of a Floating and Migrated Plate Screw in a Patient with a Failed Anterior Cervical Discectomy and Fusion.

BACKGROUND: Anterior cervical discectomy and fusion (ACDF) is a commonly performed procedure for degenerative cervical spine disease. Rare complications of ACDF surgery include hardware failure, in the form of screw loosening and migration, or rod breakage. We present a case in which we removed a migrated screw lodged in the esophagus from a patient with a failed anterior cervical fusion. OBJECTIVE: To present a surgical technique and considerations to remove a migrated screw. METHODS: The previous ACDF incision was reopened and exposure was gained under the guidance of a head and neck surgeon. Longus coli were mobilized off the spine bilaterally with electrocautery. After dissection, the screw was found lodged in the longitudinal muscle of the esophageal wall and excised with the use of a 15-blade. The integrity of the esophageal mucosa and submucosa was maintained and subsequently checked with rigid esophagoscopy. Fluoroscopy was used to confirm that all hardware was removed, with the exception of the anterior cages. RESULTS: The dislodged screw, which was embedded in the esophagus, was successfully removed. CONCLUSIONS: Failure of an ACDF carries a risk of screw migration, which may be asymptomatic even if the screw is lodged in the esophagus. Additional considerations are required with potential violations of the adjacent viscera.

Mapping the geographic migration of United States neurosurgeons across training and current practice regions: associations with academic productivity.

OBJECTIVE: Characterizing changes in the geographic distribution of neurosurgeons in the United States (US) may inform efforts to provide a more equitable distribution of neurosurgical care. Herein, the authors performed a comprehensive analysis of the geographic movement and distribution of the neurosurgical workforce. METHODS: A list containing all board-certified neurosurgeons practicing in the US in 2019 was obtained from the American Association of Neurological Surgeons membership database. Chi-square analysis and a post hoc comparison with Bonferroni correction were performed to assess differences in demographics and geographic movement throughout neurosurgeon careers. Three multinomial logistic regression models were performed to further evaluate relationships among training location, current practice location, neurosurgeon characteristics, and academic productivity. RESULTS: The study cohort included 4075 (3830 male, 245 female) neurosurgeons practicing in the US. Seven hundred eighty-one neurosurgeons practice in the Northeast, 810 in the Midwest, 1562 in the South, 906 in the West, and 16 in a US territory. States with the lowest density of neurosurgeons included Vermont and Rhode Island in the Northeast; Arkansas, Hawaii, and Wyoming in the West; North Dakota in the Midwest; and Delaware in the South. Overall, the effect size, as measured by Cramér's V statistic, between training stage and training region is relatively modest at 0.27 (1.0 is complete dependence); this finding was reflected in the similarly modest pseudo R2 values of the multinomial logit models, which ranged from 0.197 to 0.246. Multinomial logistic regression with L1 regularization revealed significant associations between current practice region and residency region, medical school region, age, academic status, sex, or race (p < 0.05). On subanalysis of the academic neurosurgeons, the region of residency training correlated with an advanced degree type in the overall neurosurgeon cohort, with more neurosurgeons than expected holding Doctor of Medicine and Doctor of Philosophy degrees in the West (p = 0.021). CONCLUSIONS: Female neurosurgeons were less likely to practice in the South, and neurosurgeons in the South and West had reduced odds of holding academic rather than private positions. The Northeast was the most likely region to contain neurosurgeons who had completed their training in the same locality, particularly among academic neurosurgeons who did their residency in the Northeast.

Patient perception of spinal cord injury through social media: An analysis of 703 Instagram and 117 Twitter posts.

Introduction: Social media has developed exponentially over the last decade as a means for individuals and patients to connect to others and has provided a unique opportunity for physicians to provide broader information to the general public to attempt to positively modify health behavior. The purpose of this study was to assess the patient's perception of spinal cord injury (SCI) on social media. Methods: Instagram and Twitter social media platforms were analyzed to determine posts written by patients with SCI. The initial search for Instagram posts tagged with "#spinalcordinjury" yielded over 270,000 posts in April 2021. Posts pertaining to the patient's experience were retrospectively collected from January 2020 to April 2021. Twitter posts that included "#spinalcordinjury," "@spinalcordinjury," and "spinal cord injury" were retrospectively collected in April 2021. One hundred seventeen tweets were found that were directly from a patient with SCI. Themes associated with patients' experiences living with SCI were coded. Results: The most common theme on Instagram was spreading positivity and on Twitter was the appearance of the wheelchair (75.8% and 37.3%, respectively). Other common themes on Instagram were the appearance of a wheelchair (71.8%), recovery or rehabilitation (29.9%), and life satisfaction (29.0%). Prevalent themes on Twitter included spreading positivity (23.2%) and recovery or rehabilitation (21.3%). Conclusion: The prevalence of themes of positivity and awareness may indicate the utilization of social media as a support mechanism for patients living with SCI. Identification of prevalent themes is important for the holistic treatment of SCI survivors.

Glycopeptide-specific monoclonal antibodies suggest new roles for O-GlcNAc.

Studies of post-translational modification by beta-N-acetyl-D-glucosamine (O-GlcNAc) are hampered by a lack of efficient tools such as O-GlcNAc-specific antibodies that can be used for detection, isolation and site localization. We have obtained a large panel of O-GlcNAc-specific IgG monoclonal antibodies having a broad spectrum of binding partners by combining three-component immunogen methodology with hybridoma technology. Immunoprecipitation followed by large-scale shotgun proteomics led to the identification of more than 200 mammalian O-GlcNAc-modified proteins, including a large number of new glycoproteins. A substantial number of the glycoproteins were enriched by only one of the antibodies. This observation, combined with the results of inhibition ELISAs, suggests that the antibodies, in addition to their O-GlcNAc dependence, also appear to have different but overlapping local peptide determinants. The monoclonal antibodies made it possible to delineate differentially modified proteins of liver in response to trauma-hemorrhage and resuscitation in a rat model.

Cerebellar talcosis following posterior reversible encephalopathy syndrome in an intravenous methamphetamine abuser.

BACKGROUND: Intravenous (IV) methamphetamine abuse is associated with a variety of short- and long-term effects on the nervous system, some of which have yet to be fully elucidated. One known systemic complication that has not been described in nervous system tissues is the deposition of substrate crystals contained in injectable drugs. CASE DESCRIPTION: An unusual case is presented of a 35-year-old active IV methamphetamine abuser with posterior reversible encephalopathy syndrome (PRES) who subsequently developed multifocal bilateral cerebellar enhancing lesions and leptomeningeal enhancement due to biopsy-proven crystalline deposits. CONCLUSION: Although large crystalline substances will not normally penetrate the blood-brain barrier (BBB), during a state of BBB compromise such as with PRES, talc deposition may occur in the central nervous system.

Rapid Evolution and Rupture of an Incidental Aneurysm During Hyperdynamic Therapy for Cerebral Vasospasm.

BACKGROUND: Aneurysmal subarachnoid hemorrhage (aSAH) is associated with high morbidity and mortality. Among the most common sequelae of aSAH is delayed cerebral ischemia. Hyperdynamic therapy (fluid supplementation and hypertension) is used to increase cerebral perfusion. However, the safety of hyperdynamic therapy in patients with separate unruptured, unsecured intracranial aneurysms is not well-established. Herein, a rare case demonstrating the rapid evolution and rupture of an incidental unsecured aneurysm in the setting of hyperdynamic therapy is presented. CASE DESCRIPTION: A 56-year-old woman without significant medical history presented with aSAH secondary to rupture of a 3-mm left posterior inferior cerebellar artery aneurysm. After endovascular treatment of this aneurysm, she developed symptomatic vasospasm prompting initiation of hyperdynamic therapy. Seven days after initiation of hyperdynamic therapy, she experienced rupture of an incidental pericallosal artery aneurysm that was found to have increased in size during the hyperdynamic therapy. She ultimately survived and was functionally independent approximately 1 year after her initial ictus. CONCLUSIONS: This case demonstrates that enlargement and rupture of an incidental, previously unruptured aneurysm may occur during hyperdynamic therapy.

Immunovirotherapy for the Treatment of Glioblastoma and Other Malignant Gliomas.

Glioblastoma multiforme (GBM) represents one of the most challenging malignancies due to many factors including invasiveness, heterogeneity, and an immunosuppressive microenvironment. Current treatment modalities have resulted in only modest effect on outcomes. The development of viral vectors for oncolytic immunovirotherapy and targeted drug delivery represents a promising therapeutic prospect for GBM and other brain tumors. A host of genetically engineered viruses, herpes simplex virus, poliovirus, measles, and others, have been described and are at various stages of clinical development. Herein we provide a review of the advances and current state of oncolytic virotherapy for the targeted treatment of GBM and malignant gliomas.

Impact of Anesthetic Variation in Endovascular Treatment of Acute Ischemic Stroke.

Background Given recent technological advancements leading to better outcomes in endovascular therapy for acute ischemic stroke (AIS), updated guidelines recommend thrombectomy as the standard of care in acute large vessel occlusions. However, use of general anesthesia versus conscious sedation continues to be discussed. Two previous randomized trials have shown no significant difference between the use of conscious sedation compared with general anesthesia. Methods The authors performed a retrospective analysis of all consecutive patients with acute ischemia who underwent intra-arterial thrombectomy between September 2014 and May 2020 at a Level 1 stroke center. Patient characteristics along with clinical and operative data were extracted. Frequency distributions of selected characteristics were obtained and statistical significance of any differences according to the mode of anesthesia was assessed. Results A total of 480 patients were included in this study, 257 underwent general anesthesia and 223 underwent conscious sedation. Length of stay (LOS) in the ICU nor length of hospital stay was significantly different between groups. Change in National Institutes of Health Stroke Scale (NIHSS) score from admission to discharge, procedure times, and discharge disposition were not found to be significantly associated with either group although there was a trend towards longer door to puncture time with general anesthesia. Discharge disposition was found to be significantly associated with admission NIHSS (p=0.04). There was a trend towards longer hospital stay in patients with worse admission NIHSS (p=0.09). Success of thrombectomy was not significantly different between both anesthesia groups (p=0.37). Conclusions This large, single-center retrospective cohort study echoes the results of two previous randomized controlled trials in demonstrating non-inferiority of general anesthesia versus conscious sedation in cases of intra-arterial thrombectomy for AIS. These results contrast those of previously published retrospective studies.

Intraventricular metastatic melanoma: A case report and review of the literature.

Intraventricular melanoma is a very rare and highly malignant disease. Safe resection is the mainstay of treatment, but no standard guidelines exist for adjuvant therapy. Early histologic and molecular diagnosis is key for improved survival.

Incidence and risk factors for seizures associated with deep brain stimulation surgery.

OBJECTIVE: The objective of this study was to determine the incidence of seizures following deep brain stimulation (DBS) electrode implantation and to evaluate factors associated with postoperative seizures. METHODS: The authors performed a single-center retrospective case-control study. The outcome of interest was seizure associated with DBS implantation. Univariate analyses were performed using the Student t-test for parametric continuous outcomes. The authors used the Kruskal-Wallis test or Wilcoxon rank-sum test for nonparametric continuous outcomes, chi-square statistics for categorical outcomes, and multivariate logistic regression for binomial variables. RESULTS: A total of 814 DBS electrode implantations were performed in 645 patients (478 [58.7%] in men and 520 [63.9%] in patients with Parkinson's disease). In total, 22 (3.4%) patients who had undergone 23 (2.8%) placements experienced seizure. Of the 23 DBS implantation-related seizures, 21 were new-onset seizures (3.3% of 645 patients) and 2 were recurrence or worsening of a prior seizure disorder. Among the 23 cases with postimplantation-related seizure, epilepsy developed in 4 (17.4%) postoperatively; the risk of DBS-associated epilepsy was 0.50% per DBS electrode placement and 0.63% per patient. Nine (39.1%) implantation-related seizures had associated postoperative radiographic abnormalities. Multivariate analyses suggested that age at surgery conferred a modest increased risk for postoperative seizures (OR 1.06, 95% CI 1.02-1.10). Sex, primary diagnosis, electrode location and sidedness, and the number of trajectories were not significantly associated with seizures after DBS surgery. CONCLUSIONS: Seizures associated with DBS electrode placement are uncommon, typically occur early within the postoperative period, and seldom lead to epilepsy. This study suggests that patient characteristics, such as age, may play a greater role than perioperative variables in determining seizure risk. Multiinstitutional studies may help better define and mitigate the risk of seizures after DBS surgery.

Tumor edge-to-core transition promotes malignancy in primary-to-recurrent glioblastoma progression in a PLAGL1/CD109-mediated mechanism.

BACKGROUND: Glioblastoma remains highly lethal due to its inevitable recurrence. Most of this recurrence is found locally, indicating that postsurgical tumor-initiating cells (TICs) accumulate at the tumor edge. These edge-TICs then generate local recurrence harboring new core lesions. Here, we investigated the clinical significance of the edge-to-core (E-to-C) signature generating glioblastoma recurrence and sought to identify its central mediators. METHODS: First, we examined the association of E-to-C-related expression changes to patient outcome in matched primary and recurrent samples (n = 37). Specifically, we tested whether the combined decrease of the edge-TIC marker PROM1 (CD133) with the increase of the core-TIC marker CD109, representing E-to-C transition during the primary-to-recurrence progression, indicates poorer patient outcome. We then investigated the specific molecular mediators that trigger tumor recurrence driven by the E-to-C progression. Subsequently, the functional and translational significance of the identified molecule was validated with our patient-derived edge-TIC models in vitro and in vivo. RESULTS: Patients exhibiting the CD133low/CD109high signature upon recurrence representing E-to-C transition displayed a strong association with poorer progression-free survival and overall survival among all tested patients. Differential gene expression identified that PLAGL1 was tightly correlated with the core TIC marker CD109 and was linked to shorter patient survival. Experimentally, forced PLAGL1 overexpression enhanced, while its knockdown reduced, glioblastoma edge-derived tumor growth in vivo and subsequent mouse survival, suggesting its essential role in the E-to-C-mediated glioblastoma progression. CONCLUSIONS: E-to-C axis represents an ongoing lethal process in primary glioblastoma contributing to its recurrence, partly in a PLAGL1/CD109-mediated mechanism.