Concomitant Traumatic Brain Injury Delays Surgery in Patients With Traumatic Spinal Cord Injury.

BACKGROUND AND OBJECTIVES: Growing evidence supports prompt surgical decompression for patients with traumatic spinal cord injury (tSCI). Rates of concomitant tSCI and traumatic brain injury (TBI) range from 10% to 30%. Concomitant TBI may delay tSCI diagnosis and surgical intervention. Little is known about real-world management of this common injury constellation that carries significant clinical consequences. This study aimed to quantify the impact of concomitant TBI on surgical timing in a national cohort of patients with tSCI. METHODS: Patient data were obtained from the National Trauma Data Bank (2007-2016). Patients admitted for tSCI and who received surgical intervention were included. Delayed surgical intervention was defined as surgery after 24 hours of admission. Multivariable hierarchical regression models were constructed to measure the risk-adjusted association between concomitant TBI and delayed surgical intervention. Secondary outcome included favorable discharge status. RESULTS: We identified 14 964 patients with surgically managed tSCI across 377 North American trauma centers, of whom 2444 (16.3%) had concomitant TBI and 4610 (30.8%) had central cord syndrome (CCS). The median time to surgery was 20.0 hours for patients without concomitant TBI and 24.8 hours for patients with concomitant TBI. Hierarchical regression modeling revealed that concomitant TBI was independently associated with delayed surgery in patients with tSCI (odds ratio [OR], 1.3; 95% CI, 1.1-1.6). Although CCS was associated with delayed surgery (OR, 1.5; 95% CI, 1.4-1.7), we did not observe a significant interaction between concomitant TBI and CCS. In the subset of patients with concomitant tSCI and TBI, patients with severe TBI were significantly more likely to experience a surgical delay than patients with mild TBI (OR, 1.4; 95% CI, 1.0-1.9). CONCLUSION: Concomitant TBI delays surgical management for patients with tSCI. This effect is largest for patients with tSCI with severe TBI. These findings should serve to increase awareness of concomitant TBI and tSCI and the likelihood that this may delay time-sensitive surgery.

Craniotomy versus craniectomy for traumatic acute subdural hematoma-coarsened exact matched analysis of outcomes.

BACKGROUND AND OBJECTIVES: Acute subdural hematoma (aSDH) after traumatic brain injury frequently requires emergent craniotomy (CO) or decompressive craniectomy (DC). We sought to determine the variables associated with either surgical approach and to compare outcomes between matched patients. METHODS: A multi-center retrospective review was used to identify traumatic aSDH patients who underwent CO or DC. Patient variables independently associated with surgical approach were used for coarsened exact matching.Multivariate logistic regression and multivariate Cox proportional-hazards regression wereconducted on matched patients to determine independent predictors of mortality. RESULTS: Seventy-six patients underwent CO and sixty-two underwent DC for aSDH evacuation. DC patients were21.4 years younger (P < 0.001), more likely to be male (80.6 % vs 60.5 %,P = 0.011), and present with GCS ≤ 8 (64.5 % vs 36.8 %,P = 0.001). Age (P < 0.001), epidural hematoma (P = 0.01), skull fracture (P = 0.001), and cisternal effacement (P = 0.02) were independently associated with surgical approach. After coarsened exact matching, DC (P = 0.008), older age (P = 0.007), male sex (P = 0.04), and intraventricular hemorrhage (P = 0.02), were independently associated with inpatient mortality. Multivariate Cox proportional-hazards regression demonstrated that DC was independently associated with mortality at 90-days (P = 0.001) and 1-year post-operation (P = 0.003). CONCLUSION: aSDH patients who receive surgical evacuation via DC as opposed to CO are younger, more likely to be male, and have worse clinical exam. After controlling for patient differences via coarsened exact matching, DC is independently associated with mortality.

Seq-ing the SINEs of central nervous system tumors in cerebrospinal fluid.

It is often challenging to distinguish cancerous from non-cancerous lesions in the brain using conventional diagnostic approaches. We introduce an analytic technique called Real-CSF (repetitive element aneuploidy sequencing in CSF) to detect cancers of the central nervous system from evaluation of DNA in the cerebrospinal fluid (CSF). Short interspersed nuclear elements (SINEs) are PCR amplified with a single primer pair, and the PCR products are evaluated by next-generation sequencing. Real-CSF assesses genome-wide copy-number alterations as well as focal amplifications of selected oncogenes. Real-CSF was applied to 280 CSF samples and correctly identified 67% of 184 cancerous and 96% of 96 non-cancerous brain lesions. CSF analysis was considerably more sensitive than standard-of-care cytology and plasma cell-free DNA analysis in the same patients. Real-CSF therefore has the capacity to be used in combination with other clinical, radiologic, and laboratory-based data to inform the diagnosis and management of patients with suspected cancers of the brain.

The Neurodevelopmental and Molecular Landscape of Medulloblastoma Subgroups: Current Targets and the Potential for Combined Therapies.

Medulloblastoma is the most common malignant pediatric brain tumor and is associated with significant morbidity and mortality in the pediatric population. Despite the use of multiple therapeutic approaches consisting of surgical resection, craniospinal irradiation, and multiagent chemotherapy, the prognosis of many patients with medulloblastoma remains dismal. Additionally, the high doses of radiation and the chemotherapeutic agents used are associated with significant short- and long-term complications and adverse effects, most notably neurocognitive delay. Hence, there is an urgent need for the development and clinical integration of targeted treatment regimens with greater efficacy and superior safety profiles. Since the adoption of the molecular-based classification of medulloblastoma into wingless (WNT) activated, sonic hedgehog (SHH) activated, group 3, and group 4, research efforts have been directed towards unraveling the genetic, epigenetic, transcriptomic, and proteomic profiles of each subtype. This review aims to delineate the progress that has been made in characterizing the neurodevelopmental and molecular features of each medulloblastoma subtype. It further delves into the implications that these characteristics have on the development of subgroup-specific targeted therapeutic agents. Furthermore, it highlights potential future avenues for combining multiple agents or strategies in order to obtain augmented effects and evade the development of treatment resistance in tumors.

Patient Safety Indicator 04 Does Not Consistently Identify Failure to Rescue in the Neurosurgical Population.

BACKGROUND: Improving neurosurgical quality metrics necessitates the analysis of patient safety indicator (PSI) 04, a measure of failure to rescue (FTR). OBJECTIVE: To demonstrate that PSI 04 is not an appropriate measure for capturing FTR within neurosurgery. METHODS: We conducted a single-center retrospective cohort study. Patients from January 1, 2017 to June 1, 2021, who sustained a PSI 04-attributed complication (pneumonia, deep vein thrombosis/pulmonary embolism, sepsis, shock/cardiac arrest, or gastrointestinal hemorrhage/acute ulcer), underwent a neurosurgical procedure, had inpatient mortality, and were identified using patient safety indicator 04 (PSI 04) tracking algorithm. The primary outcome was whether the attributed PSI 04 designation was the primary driver of mortality. RESULTS: We identified 67 patients who met the PSI 04 criteria (median age, 61 years; female sex, 43.4%). Nearly 20% of patients met the PSI complication criteria before admission. Patients who underwent emergent bedside procedures were more likely to present with a poor Glasgow Coma Scale ( P = .016), more likely to be intubated before admission ( P = .016), and less likely to have mortality due to a PSI 04-related complication ( P = .002). PSI 04-related complications were identified as the cause of death in only 43.2% of cases. Procedures occurring in the interventional radiology suite (odds ratio, 23.2; 95% CI, 3.5-229.3; P = .003) or the operating room (odds ratio, 6.2; 95% CI, 1.25-39.5; P = .03) were more likely to have mortality because of a PSI 04-related complication compared with bedside procedures. CONCLUSION: In total, 65.7% of patients were inappropriately flagged as meeting PSI 04 criteria. PSI 04 currently identifies patients with complications unrelated to operating room procedures. Improvement in patient safety within neurosurgery necessitates the development of a subspecialty specific measure to capture FTR.

Predictors of Blunt Cerebrovascular Injury, Stroke, and Mortality in Patients with Cervical Spine Trauma.

BACKGROUND: Blunt cerebrovascular injury (BCVI), defined as blunt traumatic injury to the carotid or vertebral arteries, is associated with significant risk of stroke and mortality. Cervical spine trauma is a recognized risk factor for BCVI. OBJECTIVE: The objective of this study was to identify significant predictors of BCVI and its sequelae in patients with known cervical spine injury. METHODS: Patients from 2007 to 2018 with blunt cervical spine injury diagnoses were identified in the National Trauma Data Bank. Multivariable logistic regression models were used to identify patient baseline and injury characteristics associated with BCVI, stroke, and mortality. RESULTS: We identified 229,254 patients with cervical spine injury due to blunt trauma. The overall rate of BCVI was 1.6%. Factors associated with BCVI in patients with cervical spine injury included lower Glasgow Coma Scale, motor vehicle crash, higher Injury Severity Score, concomitant traumatic brain or spinal cord injury, and current smoking status. BCVI was a strong predictor of stroke (odds ratio, 8.2; 95% confidence interval, 5.7-12.0) and was associated with mortality (odds ratio, 1.7; 95% confidence interval, 1.3-2.2). Stroke occurred in 3.3% of patients with BCVI versus 0.02% for patients without BCVI. CONCLUSIONS: While BCVI is rare following cervical spine injury due to blunt trauma, it is a significant predictor of stroke and mortality. The risk factors associated with BCVI, stroke, and mortality identified here should be used in the development of more effective predictive tools to improve care.

Internal neurolysis versus intraoperative glycerin rhizotomy for trigeminal neuralgia.

OBJECTIVE: Internal neurolysis (IN) and intraoperative glycerin rhizotomy (ioGR) are emerging surgical options for patients with trigeminal neuralgia without neurovascular contact. The objective of this study was to compare the neurological outcomes of patients who underwent IN with those of patients who underwent ioGR. METHODS: The authors retrospectively reviewed all patients who underwent IN or ioGR for trigeminal neuralgia at our institution. Patient demographic characteristics and immediate postoperative outcomes, as well as long-term neurological outcomes, were compared. RESULTS: Of 1044 patients who underwent open surgical treatment for trigeminal neuralgia, 56 patients underwent IN and 91 underwent ioGR. Of these 147 patients, 37 had no evidence of intraoperative neurovascular conflict. All patients who underwent IN and 96.7% of patients who underwent ioGR had immediate postoperative pain relief. At last follow-up, patients who underwent IN had lower Barrow Neurological Institute (BNI) pain intensity scores (p = 0.05), better BNI facial numbness scores (p < 0.01), and a greater degree of pain improvement (p = 0.05) compared with those who underwent ioGR. Patients who underwent IN also had significantly lower rates of symptomatic pain recurrence (p < 0.01) at last follow-up over an average of 9.5 months. CONCLUSIONS: IN appears to provide patients with a greater degree of pain relief, lower rates of facial numbness, and lower rates of pain recurrence compared with ioGR. Future prospective studies will better characterize long-term pain recurrence and outcomes.

Advancements in the treatment of traumatic spinal cord injury during military conflicts.

Significant advancements in the treatment of spinal cord injury (SCI) were developed in the setting of military conflicts, partly due to the large numbers of injuries sustained by service members. No effective SCI treatment options existed into the early 20th century, and soldiers who sustained these injuries were usually considered untreatable. Extensive progress was made in SCI treatment during and after World War II, as physical therapy was increasingly encouraged for patients with SCI, multidisciplinary teams oversaw care, pathophysiology was better understood, and strategies were devised to prevent wound infection and pressure sores. Recent conflicts in Iraq and Afghanistan have caused a substantial rise in the proportion of SCIs among causes of casualties and wounds, largely due to new forms of war and weapons, such as improvised explosive devices. Modern military SCIs resulting from blast mechanisms are substantively different from traumatic SCIs sustained by civilians. The treatment paradigms developed over the past 100 years have increased survival rates and outcomes of soldiers with SCI. In this paper, the authors review the role of military conflicts in the development of therapeutic interventions for SCI and discuss how these interventions have improved outcomes for soldiers and civilians alike.

The Role of Preoperative Magnetic Resonance Imaging in Assessing Neurovascular Compression Before Microvascular Decompression in Trigeminal Neuralgia.

BACKGROUND: Preoperative magnetic resonance imaging (MRI) is a standard component of the preoperative clinical workup for patients before 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 before 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 were determined for general MRI, high-resolution MRI, and non-high resolution. RESULTS: Overall, preoperative MRI before MVD showed 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. A total of 958 patients (93.9%) underwent high-resolution preoperative MRI with skull base sequences. This imaging showed 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. 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%. The negative predictive values of general, high-resolution, and non-high-resolution MRIs were all <50%. CONCLUSIONS: Preoperative MRI may offer a high predictive value for neurovascular conflict and should be part of the standard preoperative care workup for patients with trigeminal neuralgia. However, lack of neurovascular conflict on preoperative imaging is not sufficient to exclude patients from undergoing MVD.

Current and Future Frontiers of Molecularly Defined Oligodendrogliomas.

Oligodendrogliomas are a subtype of adult diffuse glioma characterized by their better responsiveness to systemic chemotherapy than other high-grade glial tumors. The World Health Organization (WHO) 2021 brain tumor classification highlighted defining molecular markers, including 1p19q codeletion and IDH mutations which have become key in diagnosing and treating oligodendrogliomas. The management for patients with oligodendrogliomas includes observation or surgical resection potentially followed by radiation and chemotherapy with PCV (Procarbazine, Lomustine, and Vincristine) or Temozolomide. However, most of the available research about oligodendrogliomas includes a mix of histologically and molecularly diagnosed tumors. Even data driving our current management guidelines are based on post-hoc subgroup analyses of the 1p19q codeleted population in landmark prospective trials. Therefore, the optimal treatment paradigm for molecularly defined oligodendrogliomas is incompletely understood. Many questions remain open, such as the optimal timing of radiation and chemotherapy, the response to different chemotherapeutic agents, or what genetic factors influence responsiveness to these agents. Ultimately, oligodendrogliomas are still incurable and new therapies, such as targeting IDH mutations, are necessary. In this opinion piece, we present relevant literature in the field, discuss current challenges, and propose some studies that we think are necessary to answer these critical questions.

Safety and Cost Savings Associated with Reduced Inpatient Hospitalization for Microvascular Decompression.

OBJECTIVES: Microvascular decompression (MVD) has grown as a first-line surgical intervention for severe facial pain from trigeminal neuralgia and/or hemifacial spasm. We sought to examine the safety and cost-benefits of discharging patients with MVD within 1 day of admission. METHODS: We retrospectively reviewed patients undergoing MVD at our institution from 2008 to 2020. Patients were sorted by 1 day, 2 days, or >2 days until discharge and by year from 2008 to 2013, 2014 to 2018, or 2019 to 2020. Patient presenting characteristics, intraoperative measures, and complications were documented. Statistical differences were calculated by one-way analysis of variance and χ2 analyses. RESULTS: Our cohort included 976 patients undergoing MVD, with 231 (23.6%) between 2008 and 2013, 517 (52.9%) between 2014 and 2018, and 228 (23.3%) between 2019 and 2020. Over time, postoperative admission rates to the critical care unit, total inpatient hospital admission times, and Barrow Neurological Institute scores at first follow-up decreased. Postoperative complications, including cerebrospinal fluid leak, decreased significantly. In addition, patients discharged within 1 day of admission incurred a total hospital cost of $26,689, which was $3588 lower than patients discharged within more than 1 day of admission, P < 0.0001. Discharging carefully selected patients who are appropriate for discharge within 1 day of admission could translate to a potential cost-savings of $255,346 per year in our clinical practice. CONCLUSIONS: In our experience, MVDs are a safe, elective intervention. Our findings suggest that postoperative day 1 discharge in patients with an uncomplicated postoperative course may be safe while improving hospital resource use.

Reexamining the Role of Postoperative ICU Admission for Patients Undergoing Elective Craniotomy: A Systematic Review.

OBJECTIVES: The standard-of-care for postoperative care following elective craniotomy has historically been ICU admission. However, recent literature interrogating complications and interventions during this postoperative ICU stay suggests that all patients may not require this level of care. Thus, hospitals began implementing non-ICU postoperative care pathways for elective craniotomy. This systematic review aims to summarize and evaluate the existing literature regarding outcomes and costs for patients receiving non-ICU care after elective craniotomy. DATA SOURCES: A systematic review of the PubMed database was performed following PRISMA guidelines from database inception to August 2021. STUDY SELECTION: Included studies were published in peer-reviewed journals, in English, and described outcomes for patients undergoing elective craniotomies without postoperative ICU care. DATA EXTRACTION: Data regarding study design, patient characteristics, and postoperative care pathways were extracted independently by two authors. Quality and risk of bias were evaluated using the Oxford Centre for Evidence-Based Medicine Levels of Evidence tool and Risk Of Bias In Non-Randomized Studies-of Interventions tool, respectively. DATA SYNTHESIS: In total, 1,131 unique articles were identified through the database search, with 27 meeting inclusion criteria. Included articles were published from 2001 to 2021 and included non-ICU inpatient care and same-day discharge pathways. Overall, the studies demonstrated that postoperative non-ICU care for elective craniotomies led to length of stay reduction ranging from 6 hours to 4 days and notable cost reductions. Across 13 studies, 53 of the 2,469 patients (2.1%) intended for postoperative management in a non-ICU setting required subsequent care escalation. CONCLUSIONS: Overall, these studies suggest that non-ICU care pathways for appropriately selected postcraniotomy patients may represent a meaningful opportunity to improve care value. However, included studies varied greatly in patient selection, postoperative care protocol, and outcomes reporting. Standardization and multi-institutional collaboration are needed to draw definitive conclusions regarding non-ICU postoperative care for elective craniotomy.

Automated prediction of the Thoracolumbar Injury Classification and Severity Score from CT using a novel deep learning algorithm.

OBJECTIVE: Damage to the thoracolumbar spine can confer significant morbidity and mortality. The Thoracolumbar Injury Classification and Severity Score (TLICS) is used to categorize injuries and determine patients at risk of spinal instability for whom surgical intervention is warranted. However, calculating this score can constitute a bottleneck in triaging and treating patients, as it relies on multiple imaging studies and a neurological examination. Therefore, the authors sought to develop and validate a deep learning model that can automatically categorize vertebral morphology and determine posterior ligamentous complex (PLC) integrity, two critical features of TLICS, using only CT scans. METHODS: All patients who underwent neurosurgical consultation for traumatic spine injury or degenerative pathology resulting in spine injury at a single tertiary center from January 2018 to December 2019 were retrospectively evaluated for inclusion. The morphology of injury and integrity of the PLC were categorized on CT scans. A state-of-the-art object detection region-based convolutional neural network (R-CNN), Faster R-CNN, was leveraged to predict both vertebral locations and the corresponding TLICS. The network was trained with patient CT scans, manually labeled vertebral bounding boxes, TLICS morphology, and PLC annotations, thus allowing the model to output the location of vertebrae, categorize their morphology, and determine the status of PLC integrity. RESULTS: A total of 111 patients were included (mean ± SD age 62 ± 20 years) with a total of 129 separate injury classifications. Vertebral localization and PLC integrity classification achieved Dice scores of 0.92 and 0.88, respectively. Binary classification between noninjured and injured morphological scores demonstrated 95.1% accuracy. TLICS morphology accuracy, the true positive rate, and positive injury mismatch classification rate were 86.3%, 76.2%, and 22.7%, respectively. Classification accuracy between no injury and suspected PLC injury was 86.8%, while true positive, false negative, and false positive rates were 90.0%, 10.0%, and 21.8%, respectively. CONCLUSIONS: In this study, the authors demonstrate a novel deep learning method to automatically predict injury morphology and PLC disruption with high accuracy. This model may streamline and improve diagnostic decision support for patients with thoracolumbar spinal trauma.

Case Series in the Utility of Invasive Blood Pressure Monitoring in Microvascular Decompression.

BACKGROUND: The utility of arterial lines in microvascular decompression (MVD) is not well described. OBJECTIVE: To examine the safety and costs of arterial lines compared with noninvasive blood pressure (NIBP) monitoring in MVDs. METHODS: We retrospectively reviewed patients undergoing MVD from 2012 to 2020. Patients were grouped by procedure date from 2012 to 2014 and 2015 to 2020, reflecting our institution's decreasing trend in arterial line placement around 2014 to 2015. Patient features, intraoperative characteristics, and postoperative complications were collected for all cases. Statistical differences were evaluated using chi-squared analyses and t-tests. RESULTS: Eight hundred fifty-eight patients underwent MVDs, with 204 between 2012 and 2014 and 654 between 2015 and 2020. Over time, the frequency of arterial line placement decreased from 64.2% to 30.1%, P < .001. Arterial lines involved 11 additional minutes of preincision time, P < .001. Patients with arterial lines required both increased doses and costs of vasoactive medications intraoperatively. Patients receiving arterial lines demonstrated no significant differences in complications compared with patients with NIBP monitoring. On average, patients with arterial lines incurred $802 increased costs per case compared with NIBP monitoring. CONCLUSION: NIBP monitoring in MVDs provides neurologically and hemodynamically safe outcomes compared with invasive blood pressure monitoring. For patients without significant cardiopulmonary risk factors, NIBP monitoring may be a cost-effective alternative in MVDs.

Drug Repurposing for Glioblastoma and Current Advances in Drug Delivery-A Comprehensive Review of the Literature.

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults with an extremely poor prognosis. There is a dire need to develop effective therapeutics to overcome the intrinsic and acquired resistance of GBM to current therapies. The process of developing novel anti-neoplastic drugs from bench to bedside can incur significant time and cost implications. Drug repurposing may help overcome that obstacle. A wide range of drugs that are already approved for clinical use for the treatment of other diseases have been found to target GBM-associated signaling pathways and are being repurposed for the treatment of GBM. While many of these drugs are undergoing pre-clinical testing, others are in the clinical trial phase. Since GBM stem cells (GSCs) have been found to be a main source of tumor recurrence after surgery, recent studies have also investigated whether repurposed drugs that target these pathways can be used to counteract tumor recurrence. While several repurposed drugs have shown significant efficacy against GBM cell lines, the blood-brain barrier (BBB) can limit the ability of many of these drugs to reach intratumoral therapeutic concentrations. Localized intracranial delivery may help to achieve therapeutic drug concentration at the site of tumor resection while simultaneously minimizing toxicity and side effects. These strategies can be considered while repurposing drugs for GBM.

Pharmacological strategies for improving the prognosis of glioblastoma.

Introduction: Treatments for brain cancer have radically evolved in the past decade due to a better understanding of the interplay between the immune system and tumors of the central nervous system (CNS). However, glioblastoma multiforme (GBM) remains the most common and lethal CNS malignancy affecting adults.Areas covered: The authors review the literature on glioblastoma pharmacologic therapies with a focus on trials of combination chemo-/immunotherapies and drug delivery platforms from 2015 to 2021.Expert opinion: Few therapeutic advances in GBM treatment have been made since the Food and Drug Administration (FDA) approval of the BCNU-eluting wafer, Gliadel, in 1996 and oral temozolomide (TMZ) in 2005. Recent advances in our understanding of GBM have promoted a wide assortment of new therapeutic approaches including combination therapy, immunotherapy, vaccines, and Car T-cell therapy along with developments in drug delivery. Given promising preclinical data, these novel pharmacotherapies for the treatment of GBM are currently being evaluated in various stages of clinical trials.

Targeting of cyclin-dependent kinases in atypical teratoid rhabdoid tumors with multikinase inhibitor TG02.

OBJECTIVE: Atypical teratoid rhabdoid tumors (ATRTs) are aggressive pediatric brain tumors with no current standard of care and an estimated median patient survival of 12 to 18 months. Previous genetic analyses have implicated cyclin D1 and enhancer of zeste homolog 2 (EZH2), a histone methyltransferase that is implicated in many cancers, as key drivers of tumorigenicity in ATRTs. Since the effects of EZH2 and cyclin D1 are facilitated by a host of cyclin-dependent kinases (CDKs), the authors sought to investigate the potential therapeutic effects of targeting CDKs in ATRTs with the multi-CDK inhibitor, TG02. METHODS: Human ATRT cell lines BT12, BT37, CHLA05, and CHLA06 were selected for investigation. The effects of TG02 on cell viability, proliferation, clonogenicity, and apoptosis were assessed via Cell Counting Kit-8 assays, cell counting, clonogenic assays, and flow cytometry, respectively. Similar methods were used to determine the effects of TG02 combined with radiation therapy (RT) or cisplatin. Synergism indices for TG02-cisplatin combination therapy were calculated using CompuSyn software. RESULTS: TG02 was observed to significantly impair ATRT cell growth in vitro by limiting cell proliferation and clonogenicity, and by inducing apoptosis. TG02 inhibited ATRT cell proliferation and decreased cell viability in a dose-dependent manner with nanomolar half maximal effective concentration (EC50) values (BT12, 207.0 nM; BT37, 127.8 nM; CHLA05, 29.7 nM; CHLA06, 18.7 nM). TG02 (150 nM) dramatically increased the proportion of apoptotic ATRT cells 72 hours posttreatment (TG02 8.50% vs control 1.52% apoptotic cells in BT12, p < 0.0001; TG02 70.07% vs control 15.36%, p < 0.0001). Combination therapy studies revealed that TG02 acted as a potent radiosensitizer in ATRT cells (BT12 surviving fraction, RT 51.2% vs RT + TG02 21.7%). Finally, CompuSyn analysis demonstrated that TG02 acted synergistically with cisplatin against ATRT cells at virtually all therapeutic doses. These findings were consistent in cell lines that cover all three molecular subgroups of ATRTs. CONCLUSIONS: The results of this investigation have established that TG02 is an effective therapeutic against ATRTs in vitro. Given the lack of standard therapy for ATRTs, these findings help fill an unmet need and support further study of TG02 as a potential therapeutic option for patients with this deadly disease.