Discrete Mechanistic Target of Rapamycin Signaling Pathways, Stem Cells, and Therapeutic Targets.

The mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that functions via its discrete binding partners to form two multiprotein complexes, mTOR complex 1 and 2 (mTORC1 and mTORC2). Rapamycin-sensitive mTORC1, which regulates protein synthesis and cell growth, is tightly controlled by PI3K/Akt and is nutrient-/growth factor-sensitive. In the brain, mTORC1 is also sensitive to neurotransmitter signaling. mTORC2, which is modulated by growth factor signaling, is associated with ribosomes and is insensitive to rapamycin. mTOR regulates stem cell and cancer stem cell characteristics. Aberrant Akt/mTOR activation is involved in multistep tumorigenesis in a variety of cancers, thereby suggesting that the inhibition of mTOR may have therapeutic potential. Rapamycin and its analogues, known as rapalogues, suppress mTOR activity through an allosteric mechanism that only suppresses mTORC1, albeit incompletely. ATP-catalytic binding site inhibitors are designed to inhibit both complexes. This review describes the regulation of mTOR and the targeting of its complexes in the treatment of cancers, such as glioblastoma, and their stem cells.

High-Volume Centers Provide Superior Value of Care in the Surgical Treatment of Malignant Brain Tumor.

BACKGROUND: Improved outcomes in surgical patients have been associated with increasing volume of cases. This has led to the development of centers that facilitate care for a specific patient population. This study aimed to evaluate associations of outcomes with hospital characteristics in patients undergoing resection of malignant brain tumors. METHODS: The 2016-2020 National Inpatient Sample was queried for patients undergoing resection of malignant brain tumors. Teaching hospitals with caseloads >2 standard deviations above the mean (140 cases) were categorized as high-volume centers (HVCs). Value of care was evaluated by adding one point for each of the following: short length of stay, low total charges, favorable discharge disposition, and lack of major comorbidity or complication. RESULTS: In 3009 hospitals, 118,390 patients underwent resection of malignant brain tumors. HVC criteria were met by 91 (3%) hospitals. HVCs were more likely to treat patients of younger age or higher socioeconomic status (P < 0.01 for all). The Mid-Atlantic and South Atlantic regions had the highest percentage of cases and number of HVCs. Value of care was higher at HVCs (P < 0.01). Care at HVCs was associated with decreased complications (P < 0.01 for all) and improved patient outcomes (P < 0.01 for all). CONCLUSIONS: Patients undergoing craniotomy for malignant brain neoplasms have superior outcomes in HVCs. Trends of centralization may reflect the benefits of multidisciplinary treatment, geographic preferences, publicity, and cultural impact. Improvement of access to care is an important consideration as this trend continues.

Brain Metastases Are Regulated by Immuno-inflammatory Signaling Pathways Governed by STAT3, MAPK and Tumor Suppressor p53 Status: Possible Therapeutic Targets.

BACKGROUND/AIM: Brain metastasis (BM) is a complex multi-step process involving various immune checkpoint proteins. Mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinases 1/2 (ERK1/2), and signal transducer and activator of transcription 3 (STAT3) are implicated in tumorigenesis and are critical upstream regulators of Programmed Death Ligand 1 (PD-L1), an immunotherapy target. Tumor suppressor p53, dysregulated in cancers, regulates STAT3 and ERK1/2 signaling. This study examined the roles of STAT3, MAPK and p53 status in BM initiation and maintenance. MATERIALS AND METHODS: Twenty-six BM, with various primary malignancies, were used (IRB-approved) to determine mutant p53 (p53mt), pSTAT3Tyr705, pERK1/2Thr202/Tyr204, and PD-L1 expression using immunohistochemistry. cDNA microarray was used for gene expression analysis. Brain-metastatic breast cancer cells (MDA-MB-231) were treated with STAT3 (NSC74859) or MAPK/ERK1/2 (U0126) inhibitors in regular or astrocytic media. ERK1/2 pathway was assessed using western blotting, and cell proliferation and migration were determined using MTT and scratch-wound assays, respectively. RESULTS: pSTAT3Tyr705 and pERK1/2Thr202/Tyr204 were expressed at tumor margins, whereas p53mt and PD-L1 were uniformly expressed, with significant overlap between expression of these proteins. Gene expression analysis identified alterations in 18 p53- and 32 STAT3- or MAPK-associated genes contributing to dysregulated immune responses and cell cycle regulation. U0126 and NSC74859 reduced pERK1/2Thr202/Tyr204 expression. Cell proliferation decreased following each treatment (p≤0.01). Migration stagnated following U0126 treatment in astrocytic media (p≤0.01). CONCLUSION: Activation of STAT3 and ERK1/2 promotes BM and provides compelling evidence for use of STAT3, ERK1/2 and p53 status as potential immunotherapeutic targets in BM.

The story of dexamethasone and how it became one of the most widely used drugs in neurosurgery.

Dexamethasone, a long-acting potent glucocorticoid, is one of the most widely used medications in neurosurgery. In this paper, the authors recount the history of dexamethasone's rise in neurosurgery and discuss its use in brain tumors in the context of emerging neuro-oncological immunotherapies. In 1958, Glen E. Arth synthesized a 16-alpha-methylated analog of cortisone (dexamethasone) for treatment of rheumatoid arthritis. Joseph Galicich, a neurosurgery resident at the time, applied the rheumatological drug to neurosurgery. He gave doses to patients who had undergone craniotomy for tumor removal and saw their paresis improve, midline shift resolve, and mortality rates decrease. He advocated for clinical trials and the drug became a mainstay in neurosurgery. As neuro-oncological treatments evolve to include immunotherapy, the immunosuppressive effects of dexamethasone are becoming an unwanted effect. The question then becomes: how does one treat the patient's symptoms if the only drug that has been used throughout history may become a detriment to their oncological treatment? Since its discovery, dexamethasone has maintained an impressive staying power in the field, acting as a standard drug for cerebral edema for more than 60 years. However, with the advent of immunotherapy, research is warranted to evaluate ways of treating symptomatic edema in the context of modern neuro-oncological therapies.

Treatment of Chiari malformations with craniovertebral junction anomalies: Where do we stand today?

Background: Chiari malformation type 1 (CM-1) is characterized by cerebellar tonsil herniation through the foramen magnum and can be associated with additional craniovertebral junction anomalies (CVJA). The pathophysiology and treatment for CM-1 with CVJA (CM-CVJA) is debated. Objective: To evaluate the trends and outcomes of surgical interventions for patients with CM-CVJA. Methods: A systematic review of the literature was performed to obtain articles describing surgical interventions for patients with CM-CVJA. Articles included were case series describing surgical approach; reviews were excluded. Variables evaluated included patient characteristics, approach, and postoperative outcomes. Results: The initial query yielded 403 articles. Twelve articles, published between 1998-2020, met inclusion criteria. From these included articles, 449 patients underwent surgical interventions for CM-CVJA. The most common CVJAs included basilar invagination (BI) (338, 75.3%), atlantoaxial dislocation (68, 15.1%) odontoid process retroflexion (43, 9.6%), and medullary kink (36, 8.0%). Operations described included posterior fossa decompression (PFD), transoral (TO) decompression, and posterior arthrodesis with either occipitocervical fusion (OCF) or atlantoaxial fusion. Early studies described good results using combined ventral and posterior decompression. More recent articles described positive outcomes with PFD or posterior arthrodesis in combination or alone. Treatment failure was described in patients with PFD alone that later required posterior arthrodesis. Additionally, reports of treatment success with posterior arthrodesis without PFD was seen. Conclusion: Patients with CM-CVJA appear to benefit from posterior arthrodesis with or without decompressive procedures. Further definition of the pathophysiology of craniocervical anomalies is warranted to identify patient selection criteria and ideal level of fixation.

Oncolytic Virotherapy for High-Grade Glioma and Current Evidence and Factors to Consider for Incorporation into Clinical Practice.

Brain tumor incidence is on the rise, and glioblastoma comprises the majority of primary tumors. Despite maximal safe resection and adjuvant chemoradiation, median survival for high-grade glioma remains poor. For this reason, it is important to develop and incorporate new treatment strategies. Oncolytic virotherapy has emerged as a viable new therapeutic entity to fill this gap. Preclinical research has shown oncolytic virotherapy to be a robust and effective treatment option for brain tumors, and clinical trials for both adult and pediatric high-grade glioma are underway. The unique and protected environment of the nervous system, in part due to the blood-brain barrier, prevents traditional systemic therapies from achieving adequate penetration. Brain tumors are also heterogenous in nature due to their diverse molecular profiles, further complicating systemic treatment efforts. Oncolytic viruses may serve to fill this gap in brain tumor treatment given their amenability to genetic modification and ability to target unique tumor epitopes. In addition, direct inoculation of the oncolytic virus agent to the tumor bed following surgical resection absolves risk of systemic side effects and ensures adequate delivery. As virotherapy transitions from bench to bedside, it is important to discuss factors to make this transition more seamless. In this article, we describe the current clinical evidence as it pertains to oncolytic virotherapy and the treatment of brain tumors as well as factors to consider for its incorporation into neurosurgical workflow.

Disparities in anterior cervical discectomy and fusion provision and outcomes for cervical stenosis.

Background: Disparities in neurosurgical care have emerged as an area of interest when considering the impact of social determinants on access to health care. Decompression via anterior cervical discectomy and fusion (ACDF) for cervical stenosis (CS) may prevent progression towards debilitating complications that may severely compromise one's quality of life. This retrospective database analysis aims to elucidate demographic and socioeconomic trends in ACDF provision and outcomes of CS-related pathologies. Methods: The Healthcare Cost and Utilization Project National Inpatient Sample database was queried between 2016 and 2019 using International Classification of Diseases 10th edition codes for patients undergoing ACDF as a treatment for spinal cord and nerve root compression. Baseline demographics and inpatient stay measures were analyzed. Results: Patients of White race were significantly less likely to present with manifestations of CS such as myelopathy, plegia, and bowel-bladder dysfunction. Meanwhile, Black patients and Hispanic patients were significantly more likely to experience these impairments representative of the more severe stages of the degenerative spine disease process. White race conferred a lesser risk of complications such as tracheostomy, pneumonia, and acute kidney injury in comparison to non-white race. Insurance by Medicaid and Medicare conferred significant risks in terms of more advanced disease prior to intervention and negative inpatient. Patients in the highest quartile of median income consistently fared better than patients in the lowest quartile across almost every aspect ranging from degree of progression at initial presentation to incidence of complications to healthcare resource utilization. All outcomes for patients age > 65 were worse than patients who were younger at the time of the intervention. Conclusions: Significant disparities exist in the trajectory of CS and the risks associated with ACDF amongst various demographic cohorts. The differences between patient populations may be reflective of a larger additive burden for certain populations, especially when considering patients' intersectionality.

Epidemiology, management, and treatment outcomes of metastatic spinal melanoma.

Metastatic spinal melanoma is a rare and aggressive disease process with poor prognosis. We review the literature on metastatic spinal melanoma, focusing on its epidemiology, management, and treatment outcomes. Demographics of metastatic spinal melanoma are similar to those for cutaneous melanoma, and cutaneous primary tumors tend to be most common. Decompressive surgical intervention and radiotherapy have traditionally been considered mainstays of treatment, and stereotactic radiosurgery has emerged as a promising approach in the operative management of metastatic spinal melanoma. While survival outcomes for metastatic spinal melanoma remain poor, they have improved in recent years with the advent of immune checkpoint inhibition, used in conjunction with surgery and radiotherapy. New treatment options remain under investigation, especially for patients with disease refractory to immunotherapy. We additionally explore several of these promising future directions. Nevertheless, further investigation of treatment outcomes, ideally incorporating high-quality prospective data from randomized controlled trials, is needed to identify optimal management of metastatic spinal melanoma.

Adult Trauma Patients With Thoracolumbar Injury Classification and Severity Score of 4: A Systematic Review.

STUDY DESIGN: Systematic review. OBJECTIVE: Evaluate characteristics of patients with thoracolumbar injury classification and severity (TLICS) score of 4 (To4) severity traumatic thoracolumbar injury. SUMMARY OF BACKGROUND DATA: The TLICS score is used to predict the need for operative versus nonoperative management in adult patients with traumatic thoracolumbar injury. Ambiguity exists in its application and score categorization. METHODS: A systematic review of the literature was performed. The databases of MEDLINE, Embase, Web of Science, and Cochrane Review were queried. Studies included adults with traumatic thoracolumbar injury with assigned TLICS score and description of management strategy. RESULTS: A total of 16 studies met inclusion criteria representing 1911 adult patients with traumatic thoracolumbar injury. There were 503 (26.32%) patients with To4, of which 298 (59.24%) were operative. Studies focusing on the thoracolumbar junction and AO Type A fracture morphology had To4 patient incidences of 11.15% and 52.94%, respectively. Multiple studies describe better quality of life, pain scores, and radiographic outcomes in To4 who underwent operative treatment patients. CONCLUSION: To4 injuries are more commonly AO Type A and located in the thoracolumbar junction in adult patients with traumatic thoracolumbar injury. Despite ambiguous recommendations regarding treatment provided by TLICS, outcomes favor operative intervention in this subset of traumatic thoracolumbar injury patients.

Frailty is a risk factor for intracranial abscess and is associated with longer length of stay: a retrospective single institution case-control study.

BACKGROUND: Intracranial abscess (IA) causes significant morbidity and mortality. The impact of baseline frailty status on post-operative outcomes of IA patients remains largely unknown. The present study evaluated if frailty status can be used to prognosticate outcomes in IA patients. METHODS: We retrospectively reviewed all IA patients undergoing craniotomy at our institution from 2011 to 2018 (n =18). These IA patients were age and gender matched with patients undergoing craniotomy for intracranial tumor (IT), an internal control for comparison. Demographic and clinical data were collected to measure frailty, using the modified frailty index-11 (mFI-11), pre-operative American Society of Anesthesiologists Physical Status Classification System (ASA), and study their association with post-operative complications, as measured by the Clavien-Dindo Grade (CDG). RESULTS: No significant difference in mFI-11 or ASA score was observed between the IA and IT groups (p = 0.058 and p = 0.131, respectively). IA patients had significantly higher CDG as compared with the control IT patients (p < 0.001). There was a trend towards increasing LOS in the IA group as compared to the IT group (p = 0.053). Increasing mFI and ASA were significant predictors of LOS by multiple linear regression in the IA group (p = 0.006 and p = 0.001, respectively), but not in the control IT group. Neither mFI-11 nor ASA were found to be predictors for CDG in either group. Within this case-control group of patients, we found an increase for odds of having IA with increasing mFI (OR 1.838, CI 95% 1.016-3.362, p = 0.044). CONCLUSIONS: Frail IA patients tend to have more severe postoperative complications. The mFI-11 seems to predict increased resource utilization in the form of LOS. This study provides the initial retrospective data of another neurosurgical pathology where frailty leads to significantly worse outcomes. We also found that mFI may serve as a potential risk factor for severe disease.

Leptomeningeal disease in glioblastoma: endgame or opportunity?

INTRODUCTION: Glioblastoma is an aggressive cancer with a notoriously poor prognosis. Recent advances in treatment have increased overall survival, though this may be accompanied by an increased incidence of leptomeningeal disease (LMD). LMD carries a particularly severe prognosis and remains a late stage manifestation of glioblastoma without satisfactory treatment. The objective of this review is to survey the literature on treatment of LMD in glioblastoma and to more fully characterize the current therapeutic strategies. METHODS: The authors performed a systematic review following PRISMA criteria on PubMed and OVID databases. Articles that included adult patients with LMD from glioblastoma were retrieved and reviewed. RESULTS: LMD in glioblastoma patients is increasing in incidence, with reports of up to 21%. The overall survival without treatment is alarmingly brief, with patients surviving between 1.6-3.8 months. All studies showed that treatment does improve overall survival significantly, increasing to 11.7 months in one study. However, no one adjuvant or surgical therapy has been shown to improve survival in LMD significantly over another. Direct treatment methods include chemotherapy (standard, anti-angiogenic, intrathecal, immunotherapy), and radiation. Hydrocephalus is a complication in LMD that can be treated with ventriculoperitoneal shunt placement, however treating hydrocephalus and delivering intrathecal chemotherapy is a challenge. CONCLUSION: Though evidence remains lacking and there is no consensus, treatments show a trend towards improving survival and should be considered on a case-by-case basis. Further studies are necessary in the pursuit of a standard of care.

Frailty as a Predictor of Postoperative Complications Following Skull Base Surgery.

OBJECTIVE/HYPOTHESIS: Frailty has emerged as a powerful risk stratification tool across surgical specialties; however, an analysis of the impact of frailty on outcomes following skull base surgery has not been published. The aim of this study was to assess the validity of the 5-factor modified frailty index (mFI-5) as a predictor of perioperative morbidity and mortality in patients undergoing skull base surgery. METHODS: A mFI-5 score was calculated for patients undergoing skull base surgeries using the National Surgical Quality Improvement Program (NSQIP) database from 2005 to 2018. Multivariate logistic regression analysis was used to evaluate the association of increasing frailty with complications in the 30-day postoperative period, with a subanalysis by operative location. RESULTS: A total of 17,912 patients who underwent skull base procedures were identified, with 45.5% of patients having a frailty score of one or greater; 44.9% were male and the mean age was 52.0 (±16.1 SD) years. Multivariable regression analysis revealed frailty to be an independent predictor of overall complications (odds ratio [OR]: 1.325, P < .001), life-threatening complications (OR: 1.428, P < .001), and mortality (OR: 1.453, P < .001). Higher frailty also correlated with increased length of stay. When procedures were stratified by operative location, frailty correlated significantly with overall complications for middle, posterior, and multiple-fossae operations but not the anterior fossa. CONCLUSIONS: Frailty demonstrates a significant and stepwise association with life-threatening postoperative morbidity, mortality, and length of stay following skull base surgeries. mFI-5 is an objective and easily calculable measure of preoperative risk, which may facilitate perioperative planning and counseling regarding outcomes prior to surgery. LEVEL OF EVIDENCE: 3 Laryngoscope, 131:1977-1984, 2021.

Lateral Myelotomy for Resection of a Ruptured Intramedullary Cervico-Thoracic Cavernous Malformation.

BACKGROUND AND IMPORTANCE: Intramedullary spinal cord cavernous malformations represent 5% to 12% of spinal vascular disease. Most patients present with acute or progressive neurological symptoms, including motor weakness or sensory loss. Surgical resection is the only definitive management and is recommended for symptomatic lesions that are surgically accessible. CLINICAL PRESENTATION: A 35-yr-old woman presented with a sudden onset of pain and temperature sensation loss in the left lower extremity. Magnetic resonance imaging of the spine showed a hemorrhage located ventral and slightly lateral to the right of the midline of the spinal cord from C7 through T3. Ultimately, a right lateral myelotomy between the ventral and dorsal roots was performed, and the cavernous malformation was removed. Postoperative imaging confirmed gross total resection of the cavernous malformation. CONCLUSION: In this article, we report a highly unusual case of a multisegment, ruptured intramedullary cavernous malformation that was ultimately resected through a lateral myelotomy approach. This case demonstrates that a lateral approach to the spinal cord substance can be utilized for ruptured cavernous malformation, especially if there is hemorrhage at the surface of the spinal cord. This can be used as an entry into the anterolateral compartment of the spinal cord, which would otherwise be regarded as a highly morbid approach due to the sensory deficits induced. We believe this entry point to the spinal cord is feasible in highly select cases such as this.

Resection of an upper cervical aneurysmal bone cyst and spinal reconstruction using a midline mandibular osteotomy in a pediatric patient.

The authors report on the surgical management of an extensive lesion of the upper cervical spine that required an uncommon transmandibular approach to facilitate exposure, resection, and stabilization in a pediatric patient. A 6-year-old boy with a large aneurysmal bone cyst of the C-2 vertebra presented with progressive weakness and right-sided neck pain. The lesion extended laterally into the soft tissue of the neck, inferiorly to C-4, and posteriorly around the spinal cord. A transmandibular osteotomy was performed to provide adequate exposure for complete resection of the mass and anterior C1-3 instrumentation and fusion. Subsequently, the patient underwent occiput to C-4 posterior instrumentation and fusion. The patient tolerated the operation well and had regained all function at 3 and 11 months' follow-up. No neurological complications or problems of speech, swallowing, or respiration occurred. Even in pediatric patients, the transmandibular approach for the treatment of upper cervical spine lesions is an effective method of maximizing exposure for complex lesions requiring resection and stabilization.

PPARγ activation prevents impairments in spatial memory and neurogenesis following transient illness.

The detrimental effects of illness on cognition are familiar to virtually everyone. Some effects resolve quickly while others may linger after the illness resolves. We found that a transient immune response stimulated by lipopolysaccharide (LPS) compromised hippocampal neurogenesis and impaired hippocampus-dependent spatial memory. The immune event caused an ∼50% reduction in the number of neurons generated during the illness and the onset of the memory impairment was delayed and coincided with the time when neurons generated during the illness would have become functional within the hippocampus. Broad spectrum non-steroidal anti-inflammatory drugs attenuated these effects but selective Cox-2 inhibition was ineffective while PPARγ activation was surprisingly effective at protecting both neurogenesis and memory from the effects of LPS-produced transient illness. These data may highlight novel mechanisms behind chronic inflammatory and neuroinflammatory episodes that are known to compromise hippocampus-dependent forms of learning and memory.

Stereotactic radiosurgery for pineal region tumors.

The role of radiosurgery in the management of pineal region tumors is still in its incipient stages, although over the past few years its use has expanded, both as a primary treatment modality and as an adjunct to conventional therapies. This article gives a detailed overview of the recent literature regarding the merits of stereotactic radiosurgery to pineal region tumors, and offers guidelines for the practicing neurosurgeon and neuro-oncologist for the incorporation of radiosurgery into the clinical management of these difficult lesions.

Epidermoid tumors of the temporal lobe as epileptogenic foci.

Intracerebral epidermoid tumors of the temporal lobe are exceedingly rare. The vast majority of these slow-growing tumors remain clinically silent while only a select few are associated with overt symptomatology. We report two patients with epidermoid tumors whose unique location in the temporal lobe resulted in secondarily generalized seizures. Our first patient, a 19-year-old female, presented with a secondarily generalized tonic-clonic seizure and MRI revealed a superior temporal lobe lesion that was subsequently treated with an awake craniotomy and gross total resection. Our second patient was a 71-year-old male with a recent seizure history and known left temporal lobe lesion. The patient underwent craniotomy for gross total resection of the mass. In these two patients, we found that MRI proved diagnostic and surgical resection was curative. Our clinical experience and review of the literature indicate that gross total resection of these lesions confers control of localization-related epilepsy.

Training in endovascular surgical neuroradiology.

BACKGROUND: During the past few years, the field of endovascular surgical neuroradiology has been expanding. Neurosurgeons, radiologists, and neurologists are currently being trained. We analyzed data from a national survey of endovascular training programs to assess the current training status and future projections. METHODS: Survey participation requests were sent out to program directors and members of the Society of Endovascular Neurosurgery, the Society of Neurointerventional Surgery, and the Society of Vascular and Interventional Neurology. The format was an on-line survey designed by the authors, and completed through the SurveyMonkey.com website. Forty-three programs were identified and invited to participate. RESULTS: We achieved a response rate of 81% (n = 35). Twenty-seven (79%) of the 35 respondents listed their training program as academic, and 7 (20%) listed it as a mixture of academic with private practice. The training program faculty consisted of 57 radiologists, 39 neurosurgeons, and 10 neurologists. Length of fellowship offered was the same for all specialties in 43%, and differed based on clinical experience/background in 51%. Of the programs, 86% offered a 2-year fellowship, 49% had a mandatory resident rotation, 17% offered an infolded complete fellowship for residents, and 34% offered an infolded partial fellowship. Only 9% reported no resident exposure at all. There were 12% of respondents who reported to have knowledge of vascular surgeons or cardiologists performing intracranial procedures. At the time of the survey, there were 68 fellows in training, and most entered training immediately after residency (38%), whereas 26% entered after a fellowship and another 26% trained while in residency. There will be a 14% increase of graduates within the next 5 years. Comparing the past 5 years (2003-2007) with future 5-year projections (2008-2012), the number of radiologists is declining by 37% (73 vs. 46), whereas the number of neurosurgeons (74 vs. 106) and neurologists (20 vs. 37) is increasing by 42.5% and 112%, respectively. CONCLUSIONS: This survey suggests that there is a strong interest in endovascular surgical neuroradiology. The overall number of graduates is increasing, particularly in neurosurgery and neurology. Although the majority of current faculty is still comprised of neuroradiologists, the number of graduates in radiology will be decreasing during the next 5 years, reflecting a trend toward greater subspecialization within the fields of neurosurgery and neurology. Peer-Review Article.