Evolution of Surgical Management of Pineal Region Tumors in the Pediatric Population: A 17-Year Experience at a Single Institution.

INTRODUCTION: Pineal region tumors have historically been challenging to treat. Advances in surgical techniques have led to significant changes in care and outcomes for these patients, and this is well demonstrated by our single institution's experience over a 17-year-period in which the evolution of diagnosis, treatment, and outcomes of pineal tumors in pediatric patients will be outlined. METHODS: We retrospectively collected data on all pediatric patients with pineal region lesions treated with surgery at Children's National Hospital (CNH) from 2005 to 2021. Variables analyzed included presenting symptoms, presence of hydrocephalus, diagnostic and surgical approach, pathology, and adverse events, among others. IRB approval was obtained (IRB: STUDY00000009), and consent was waived due to minimal risk to patients included. RESULTS: A total of 43 pediatric patients with pineal region tumors were treated during a 17-year period. Most tumors in our series were germinomas (n = 13, 29.5%) followed by pineoblastomas (n = 10, 22.7%). Twenty seven of the 43 patients (62.8%) in our series received a biopsy to establish diagnosis, and 44.4% went on to have surgery for resection. The most common open approach was posterior interhemispheric (PIH, transcallosal) - used for 59.3% of the patients. Gross total resection was achieved in 50%; recurrence occurred in 20.9% and mortality in 11% over a median follow-up of 47 months. Endoscopic third ventriculostomy (ETV) was employed to treat hydrocephalus in 26 of the 38 patients (68.4%) and was significantly more likely to be performed from 2011 to 2021. Most (73%) of the patients who received an ETV also underwent a concurrent endoscopic biopsy. No difference was found in recurrence rate or mortality in patients who underwent resection compared to those who did not, but complications were more frequent with resection. There was disagreement between frozen and final pathology in 18.4% of biopsies. CONCLUSION: This series describes the evolution of surgical approaches and outcomes over a 17-year-period at a single institution. Complication rates were higher with open resection, reinforcing the safety of pursuing endoscopic biopsy as an initial approach. The most significant changes occurred in the preferential use of ETVs over ventriculoperitoneal shunts. Though there has been a significant evolution in our understanding of and treatment for these tumors, in our series, the outcomes for these patients have not significantly changed over that time.

Cervical intramedullary teratoma: a case report and systematic review of the literature.

Here, we report a case of a 3-year-old female who presented to clinic with an enlarging mass in the posterior cervical midline. The mass was present since birth and demonstrated no cutaneous stigmata. Plain film, CT, and MRI of the cervical spine (C3-C5) revealed enlargement of the spinal canal, soft tissue calcification, spinal dysraphism, and an intramedullary, predominantly fatty, mass. The mass had associated calcifications and a highly proteinaceous cyst. Surgical resection of the spinal lesion was subsequently performed. Histopathological evaluation revealed a mature teratoma. Cervical spinal teratomas in the pediatric population are rare entities with few cases currently reported in the literature. We conducted a systematic review to outline the current evidence detailing cases of intramedullary spinal cord teratomas. Six articles were included for final review. All patients in the included articles underwent maximal surgical resection with one patient also receiving chemotherapy and radiation. With our report, we aim to add to the literature on cervical intramedullary spinal cord teratomas in the pediatric population.

Immunotherapeutic treatments for spinal and peripheral nerve tumors: a primer.

OBJECTIVE: Spinal and peripheral nerve tumors are a heterogeneous group of neoplasms that can be associated with significant morbidity and mortality despite the current standard of care. Immunotherapy is an emerging therapeutic option to improve the prognoses of these tumors. Therefore, the authors sought to present an updated and unifying review on the use of immunotherapy in treating tumors of the spinal cord and peripheral nerves, including a discussion on mechanism of action, drug delivery, current treatment techniques, and preclinical and clinical studies. METHODS: Current data in the literature regarding immunotherapy were collated and summarized. Targeted tumors included primary and secondary spinal tumors, as well as peripheral nerve tumors. RESULTS: Four primary modalities of immunotherapy (CAR T cell, monoclonal antibody, viral, and cytokine) have been reported to target spine and peripheral nerve tumors. Of the primary spinal tumors, spinal cord astrocytomas had the most preclinical evidence supporting immunotherapy success with CAR T-cell therapy targeting the H3K27M mutation, whereas spinal schwannomas and ependymomas had the most evidence reported for monoclonal antibody therapy preclinically. Of the secondary spinal tumors, primary CNS lymphomas demonstrated some clinical response to immunotherapy, whereas multiple myeloma and bone tumor experiences with immunotherapy were largely limited to concept only. Within peripheral nerve tumors, the use of immunotherapy to treat neurofibromas in the setting of syndromes has been suggested in theory, and possible immunotherapeutic targets have been identified in malignant peripheral nerve tumors. To date, there have been 2 clinical trials involving spine tumors and 2 clinical trials involving peripheral nerve tumors that have reported results, all of which are promising but require validation. CONCLUSIONS: Immunotherapy to treat spinal and peripheral nerve tumors has become an emerging area of research and interest. A large amount of preclinical data supporting the translation of this therapy into practice, aimed at ameliorating the poor prognoses of specific tumors, have been reported. Future clinical studies for translation will focus on the optimal therapy type and administration route to best target these tumors, which often preclude total surgical resection given their proximity to the neural and vascular elements of the spine.

Myelomeningocele Including Fetal Prescription.

Myelomeningocele (MMC) is one of the most common birth defects, affecting 0.2 to 0.4 per 1,000 live births in the United States. The most strongly associated risk factor is low folate level in pregnancy. For this reason, 0.4- to 1.0-mg supplementation with folic acid is recommended in all pregnancies, and high-risk pregnancies are recommended to supplement with 4.0 mg of folic acid daily. The mechanism behind the development of MMC is believed to be failure of the caudal end of the neural tube to close during primary neurulation. Screening for MMC is achieved by using α-fetoprotein levels in maternal serum or amniocentesis in the first and second trimesters of pregnancy. Ultrasonography and fetal magnetic resonance imaging are used to confirm the presence of MMC as well as the location and size of the defect. Based on the results of the Management of Myelomeningocele Study, fetal repair is performed between 23 weeks and 25 weeks and 6 days of gestational age for appropriate candidates. Postnatal repair is more common and is performed 24 to 72 hours after birth. In general, patients with lesions at lower anatomical levels have a better prognosis. Most children with MMC will have neurogenic bladder and bowel dysfunction that affect the patient's and the caregiver's quality of life. Patients with higher levels of mobility, better familial support, and higher economic status report improved quality of life compared with other patients with MMC.

The progression of diversity: Black women in neurosurgery.

While diversity in organized medicine has undoubtedly improved, a disparity remains in the racial and gender makeup of its constituents. This disparity is not distributed equally among all specialties of practice. The surgical subspecialties exemplify this phenomenon by having large gaps between the number of women and racial/ethnic minorities compared to their majority counterparts. Pertaining to neurosurgery in the US, this gap is substantial, with women reaching minority status only within the last 2 years. Among international women in neurosurgery, Black women are even further underrepresented despite efforts in recent years to close the gender gap. The reason for this disparity is likely multifactorial, as Black women demonstrate a unique intersectionality as a minority in regard to both race and gender. In this study, the authors provide historical context for the current state of diversity in neurosurgery and the global strides made by Black women within the field. The authors report recurrent themes in the experiences of Black female neurosurgery attendings and residents as revealed through personal interviews. Furthermore, they examine factors that contribute to the disproportionate representation of Black women in neurosurgery.

Spinal anesthesia in awake surgical procedures of the lumbar spine: a systematic review and meta-analysis of 3709 patients.

OBJECTIVE: Awake surgery has previously been found to improve patient outcomes postoperatively in a variety of procedures. Recently, multiple groups have investigated the utility of this modality for use in spine surgery. However, few current meta-analyses exist comparing patient outcomes in awake spinal anesthesia with those in general anesthesia. Therefore, the authors sought to present an updated systematic review and meta-analysis investigating the utility of spinal anesthesia relative to general anesthesia in lumbar procedures. METHODS: Following a comprehensive literature search of the PubMed and Cochrane databases, 14 clinical studies were included in our final qualitative and quantitative analyses. Of these studies, 5 investigated spinal anesthesia in lumbar discectomy, 4 discussed lumbar laminectomy, and 2 examined interbody fusion procedures. One study investigated combined lumbar decompression and fusion or decompression alone. Two studies investigated patients who underwent discectomy and laminectomy, and 1 study investigated a series of patients who underwent transforaminal lumbar interbody fusion, posterolateral fusion, or decompression. Odds ratios, mean differences (MDs), and 95% confidence intervals were calculated where appropriate. RESULTS: A meta-analysis of the total anesthesia time showed that time was significantly less in patients who received spinal anesthesia for both lumbar discectomies (MD -26.53, 95% CI -38.16 to -14.89; p = 0.00001) and lumbar laminectomies (MD -11.21, 95% CI -19.66 to -2.75; p = 0.009). Additionally, the operative time was significantly shorter in patients who underwent spinal anesthesia (MD -14.94, 95% CI -20.43 to -9.45; p < 0.00001). Similarly, when analyzing overall postoperative complication rates, patients who received spinal anesthesia were significantly less likely to experience postoperative complications (OR 0.29, 95% CI 0.16-0.53; p < 0.0001). Furthermore, patients who received spinal anesthesia had significantly lower postoperative pain scores (MD -2.80, 95% CI -4.55 to -1.06; p = 0.002). An identical trend was seen when patients were stratified by lumbar procedures. Patients who received spinal anesthesia were significantly less likely to require postoperative analgesia (OR 0.06, 95% CI 0.02-0.25; p < 0.0001) and had a significantly shorter hospital length of stay (MD -0.16, 95% CI -0.29 to -0.03; p = 0.02) and intraoperative blood loss (MD -52.36, 95% CI -81.55 to -23.17; p = 0.0004). Finally, the analysis showed that spinal anesthesia cost significantly less than general anesthesia (MD -226.14, 95% CI -324.73 to -127.55; p < 0.00001). CONCLUSIONS: This review has demonstrated the varying benefits of spinal anesthesia in awake spine surgery relative to general anesthesia in patients who underwent various lumbar procedures. The analysis has shown that spinal anesthesia may offer some benefits when compared with general anesthesia, including reduction in the duration of anesthesia, operative time, total cost, and postoperative complications. Large prospective trials will elucidate the true role of this modality in spine surgery.

The role of an anterior approach in the treatment of ankylosing spondylitis-associated cervical fractures: a systematic review and meta-analysis.

OBJECTIVE: Cervical fractures in patients with ankylosing spondylitis can have devastating neurological consequences. Currently, several surgical approaches are commonly used to treat these fractures: anterior, posterior, and anterior-posterior. The relative rarity of these fractures has limited the ability of surgeons to objectively determine the merits of each. The authors present an updated systematic review and meta-analysis investigating the utility of anterior surgical approaches relative to posterior and anterior-posterior approaches. METHODS: After a comprehensive literature search of the PubMed, Cochrane, and Embase databases, 7 clinical studies were included in the final qualitative and 6 in the final quantitative analyses. Of these studies, 6 compared anterior approaches with anterior-posterior and posterior approaches, while 1 investigated only an anterior approach. Odds ratios and 95% confidence intervals were calculated where appropriate. RESULTS: A meta-analysis of postoperative neurological improvement revealed no statistically significant differences in gross rates of neurological improvement between anterior and posterior approaches (OR 0.40, 95% CI 0.10-1.59; p = 0.19). However, when analyzing the mean change in neurological function, patients who underwent anterior approaches had a significantly lower mean change in postoperative neurological function relative to patients who underwent posterior approaches (mean difference [MD] -0.60, 95% CI -0.76 to -0.45; p < 0.00001). An identical trend was seen between anterior and anterior-posterior approaches; there were no statistically significant differences in gross rates of neurological improvement (OR 3.05, 95% CI 0.84-11.15; p = 0.09). However, patients who underwent anterior approaches experienced a lower mean change in neurological function relative to anterior-posterior approaches (MD -0.46, 95% CI -0.60 to -0.32; p < 0.00001). There were no significant differences in complication rates between anterior approaches, posterior approaches, or anterior-posterior approaches, although complication rates trended lower in patients who underwent anterior approaches. CONCLUSIONS: The results of this review and meta-analysis demonstrated the varying benefits of anterior approaches relative to posterior and anterior-posterior approaches in treatment of cervical fractures associated with ankylosing spondylitis. While reports demonstrated lower degrees of neurological improvement in anterior approaches, they may benefit patients with less-severe injuries if lower complication rates are desired.

Antiresorptive and anabolic medications used in the perioperative period of patients with osteoporosis undergoing spine surgery: their impact on the biology of fusion and systematic review of the literature.

OBJECTIVE: Osteoporosis represents the most common metabolic disease of the bone, with an estimated 10% of adults aged 50 years or older affected in the United States. This patient population is at increased risk for spine fracture and instrumentation-related complications after spine surgery. Surgeon knowledge of the available treatments for patients with low bone mineral density (BMD) and how they impact biology of fusion may help mitigate negative effects in the postoperative period. Recombinant parathyroid hormone, which is sold under the name teriparatide, is the most extensively studied bone-protecting agent in humans. Additionally, the success of the monoclonal antibody denosumab has led to further clinical investigations of human patients undergoing spine surgery. Another monoclonal antibody, romosozumab, was recently approved by the US FDA for human use in patients with osteoporosis. Although studies of romosozumab in patients undergoing spine surgery have not been conducted, this is a promising potential therapeutic agent based on its early success in preclinical and clinical trials. Here, the authors aimed to review the mechanisms of action and evidence of use of antiresorptive and anabolic agents in patients with osteoporosis undergoing spine surgery. METHODS: In accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, a systematic review was conducted to explore the antiresorptive and anabolic agents used in the perioperative period in patients with osteoporosis undergoing spinal surgery. The search was performed by using the PubMed, Embase, and Cochrane Library databases. Titles and abstracts were screened and subsequently selected for full review. RESULTS: The initial search returned 330 articles. Of these articles, 23 final articles were included and reviewed. Many of these articles reported that use of adjuvant agents in the perioperative period improved radiographic evidence of bony fusion and bone fusion rates. These agents tended to improve BMD postoperatively. CONCLUSIONS: Although antiosteoporosis agents are effective to varying degrees as treatments of patients with low BMD, teriparatide and bisphosphonates have been the most extensively studied with respect to spinal instrumentation. The advent of newer agents represents an area for further exploration, especially due to the current paucity of controlled investigations. It is imperative for spine surgeons to understand the mechanisms of action of these drugs and their effects on biology of fusion.

Indeterminate Cell Histiocytosis of the Spine: A Case Report.

INTRODUCTION: Indeterminate cell histiocytosis is a rare neoplastic disease characterized by proliferation of dendritic cells that share morphologic and immunophenotypic features of Langerhans cells and non-Langerhans histiocytes. ICH lesions are typically restricted to the skin; however, there have been rare reports of extracutaneous and systemic involvement. CASE PRESENTATION: We describe a case of a 13-year-old female presenting with complaints of worsening lower back pain for 1 year. CT and MRI of the lumbar spine demonstrated a well-defined bony, lytic, expansile lesion of the posterior and mid-endplate of the L4 vertebra with mass effect on the thecal sac. The patient underwent L3-L5 decompression and fusion with surgical excision of the vertebral body tumor. Microscopic examination of the lesion showed benign fibrohistiocytic proliferation with giant cells, and immunohistochemical staining revealed a phenotype consistent with indeterminate cell histiocytosis (S100+ CD1a+ langerin-). DISCUSSION/CONCLUSION: ICH is an extraordinarily rare neoplastic disease of dendritic cells that has a poorly understood pathogenesis. This case expands the spectrum of potential ICH extracutaneous involvement to now include the spine, a location previously undocumented in the literature in the pediatric population.

Carotid Body Tumor Microenvironment.

Carotid body tumors (CBTs) are rare paragangliomas, comprising 0.5% of all head and neck tumors, and 65% of head and neck paragangliomas. A majority of CBTs occur sporadically, while 15% are familial or hyperplastic in the setting of chronic hypoxia. They usually present as unilateral, well-circumscribed rubbery masses, arising at the level of the carotid bifurcation. A majority of CBTs are painless and therefore may evade diagnosis for months to years. Symptomatic lesions occur due to progressive cranial nerve IX, X, or XII dysfunction, manifesting as hoarseness, dysphagia, vertigo, coughing, or odynophagia. Other local symptoms include neck discomfort, pulsatile tinnitus, hearing loss, or carotid sinus syndrome. Appropriate workup includes a thorough physical exam followed by radiographic imaging, vascular studies, and biochemical workup with 24 h urinary catecholamine or metanephrine analysis. The management of these tumors, which involves standalone surgical resection or following embolization for larger and more vascular tumors, will also be discussed.

Prolonged Heightened Blood Pressure Following Mechanical Thrombectomy for Acute Stroke is Associated with Worse Outcomes.

BACKGROUND: Most data evaluating the relationship of post-mechanical thrombectomy (MT) blood pressure (BP) management and outcomes of patients with large vessel occlusion (LVO) focus on early BP control within the first 24 h. We investigated the correlation of daily BP trends up to the third day following MT with patient outcomes. METHODS: We retrospectively reviewed our prospectively maintained database for LVO patients treated with MT from February 2015 to December 2017. Recorded BP values for 72 h post-reperfusion were reviewed. Daily peak systolic and diastolic blood pressures (SBP, DBP) were extracted for each day post-procedure. The association and importance between BP increments of 10 mmHg and mortality, hemorrhage, and functional independence (FI = mRS ≤ 2) was analyzed in a multivariable logistic regression and random forest (RF) analyses modeling. RESULTS: A total of 212 thrombectomies were included. An increase in peak 24-h SBP was independently associated with higher likelihood of symptomatic hemorrhage (OR 1.2, p = 0.048) and decreased functional independence (OR 0.85, p = 0.03). Higher day 2 and day 3 peak SBP was strongly correlated with decreased functional independence and higher mortality. Third day SBP < 140 was independently associated with higher likelihood of functional independence (OR 4.3, p = 0.0004). Post-MT patients with and without functional independence demonstrated a similar relative decrease in peak SBP between the first 2 days following thrombectomy (p = 0.26); however, those without functional independence experienced a significant rebound increase in peak SBP on the third day following MT (mean change from day 2 to 3: FI - 3.5 mmHg, non-FI + 3.9 mmHg; p = 0.005). CONCLUSION: High daily maximum SBP and a rebound SBP on the third day following MT is independently associated with increased likelihood of functional dependence.

Endothelial dysfunction in cerebral aneurysms

Endothelial cell (EC) dysfunction is known to contribute to cerebral aneurysm (CA) pathogenesis. Evidence shows that damage or injury to the EC layer is the first event in CA formation. The mechanisms behind EC dysfunction in CA disease are interrelated and include hemodynamic stress, hazardous nitric oxide synthase (NOS) activity, oxidative stress, estrogen imbalance, and endothelial cell-to-cell junction compromise. Abnormal variations in hemodynamic stress incite pathological EC transformation and inflammatory zone formation, ultimately leading to destruction of the vascular wall and aneurysm dilation. Hemodynamic stress activates key molecular pathways that result in the upregulation of chemotactic cytokines and adhesion molecules, leading to inflammatory cell recruitment and infiltration. Concurrently, oxidative stress damages EC-to-EC junction proteins, resulting in interendothelial gap formation. This further promotes leukocyte traffic into the vessel wall and the release of matrix metalloproteinases, which propagates vascular remodeling and breakdown. Abnormal hemodynamic stress and inflammation also trigger adverse changes in NOS activity, altering proper EC mediation of vascular tone and the local inflammatory environment. Additionally, the vasoprotective hormone estrogen modulates gene expression that often suppresses these harmful processes. Crosstalk between these sophisticated pathways contributes to CA initiation, progression, and rupture. This review aims to outline the complex mechanisms of EC dysfunction in CA pathogenesis.

Concerns, Perceptions, and Career Considerations of Female Medical Students Interested in Neurosurgery: A Qualitative Case Study.

BACKGROUND: Neurosurgery exhibits notably lower representation of Black, Hispanic, and female surgeons compared to various other medical and surgical specialties. Existing research focuses on medical students' views on surgeons, factors influencing female medical students' preferences in surgical fields, and the perceived interests and concerns of students contemplating a career in neurosurgery. However, there is a significant gap in understanding the unique concerns and perspectives of female medical students interested in neurosurgery. METHODS: Semi-structured interviews with female medical students were recruited from medical schools in the DC area. Interview questions were based on Lent and Brown's Social Cognitive Career Theory. Transcripts were analyzed thematically into codes. RESULTS: In total, 8 female medical students from our institution participated. We identified three major themes that influenced medical students decision making: sense of belonging (diversity, mentorship, passionate), self-efficacy (ambitious/"gunner", intense/competitive), and outcome expectations (innovation/research, immediate impact, procedural/surgical aspect, salary, work-life balance). CONCLUSION: Female medical students face distinct challenges and factors to consider when choosing a career in neurological surgery. The biggest concern for female students was a sense of belonging. It is imperative to enhance the diversity within the neurosurgical specialty and boost the representation of female neurosurgeons. Early interventions designed to tackle and alleviate their specific concerns are pivotal in achieving this goal.

Healthcare disparities in pediatric neurosurgery: a scoping review.

OBJECTIVE: The aim of this scoping review was to identify relevant articles that have contributed to the body of knowledge describing pediatric neurosurgical healthcare disparities. Identifying healthcare disparities in pediatric neurosurgery is essential to understanding how to best provide care for this unique patient population. Although it is undoubtedly important to increase the knowledge of pediatric neurosurgical healthcare disparities, it is also important to understand the current state of the literature. METHODS: This scoping review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines. The search terms "pediatric neurosurgical disparities" and "pediatric neurosurgical inequities" were entered into the following databases: PubMed, Scopus, and Embase. RESULTS: The initial database search returned a total of 366 results from the PubMed, Embase, and Scopus databases. One hundred thirty-seven duplicates were removed, and the remaining articles were screened by title and abstract. Articles were excluded on the basis of the inclusion and exclusion criteria. Of the remaining 229 articles, 168 were excluded. Sixty-one full-text articles were then examined for eligibility, and 28 did not reach the specified inclusion and exclusion criteria. The remaining 33 articles were included for final review. The results of the reviewed studies were stratified on the basis of disparity type. CONCLUSIONS: Although there has been an increase in the number of publications discussing pediatric neurosurgical healthcare disparities within the last decade, there still remains a scarcity of information regarding healthcare disparities in neurosurgery. Furthermore, less information exists that specifically addresses healthcare disparities in the pediatric population.

The Use of Carbon Fiber-Reinforced Instrumentation in Patients with Spinal Oncologic Tumors: A Systematic Review of Literature and Future Directions.

INTRODUCTION: Metastatic spine tumors affect over 30% of patients who have been diagnosed with cancer. While techniques in surgical intervention have undoubtedly evolved, there are some pitfalls when spinal instrumentation is required for stabilization following tumor resection. However, the use of carbon fiber-reinforced polyetheretherketone (CFR-PEEK) implants has become increasingly popular due to improved radiolucency and positive osteobiologic properties. Here, we present a systematic review describing the use of CFR-PEEK-coated instrumentation in the oncologic population while identifying advantages and potential shortcomings of these devices. METHODS: In accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, a systematic review was conducted in March 2022 to identify articles detailing the use of CFR-PEEK implants for spinal instrumentation in patients with primary and secondary spine tumors. The search was performed using the PubMed, Scopus, and Embase databases. RESULTS: An initial search returned a total of 85 articles among the three databases used. After the exclusion of duplicates and screening of abstracts, 21 full-text articles were examined for eligibility. Eleven articles were excluded due to not fitting our inclusion and exclusion criteria. Ten articles were subsequently eligible for full-text review. CONCLUSIONS: CFR-PEEK possesses a similar safety and efficacy profile to titanium implants but has distinct advantages. It limits artifact, increases early detection of local tumor recurrence, increases radiotherapy dose accuracy, and is associated with low complication rates (9.96%)-making it a promising alternative for the demands unique to the treatment/outcome of spinal oncologic patients.

FKBP38 Regulates Self-Renewal and Survival of GBM Neurospheres.

Glioblastoma is the most common malignant primary brain tumor. The outcome is dismal, despite the multimodal therapeutic approach that includes surgical resection, followed by radiation and chemotherapy. The quest for novel therapeutic targets to treat glioblastoma is underway. FKBP38, a member of the immunophilin family of proteins, is a multidomain protein that plays an important role in the regulation of cellular functions, including apoptosis and autophagy. In this study, we tested the role of FKBP38 in glioblastoma tumor biology. Expression of FKBP38 was upregulated in the patient-derived primary glioblastoma neurospheres (GBMNS), compared to normal human astrocytes. Attenuation of FKBP38 expression decreased the viability of GBMNSs and increased the caspase 3/7 activity, indicating that FKBP38 is required for the survival of GBMNSs. Further, the depletion of FKBP38 significantly reduced the number of neurospheres that were formed, implying that FKBP38 regulates the self-renewal of GBMNSs. Additionally, the transient knockdown of FKBP38 increased the LC3-II/I ratio, suggesting the induction of autophagy with the depletion of FKBP38. Further investigation showed that the negative regulation of autophagy by FKBP38 in GBMNSs is mediated through the JNK/C-Jun-PTEN-AKT pathway. In vivo, FKBP38 depletion significantly extended the survival of tumor-bearing mice. Overall, our results suggest that targeting FKBP38 imparts an anti-glioblastoma effect by inducing apoptosis and autophagy and thus can be a potential therapeutic target for glioblastoma therapy.

Flexible thecoscopy for extensive spinal arachnoiditis.

OBJECTIVE: Chronic adhesive spinal arachnoiditis (SA) is a complex disease process that results in spinal cord tethering, CSF flow blockage, intradural adhesions, spinal cord edema, and sometimes syringomyelia. When it is focal or restricted to fewer than 3 spinal segments, the disease responds well to open surgical approaches. More extensive arachnoiditis extending beyond 4 spinal segments has a much worse prognosis because of less adequate removal of adhesions and a higher propensity for postoperative scarring and retethering. Flexible neuroendoscopy can extend the longitudinal range of the surgical field with a minimalist approach. The authors present a cohort of patients with severe cervical and thoracic arachnoiditis and myelopathy who underwent flexible endoscopy to address arachnoiditis at spinal segments not exposed by open surgical intervention. These observations will inform subsequent efforts to improve the treatment of extensive arachnoiditis. METHODS: Over a period of 3 years (2017-2020), 10 patients with progressive myelopathy were evaluated and treated for extensive SA. Seven patients had syringomyelia, 1 had spinal cord edema, and 2 had spinal cord distortion. Surgical intervention included 2- to 5-level thoracic laminectomy, microscopic lysis of adhesions, and then lysis of adhesions at adjacent spinal levels performed using a rigid or flexible endoscope. The mean follow-up was 5 months (range 2-15 months). Neurological function was examined using standard measures. MRI was used to assess syrinx resolution. RESULTS: The mean length of syringes was 19.2 ± 10 cm, with a mean maximum diameter of 7.0 ± 2.9 mm. Patients underwent laminectomies averaging 3.7 ± 0.9 (range 2-5) levels in length followed by endoscopy, which expanded exposure by an average of another 2.4 extra segments (6.1 ± 4.0 levels total). Endoscopic dissection of extensive arachnoiditis in the dorsal subarachnoid space proceeded through a complex network of opaque arachnoidal bands and membranes bridging from the dorsal dura mater to the spinal cord. In less severely problematic areas, the arachnoid membrane was transparent and attached to the spinal cord through multifocal arachnoid adhesions bridging the subarachnoid space. The endoscope did not compress or injure the spinal cord. CONCLUSIONS: Intrathecal endoscopy allowed visual assessment and safe removal of intradural adhesions beyond the laminectomy margins. Further development of this technique should improve its effectiveness in opening the subarachnoid space and untethering the spinal cord in cases of extensive chronic adhesive SA.

Use of an External Ventricular Drain for Treatment of a Thoracolumbar Cerebrospinal Fluid Leak: A Case Report and Review of Literature.

Post-operative cerebrospinal fluid (CSF) leak is a known complication in spine surgery. This mostly iatrogenic issue is typically treated using a variety of modalities (i.e., bed rest, epidural patch), CSF diversion methods, or primary repair. The use of an external ventricular drain to treat this post-operative complication has been infrequently reported. We describe a case of a CSF leak after thoraco-lumbar surgery treated using an external ventricular drain and a review of the literature regarding this treatment modality. A 70-year-old man presented to our clinic with a recent diagnosis of multiple myeloma with progressive thoracic kyphosis and spinal stenosis. He developed progressive neurological deficits over the course of several weeks. Radiological studies showed significant thoracic kyphosis and severe cord compression in the thoraco-lumbar area. The patient underwent a T9-L4 posterior instrumentation and fusion with decompression surgery that developed post-operative wound infection and a CSF leak. An external ventricular drain (EVD) was used successfully as a CSF diversion method where direct thoracolumbar approaches were not feasible. Given the effectiveness of EVD placement in treating this post-operative complication, we concluded that the use of an EVD can be a potentially safe and effective way to treat thoracolumbar CSF leakage when lumbar or cervical drainage is not feasible.

Non-invasive in situ Visualization of the Murine Cranial Vasculature.

Understanding physiologic and pathologic central nervous system function depends on our ability to map the entire in situ cranial vasculature and neurovascular interfaces. To accomplish this, we developed a non-invasive workflow to visualize murine cranial vasculature via polymer casting of vessels, iterative sample processing and micro-computed tomography, and automatic deformable image registration, feature extraction, and visualization. This methodology is applicable to any tissue and allows rapid exploration of normal and altered pathologic states.

Targeting protein arginine methyltransferase 5 sensitizes glioblastoma to trametinib.

Background: The prognosis of glioblastoma (GBM) remains dismal because therapeutic approaches have limited effectiveness. A new targeted treatment using MEK inhibitors, including trametinib, has been proposed to improve GBM therapy. Trametinib had a promising preclinical effect against several cancers, but its adaptive treatment resistance precluded its clinical translation in GBM. Previously, we have demonstrated that protein arginine methyltransferase 5 (PRMT5) is upregulated in GBM and its inhibition promotes apoptosis and senescence in differentiated and stem-like tumor cells, respectively. We tested whether inhibition of PRMT5 can enhance the efficacy of trametinib against GBM. Methods: Patient-derived primary GBM neurospheres (GBMNS) with transient PRMT5 knockdown were treated with trametinib and cell viability, proliferation, cell cycle progression, ELISA, and western blot were analyzed. In vivo, NSG mice were intracranially implanted with PRMT5-intact and -depleted GBMNS, treated with trametinib by daily oral gavage, and observed for tumor progression and mice survival rate. Results: PRMT5 depletion enhanced trametinib-induced cytotoxicity in GBMNS. PRMT5 knockdown significantly decreased trametinib-induced AKT and ERBB3 escape pathways. However, ERBB3 inhibition alone failed to block trametinib-induced AKT activity suggesting that the enhanced antitumor effect imparted by PRMT5 knockdown in trametinib-treated GBMNS resulted from AKT inhibition and not ERBB3 inhibition. In orthotopic murine xenograft models, PRMT5-depletion extended the survival of tumor-bearing mice, and combination with trametinib further increased survival. Conclusion: Combined PRMT5/MEK inhibition synergistically inhibited GBM in animal models and is a promising strategy for GBM therapy.