Childhood Brain Tumors: A Review of Strategies to Translate CNS Drug Delivery to Clinical Trials.

Brain and spinal tumors affect 1 in 1000 people by 25 years of age, and have diverse histological, biological, anatomical and dissemination characteristics. A mortality of 30-40% means the majority are cured, although two-thirds have life-long disability, linked to accumulated brain injury that is acquired prior to diagnosis, and after surgery or chemo-radiotherapy. Only four drugs have been licensed globally for brain tumors in 40 years and only one for children. Most new cancer drugs in clinical trials do not cross the blood-brain barrier (BBB). Techniques to enhance brain tumor drug delivery are explored in this review, and cover those that augment penetration of the BBB, and those that bypass the BBB. Developing appropriate delivery techniques could improve patient outcomes by ensuring efficacious drug exposure to tumors (including those that are drug-resistant), reducing systemic toxicities and targeting leptomeningeal metastases. Together, this drug delivery strategy seeks to enhance the efficacy of new drugs and enable re-evaluation of existing drugs that might have previously failed because of inadequate delivery. A literature review of repurposed drugs is reported, and a range of preclinical brain tumor models available for translational development are explored.

Application of the subdural evacuating port system for the drainage of postoperative tension pneumocephalus: A technical note.

Background: Tension pneumocephalus is a neurosurgical emergency requiring prompt intervention. A variety of either temporizing or definitive methods was previously described as part of its management. Here, we report on an off-label use of a bed-side device and the subdural evacuating port system (SEPS)™ for the treatment of tension pneumocephalus. Methods: The SEPS™ (Medtronic Dublin, Ireland) is a minimally invasive tool that is indicated for the removal of chronic or subacute subdural hematomas and at the patient's bedside. We describe the use of this system to evacuate tension pneumocephalus. Results: A 44-year-old patient operated in our institution was presented with sudden obtundation 4 days post resection of esthesioneuroblastoma. Imaging confirmed a significant tension pneumocephalus. Immediate bedside decompression using a SEPS bolt placed frontally was performed, achieving rapid evacuation and patient regained consciousness. A definitive skull base reconstruction was done at the operating room at a later stage. Conclusion: The SEPS™, well-known for evacuation of CSDH, can be potentially used as a bed-side tool to effectively treat mass effect created by tension pneumocephalus. As a readily-available and commercially used device, it can provide a simple and standard toolkit suitable for an emergent temporizing procedure.

Microsurgical Management of Complex Hypothalamic Hamartomas in the Era of Minimally Invasive Therapy: A Case Series and Narrative Review.

BACKGROUND: There has been a paradigm shift in the management of hypothalamic hamartoma (HH) from traditional microsurgical techniques to less invasive alternatives. However, large and extensive HH may fail to respond to these therapies, necessitating craniotomies. METHODS: All patients who underwent microsurgical resection of a complex HH by the 2 senior authors from 2011 to 2021 were included. Charts were retrospectively reviewed and demographic, clinical, imaging, and outcome data were recorded. RESULTS: Eight patients (mean age, 7 years) were included. Two had failed previous treatments. All 7 presented with gelastic seizures and cognitive dysfunction, 6 showed central precocious puberty, and 3 had behavioral problems. The mean lesion size was 21.6 mm and all had interpeduncular extension, 5 had intraventricular extension (Delalande type I, 3; type III, 4; type IV, 1). A frontotemporal orbitozygomatic approach with optic nerve decompression was used in all patients, supplemented by another approach in 3 (endoscopic transventricular, 3; transcallosal, 1). Gross total resection was achieved in 6 patients and subtotal resection in 2. Transient complications occurred in 3 patients (37.5%): self-limited sodium imbalance (n = 3), subdural hygroma (n = 2). Permanent complications occurred in 2 patients (25%): perforator infarct (n = 1) and short-term memory loss (n = 1). All patients experienced seizure resolution with preserved hypothalamic-pituitary axis function. After a mean follow-up of 41 months (range, 2-66 months), 7 patients remained seizure free, and 1 had rare seizures. Cognitive and behavioral symptoms improved in all patients. CONCLUSIONS: For large HH with interpeduncular extension, microsurgery via the frontotemporal orbitozygomatic approach is a safe and highly effective treatment modality.

Retrosigmoid transhorizontal fissure approach to lateral pontine cavernous malformation: comparison to transpetrosal presigmoid retrolabyrinthine approach.

OBJECTIVE: The retrosigmoid (RS) approach is a classic route used to access deep-seated brainstem cavernous malformation (CM). The angle of access is limited, so alternatives such as the transpetrosal presigmoid retrolabyrinthine (TPPR) approach have been used to overcome this limitation. Here, the authors evaluated a modification to the RS approach, horizontal fissure dissection by using the RS transhorizontal (RSTH) approach. METHODS: Relevant clinical parameters were evaluated in 9 patients who underwent resection of lateral pontine CM. Cadaveric dissection was performed to compare the TPPR approach and the RSTH approach. RESULTS: Five patients underwent the TPPR approach, and 4 underwent the RSTH approach. Dissection of the horizontal fissure allowed for access to the infratrigeminal safe entry zone, with a direct trajectory to the middle cerebellar peduncle similar to that used in TPPR exposure. Operative time was longer in the TPPR group. All patients had a modified Rankin Scale score ≤ 2 at the last follow-up. Cadaveric dissection confirmed increased anteroposterior working angle and middle cerebellar peduncle exposure with the addition of horizontal fissure dissection. CONCLUSIONS: The RSTH approach leads to a direct lateral path to lateral pontine CM, with similar efficacy and shorter operative time compared with more extensive skull base exposure. The RSTH approach could be considered a valid alternative for resection of selected pontine CM.

Technical aspects and operative nuances using a high-definition 4K-3-dimensional exoscope for carotid endarterectomy surgery.

PURPOSE: Carotid endarterectomy (CEA) is effective in treating carotid artery stenosis to prevent stroke. Historically, this operation has been performed utilizing loupe magnification with or without the operating microscope (OM). However, there remains a need for continued improvement in operative visualization and surgical ergonomics. Recently, newly developed digital 'exoscope' has provided the surgeon with unique lighting and magnification as well as improvements in surgical ergonomics and working angle. We sought to review our cumulative experience using a novel 4K high-definition (4K-HD) 3-dimensional (3D) exoscope (EX) for CEA surgery. METHODS: All CEA surgery cases at our institution between 2013 and 2019 using the 4K-HD 3D EX were reviewed. Operative parameters, patient outcome and operator's assessment of the EX compared to OM-assisted cases was conducted. RESULTS: 28 patients were treated, 10 of which were operated using the EX. All procedures were performed without perioperative complications, or significant differences in operative parameters (blood loss <20 cm3 and 164 ± 49.5 minutes) compared to OM-assisted cases. Operators reported improved level of comfort performing 'high' bifurcation surgery and improved visualization and posture during inspection of the distal ICA lumen as primary advantages of EX-assisted CEA over OM-assisted CEA. CONCLUSIONS: The ORBEYE EX, albeit a learning curve necessitating a short period of the OR team, provided safety and outcome comparable to OM-assisted surgery. Potential advantages noted were improved visualization and ergonomics specifically for when extreme working angles were required. Our experience suggests that the exoscope may become a valuable alternative to standard magnification tools in CEA surgery.

Diffusion Tensor Imaging Color-Coded Maps: An Alternative to Tractography.

INTRODUCTION: White matter tracts can be observed using tractograms generated from diffusion tensor imaging (DTI). However, the dependence of these white matter tract images on subjective variables, including how seed points are placed and the preferred level of fractional anisotropy, introduces interobserver inconsistency and potential lack of reliability. We propose that color-coded maps (CCM) generated from DTI can be a preferred method for the visualization of important white matter tracts, circumventing bias in preoperative brain tumor resection planning. METHODS: DTI was acquired retrospectively in 25 patients with brain tumors. Lesions included 15 tumors of glial origin, 9 metastatic tumors, 2 meningiomas, and 1 cavernous angioma. Tractograms of the pyramidal tract and/or optic radiations, based on tumor location, were created by marking seed regions of interest using known anatomical locations. We compared the degree of tract involvement and white matter alteration between CCMs and tractograms. Neurological outcomes were obtained from chart reviews. RESULTS: The pyramidal tract was evaluated in 20/25 patients, the visual tracts were evaluated in 10/25, and both tracts were evaluated in 5/25. In 19/25 studies, the same patterns of white matter alternations were found between the CCMs and tractograms. In the 6 patients where patterns differed, 2 tractograms were not useful in determining pattern alteration; in the remaining 4/6, no practical difference was seen in comparing the studies. Two patients were lost to follow-up. Thirteen patients were neurologically improved or remained intact after intervention. In these, 10 of the 13 patients showed tumor-induced white matter tract displacement on CCM. Twelve patients had no improvement of their preoperative deficit. In 9 of these 12 patients, CCM showed white matter disruption. CONCLUSION: CCMs provide a convenient, practical, and objective method of visualizing white matter tracts, obviating the need for potentially subjective and time-consuming tractography. CCMs are at least as reliable as tractograms in predicting neurological outcomes after neurosurgical intervention.

Sphenoid Wing Meningioma with Surgical Revascularization of an Injured Anterior Temporal Artery.

A 79-year-old woman presented to the emergency department following multiple falls in the previous week. Her past medical history was unremarkable except for chronic obstructive pulmonary disease. She was neurologically intact on arrival with normal laboratory data. Brain imaging revealed a right-sided sphenoid wing meningioma with considerable edema around it. Owing to her cognitive decline and recent symptoms, it was decided to proceed with surgical resection of the lesion. Considering her age and underlying disease, we planned to avoid probable complications of an aggressive resection. She underwent preoperative transarterial embolization with particles. In the supine position, a right pterional craniotomy with orbital extension was performed followed by tumor resection under microscopic magnification. One of the branches of the middle cerebral artery was engulfed by the tumor and could not be separated; therefore, the artery was cut to resect the tumor and then mobilized and reanastomosed under microscope. Doppler probe confirmed patency of the anastomosis. The patient recovered well from the surgery, experienced an uneventful hospital stay, and was discharged on postoperative day 10 after completely controlling her chronic obstructive pulmonary disease. Postoperative imaging did not show any signs of infarction, and the revascularized artery was patent on postoperative computed tomography angiography (Video 1).

Near Total Versus Gross Total Resection of Large Vestibular Schwannomas: Facial Nerve Outcome.

BACKGROUND: Large vestibular schwannomas (VSs) with brainstem compression are generally reserved for surgical resection. Surgical aggressiveness must be balanced with morbidity from cranial nerve injury. The purpose of the present investigation is to evaluate the clinical presentation, management modality, and patient outcomes following near total resection (NTR) vs gross total resection (GTR) of large VSs. OBJECTIVE: To assess facial nerve outcome differences between GTR and NTR patient cohorts. METHODS: Between January 2010 and March 2018, a retrospective chart review was completed to capture patients continuously who had VSs with Hannover grades T4a and T4b. NTR was decided upon intraoperatively. Primary data points were collected, including preoperative symptoms, tumor size, extent of resection, and postoperative neurological outcome. RESULTS: A total of 37 patients underwent surgery for treatment of large and giant (grade 4a and 4b) VSs. Facial nerve integrity was preserved in 36 patients (97%) at the completion of surgery. A total of 27 patients underwent complete resection, and 10 had near total (>95%) resection. Among patients with GTR, 78% (21/27) had House-Brackmann (HB) grade I-II facial nerve function at follow-up, whereas 100% (10/10) of the group with NTR had HB grade I-II facial nerve function. Risk of meningitis, cerebrospinal fluid leak, and sinus thromboses were not statistically different between the 2 groups. There was no stroke, brainstem injury, or death. The mean follow-up was 36 mo. CONCLUSION: NTR seems to offer a benefit in terms of facial nerve functional outcome compared to GTR in surgical management of large VSs without significant risk of recurrence.

Rechallenging Recurrent Glioblastoma with Intra-Arterial Bevacizumab with Blood Brain-Barrier Disruption Results in Radiographic Response.

BACKGROUND: High-dose bevacizumab delivered via super selective intra-arterial cerebral infusion (SIACI) is one promising clinical trial combination for patients with glioblastoma (GBM). Although both continuous intravenous and intra-arterial administration of bevacizumab, and rechallenge with intravenous bevacizumab, have demonstrated improved survival, this is the first description of rechallenging GBM with SIACI of bevacizumab. CASE DESCRIPTION: We report a case of a 43-year-old woman with recurrent GBM who had received treatment from 3 clinical trials, including a rechallenge with SIACI of bevacizumab. First, she enrolled into a phase I/II trial for patients newly diagnosed with GBM (NCT01811498) and received 3 doses of SIACI bevacizumab over 180 days in addition to standard of care chemotherapy and radiation. Following progression, as indicated on her magnetic resonance imaging scan, she consented for a separate clinical trial for her disease and received 2 cycles of temozolomide with an investigational agent. The patient was removed from the study on tumor progression. Subsequently, she was rechallenged with SIACI of bevacizumab via a third clinical trial (NCT01269853) and then completed 3 intravenous infusions. After completing the third trial, her magnetic resonance imaging scan demonstrated improvement based on Response Assessment In Neuro-Oncology criteria. CONCLUSIONS: This is the first report to highlight the effect of rechallenging a patient with SIACI of bevacizumab following disease progression after initial bevacizumab treatment and subsequent alternate clinical trial failure. There is a need to conduct further clinical trials to evaluate the benefits of rechallenge with SIACI versus intravenous bevacizumab for GBM and further explore theories of bevacizumab resistance.

Technical Aspects and Operative Nuances Using a High-Definition 3-Dimensional Exoscope for Cerebral Bypass Surgery.

BACKGROUND: Cerebral bypass operation is a technically challenging operation that requires excellent surgical visibility and efficient ergonomics to minimize complications and maximize successful revascularization. Despite the operative microscope's utilization for the past two generations, there remains a need for continued improvement in operative visualization and surgical ergonomics. OBJECTIVE: To report the positives and negatives of our initial experience using a novel 4 K high-definition (4K-HD) 3-dimensional (3D) exoscope (EX) for cranial bypass surgery. METHODS: A retrospective review over 6 mo was performed of all patients who have undergone cerebral bypass surgery at a single institution using the 4K-HD 3D EX. Advantages and disadvantages of the EX and clinical outcome of the patients were assessed. RESULTS: A total of 5 patients underwent cerebral EC-IC bypass surgery with no EX-related complications and successful revascularization. The lightweight design of the EX allowed for easy instrument maneuverability as well as uncomplicated surgical set up in the operating room. The assistance of the cosurgeon was significantly more efficient compared to that of the operating microscope. The large monitor allowed for an immersive, collaborative, and valuable educational surgical experience. CONCLUSION: Using the EX for cerebral bypass surgery, with 3D ultra-high-definition optics, enhancements of ergonomics, and improved training, we believe that the 3D 4K-HD EX may represent the next generation of operative scopes in microneurosurgery.

Lessons Learned Using a High-Definition 3-Dimensional Exoscope for Spinal Surgery.

BACKGROUND: The operative microscope has significantly advanced modern neurosurgical spine surgery but continues to be limited by high costs, suboptimal optics, poor ergonomics, and difficulties with maneuverability. We believe the novel 4K high-definition (4K-HD) 3-dimensional (3D) exoscope (EX), may improve the surgical corridor through advancements in illumination, ergonomics, magnification, and depth of field and has the potential to be utilized in neurosurgical education and training. OBJECTIVE: To evaluate the surgical potential of a novel 3D EX system in spinal surgery. METHODS: Retrospective analysis over 6 mo of all patients who have undergone spinal surgery at Northwell Health using the 3D EX. Nuances of surgical theater positioning, advantages/disadvantages of the EX and clinical sequelae of the patients were analyzed. RESULTS: All 10 patients who underwent spinal surgery utilizing the EX experienced excellent surgical and clinical outcomes without complications. The low-profile EX allowed for excellent operative corridors and instrument maneuverability. The large monitor also resulted in an immersive surgical experience, and gave team members the same 3D vision as the operator. CONCLUSION: This study demonstrates the feasibility of utilizing the 3D 4K-HD EX system and highlights potential technical assets of this novel technology in regard to optics, ergonomics, and maneuverability. Further clinical research is needed to examine the clinical effectiveness of the EX system for different surgical approaches through quantitative methodology.

Primary solitary retro-clival amyloidoma.

BACKGROUND: Amyloidosis encompasses a group of disorders sharing the common feature of intercellular deposition of amyloid protein by several different pathogenetic mechanisms. Primary solitary amyloidosis, or amyloidoma, is a rare subset of amyloidosis in which amyloid deposition is focal and not secondary to a systemic process or plasma cell dyscrasia. CASE DESCRIPTION: This 84-year-old female presented with history of multiple syncopal episodes, dysphagia, and ataxia. Motor strength was 3+/5 in the right upper extremity. Rheumatoid factor, cyclic citrullinated peptide (CCP), and anti-nuclear antibody (ANA) were normal. Serum and urine immune-electrophoresis detected no abnormal bands. Computed tomography (CT) and magnetic resonance imaging (MRI) demonstrated a non-enhancing soft-tissue mass extending from the retro-clivus to C2 posteriorly, eccentric to the right with severe mass effect on the upper cervical medullary junction. Endoscopic trans-nasal debulking of the retro-clival mass was performed with occiput to C5 posterior instrumentation for spinal stabilization. CONCLUSIONS: Primary solitary amyloidosis, unlike other forms of amyloidosis, has an excellent prognosis with local resection. Diagnosis requires special stains and a degree of suspicion for the disease. This is the first report to document an endoscopic trans-nasal approach for removal of a primary solitary amyloidosis of the retro-clivus. Management of vertebral amyloidoma involves aggressive local resection of the tumor when feasible and spine stabilization as the degree of tumor involvement mandates. Complete evaluation for the diagnosis of systemic amyloidosis is essential for the management and prognostication. Surgeons encountering such lesions must maintain high suspicion for this rare disease and advise pathologists accordingly to establish the correct diagnosis.