Establishment and characterization of patient-derived xenograft of a rare pediatric anaplastic pleomorphic xanthoastrocytoma (PXA) bearing a CDC42SE2-BRAF fusion.

Pleomorphic xanthoastrocytoma (PXA) is a rare subset of primary pediatric glioma with 70% 5-year disease free survival. However, up to 20% of cases present with local recurrence and malignant transformation into more aggressive type anaplastic PXA (AXPA) or glioblastoma. The understanding of disease etiology and mechanisms driving PXA and APXA are limited, and there is no standard of care. Therefore, development of relevant preclinical models to investigate molecular underpinnings of disease and to guide novel therapeutic approaches are of interest. Here, for the first time we established, and characterized a patient-derived xenograft (PDX) from a leptomeningeal spread of a patient with recurrent APXA bearing a novel CDC42SE2-BRAF fusion. An integrated -omics analysis was conducted to assess model fidelity of the genomic, transcriptomic, and proteomic/phosphoproteomic landscapes. A stable xenoline was derived directly from the patient recurrent tumor and maintained in 2D and 3D culture systems. Conserved histology features between the PDX and matched APXA specimen were maintained through serial passages. Whole exome sequencing (WES) demonstrated a high degree of conservation in the genomic landscape between PDX and matched human tumor, including small variants (Pearson's r = 0.794-0.839) and tumor mutational burden (~ 3 mutations/MB). Large chromosomal variations including chromosomal gains and losses were preserved in PDX. Notably, chromosomal gain in chromosomes 4-9, 17 and 18 and loss in the short arm of chromosome 9 associated with homozygous 9p21.3 deletion involving CDKN2A/B locus were identified in both patient tumor and PDX sample. Moreover, chromosomal rearrangement involving 7q34 fusion; CDC42SE-BRAF t (5;7) (q31.1, q34) (5:130,721,239, 7:140,482,820) was identified in the PDX tumor, xenoline and matched human tumor. Transcriptomic profile of the patient's tumor was retained in PDX (Pearson r = 0.88) and in xenoline (Pearson r = 0.63) as well as preservation of enriched signaling pathways (FDR Adjusted P < 0.05) including MAPK, EGFR and PI3K/AKT pathways. The multi-omics data of (WES, transcriptome, and reverse phase protein array (RPPA) was integrated to deduce potential actionable pathways for treatment (FDR < 0.05) including KEGG01521, KEGG05202, and KEGG05200. Both xenoline and PDX were resistant to the MEK inhibitors trametinib or mirdametinib at clinically relevant doses, recapitulating the patient's resistance to such treatment in the clinic. This set of APXA models will serve as a preclinical resource for developing novel therapeutic regimens for rare anaplastic PXAs and pediatric high-grade gliomas bearing BRAF fusions.

Accuracy of Depth Electrodes is Not Time-Dependent in Robot-Assisted Stereoelectroencephalography in a Pediatric Population.

BACKGROUND AND OBJECTIVES: Robot-assisted stereoelectroencephalography (sEEG) is steadily supplanting traditional frameless and frame-based modalities for minimally invasive depth electrode placement in epilepsy workup. Accuracy rates similar to gold-standard frame-based techniques have been achieved, with improved operative efficiency. Limitations in cranial fixation and placement of trajectories in pediatric patients are believed to contribute to a time-dependent accumulation of stereotactic error. Thus, we aim to study the impact of time as a marker of cumulative stereotactic error during robotic sEEG. METHODS: All patients between October 2018 and June 2022 who underwent robotic sEEG were included. Radial errors at entry and target points as well as depth and Euclidean distance errors were collected for each electrode, excluding those with errors over 10 mm. Target point errors were standardized by planned trajectory length. ANOVA and error rates over time were analyzed using GraphPad Prism 9. RESULTS: Forty-four patients met inclusion criteria for a total of 539 trajectories. Number of electrodes placed ranged from 6 to 22. Average root mean squared error was 0.45 ± 0.12 mm. Average entry, target, depth, and Euclidean distance errors were 1.12 ± 0.41 mm, 1.46 ± 0.44 mm, -1.06 ± 1.43 mm, and 3.01 ± 0.71 mm, respectively. There was no significant increased error with each sequential electrode placed (entry error P -value = .54, target error P -value = .13, depth error P -value = .22, Euclidean distance P -value = .27). CONCLUSION: No decremental accuracy over time was observed. This may be secondary to our workflow which prioritizes oblique and longer trajectories first and then into less error-prone trajectories. Further study on the effect of level of training may reveal a novel difference in error rates.

Single-Institution Comparative Study of Magnetic Resonance-Guided Laser Interstitial Thermal Therapy and Open Corpus Callosotomy.

OBJECTIVE: Open corpus callosotomy (CC) poses a higher risk of perioperative morbidity than does magnetic resonance-guided laser interstitial thermal therapy (MRgLITT) for treatment of drop and generalized seizures without documented superiority. We present a single-institution comparison between open and MRgLITT CC. METHODS: A 2-year retrospective review was performed of patients who underwent open and MRgLITT CC (January 2019-January 2021). Demographics, surgical outcome data, hospital costs, and interhemispheric connectivity with diffusion tensor imaging were compared. RESULTS: The average age in years was 9.3 and 11.4 for CC (n = 4) and MRgLITT (n = 9), respectively. Preoperative drop seizure frequency was higher in CC (25 vs. 14.5 seizures/day; P = 0.59). At 10 months follow-up, the reduction in drop seizure frequency was better in open CC, but not statistically significant (93.8% vs. 64.3%; P = 0.21). The extent of CC ablation did not correlate with seizure reduction (Pearson coefficient = 0.09). An inverse correlation between interhemispheric connectivity change (diffusion tensor imaging analysis) and drop seizure frequency reduction was noted (Pearson coefficient = -0.97). Total hospital cost was significantly lower in MRgLITT ($67,754 vs. $107,111; P = 0.004), attributed to lower intensive care unit (1.1 vs. 4 days; P= 0.004) and total hospital stay (1.8 vs. 10.5 days; P = 0.0001). Postoperative hydrocephalus was present in 75% of patients in the CC group compared with zero in the MRgLITT group. CONCLUSIONS: Our middle-volume single-institution experience shows the safety, efficacy, and cost-effective benefit of MRgLITT compared with the traditional CC with therapeutic equipoise. This study is limited by the number of patients and, hence, further patient enrollment or multicenter study is warranted.

Transhemispheric cortex remodeling promotes forelimb recovery after spinal cord injury.

Understanding the reorganization of neural circuits spared after spinal cord injury in the motor cortex and spinal cord would provide insights for developing therapeutics. Using optogenetic mapping, we demonstrated a transhemispheric recruitment of neural circuits in the contralateral cortical M1/M2 area to improve the impaired forelimb function after a cervical 5 right-sided hemisection in mice, a model mimicking the human Brown-Séquard syndrome. This cortical reorganization can be elicited by a selective cortical optogenetic neuromodulation paradigm. Areas of whisker, jaw, and neck, together with the rostral forelimb area, on the motor cortex ipsilateral to the lesion were engaged to control the ipsilesional forelimb in both stimulation and nonstimulation groups 8 weeks following injury. However, significant functional benefits were only seen in the stimulation group. Using anterograde tracing, we further revealed a robust sprouting of the intact corticospinal tract in the spinal cord of those animals receiving optogenetic stimulation. The intraspinal corticospinal axonal sprouting correlated with the forelimb functional recovery. Thus, specific neuromodulation of the cortical neural circuits induced massive neural reorganization both in the motor cortex and spinal cord, constructing an alternative motor pathway in restoring impaired forelimb function.

Iatrogenic Spinal Deformity Following Spinal Intradural Arachnoid Cyst Fenestration Despite Minimal Access With Laminoplasty and Endoscopy in a Pediatric Patient.

Spinal intradural arachnoid cysts (SAC) are non-neoplastic lesions that can cause spinal cord compression and present with myelopathy, radiculopathy, and/or back pain. Because these cysts typically span multiple levels, endoscopy could be a useful tool to avoid wide exposure. We present an 8-year-old patient with a history of gait imbalance and urinary incontinence who was found to have a SAC spanning C7 to T6 causing spinal cord compression. An osteoplastic laminoplasty was performed from T4 to T7 followed by ultrasonic verification of intracystic septations, dural opening, and cyst fenestration. A flexible endoscope was then introduced into the cystic cavity to guide complete rostral and caudal decompression of the arachnoid cyst. At six months follow-up, the patient was able to ambulate independently, but his urinary incontinence remained unchanged. Despite the combination of ultrasound and neuroendoscopy to minimize exposure, our patient suffered from worsening kyphosis from 36 degrees preoperative to 55 degrees postoperative and worsening scoliosis from 17 to 39 degrees which required treatment with a thoracolumbar sacral orthosis. Preoperative imaging demonstrated a reverse S-shaped scoliosis with the apex at T6 and T7 which were the levels included in the laminoplasty. This illustrates the need for careful preoperative risk stratification to avoid this postoperative complication.

Preoperative and Postoperative Gait Analysis and Video for Selective Dorsal Rhizotomy in Focal Hemiplegic Spasticity: 2-Dimensional Operative Video.

Selective dorsal rhizotomy (SDR) has been a well-established neurosurgical treatment option for ambulatory children with spastic diplegic cerebral palsy to reduce spasticity. Outcomes for SDR for spastic lower extremity hemiparesis has been less well described. In our experience, hemi-SDR has been an excellent intervention for children with suboptimal spasticity control despite maximizing pharmacologic and chemodenervation treatments. In Video 1, we demonstrate a focal segmental hemi-SDR at the L5-S1 level in a 7-year-old male patient with spastic hemiparesis secondary to a dysembryoplastic neuroepithelial tumor in the right inferior frontoparietal area. Rhizotomy was performed with identification and selective sectioning of dorsal nerve roots with abnormal stimulation patterns as determined by electrophysiology and clinical correlation. Dorsal nerve root fibers with unsustained discharges were spared. Postoperatively, the patient participated well in inpatient and outpatient therapies with significant progress in his mobility and activities of daily living. The patient showed improvement in gait velocity (51%), internal pressure ratio (+0.05), and step length (41% on the left and 27% on the right) 20 months after hemi-SDR. He also demonstrated a step length ratio closer to 1 (0.89) showing a more equal step length bilaterally and improved weight acceptance on the affected side. There were no changes observed on the left upper extremity. This positive outcome on spasticity control and function supports the need for further prospective studies for hemi-SDR as a treatment option for children with spastic hemiparesis.

Seemingly inconsequential yet catastrophic: the importance of wound washout with minute depressed skull fracture from a dog bite.

Depressed skull fractures from dog bites are common pediatric head injuries which are contaminated with native skin and canine oral flora. Outcomes can potentially be catastrophic. Thus, these injuries require proper initial management to prevent future complications. We present an 18-month-old female who was bitten by a Great Dane dog and resulted in a small left temporal depressed skull fracture with an underlying brain contusion. This was initially treated conservatively with antibiotics and bedside irrigation. Five weeks later, she developed a large multiloculated abscess with mass effect, which required surgical aspiration and wound debridement. After long-term antibiotics, she made a full neurologic recovery. Our case illustrates the importance of washing out a seemingly inconsequential depressed skull fracture from a dog bite to avoid development of a cerebral abscess.

Delayed presentation of a traumatic scalp arteriovenous fistula.

BACKGROUND: Arteriovenous (AV) fistulas of the scalp are extracranial vascular malformations commonly caused by trauma and typically present within 3 years. Although they follow a benign course, they can be esthetically displeasing. CASE DESCRIPTION: We present an atypical onset of scalp AV fistula in a patient with a 1-year history of the left-sided pulsatile tinnitus and scalp swelling 7 years after a traumatic epidural hematoma evacuation. Our patient was found to have an 8 mm AV fistula supplied by the deep temporal artery. Endovascular embolization was performed using eight coils. There was no complication from the procedure, and the patient's pulsatile tinnitus and swelling resolved immediately after embolization. Follow-up angiogram demonstrated complete obliteration of the AV fistula. CONCLUSION: Delayed presentation of traumatic scalp AV fistula is very rare, and it is important to keep this in the differential in patients with scalp swelling after head trauma.

Intracranial Vasospasm After Evacuation of Acute Spontaneous Subdural Hematoma.

Cerebral vasospasm is a well-known entity following aneurysmal subarachnoid hemorrhage. While it has been described in trauma, it has been much less studied. There have been no previous reports of cerebral vasospasm following spontaneous subdural hematoma or after subdural hematoma evacuation. In this case report, we present a 38-year-old otherwise healthy female who suffered an acute spontaneous subdural hematoma. After surgical evacuation of her hematoma, she developed neurologic decline. Computer tomography angiography demonstrated intracranial vasospasm. She was treated with blood pressure augmentation and nimodipine. She went on to make a full neurologic recovery.To our knowledge, this is the first reported case of cerebral vasospasm after acute spontaneous subdural hematoma or after subdural hematoma evacuation, and the patient recovered without sequelae. The promising outcome of this case may provide a framework for future similar cases. Neurosurgeons and intensivists should keep cerebral vasospasm in their differentials for patients who have neurologic decline after craniotomy for acute subdural hematoma and have an otherwise negative scan for new acute abnormality.

Characterization of standard work tools for intrathecal baclofen therapy.

PURPOSE: Intrathecal baclofen (ITB) has been an effective therapy since the 1980s, with widely reported revision, infection, and complication rates. Publications targeting surgical workflow have resulted in decreased infection and revision rates, but a standard workflow for the entire pathway has not been described. To present, define, and test standard work tools for patients receiving ITB to promote uniformity and standard of care in the field. METHODS: A multidisciplinary approach from the movement disorder program of a tertiary care center defined all steps comprising the ITB pathway, and then developed standard work tools to decrease variability with respect to preoperative workup, day of surgery protocol, post-operative care, and also evaluation and treatment with respect to pump infection or malfunction. RESULTS: Defined steps used at specific points of ITB pathway are presented with a single institution's outcome using the protocol from July 2017 to November 2020. A total of 60 procedures were performed. The overall complication rate was 14.5% at 6 months. Complications included an infection rate of 3.6% at 6 months, wound revision rate of 1.8% at 6 months, CSF leak rate of 1.7% at 6 months, and a 30-day readmission rate related to initial surgery of 6.7%. CONCLUSIONS: Workflow efficiency and optimization for ITB patients can be used to obtain lower complication rates compared to historical cohorts in literature. A single-center, retrospective review highlights this.

Preoperative Embolization With Fused CT Angiography and Tractography Facilitates Safe Resection of a Spetzler-Martin Grade IV Arteriovenous Malformation.

Brain arteriovenous malformations (BAVMs) are high-flow vascular lesions that have a propensity to rupture resulting in high rates of morbidity and mortality. Microsurgical resection of BAVMs is the standard of care for high-risk, resectable lesions. Multiple imaging modalities aid in the surgical planning and resection of high-grade BAVMs, but all have hidden variables that would prove useful if available. We present a 20-year-old male with a ruptured BAVM with concern for the involvement of the corticospinal tract (CST) and basal ganglia. We describe the melding of computed tomography angiography (CTA) and diffusion tensor imaging (DTI) in addition to preoperative embolization to aid in the planning and resection of a lesion close to eloquent structures. Post-operative CTA and DTI showed a total resection of the lesion with retained CST white matter tracts, and the patient retained the functional ability of the contralateral limbs. The combination of CTA, brain DTI, and preoperative embolization provides a framework to improve the safety of resection of BAVMs that occur near eloquent brain networks.

Restoring Cellular Energetics Promotes Axonal Regeneration and Functional Recovery after Spinal Cord Injury.

Axonal regeneration in the central nervous system (CNS) is a highly energy-demanding process. Extrinsic insults and intrinsic restrictions lead to an energy crisis in injured axons, raising the question of whether recovering energy deficits facilitates regeneration. Here, we reveal that enhancing axonal mitochondrial transport by deleting syntaphilin (Snph) recovers injury-induced mitochondrial depolarization. Using three CNS injury mouse models, we demonstrate that Snph-/- mice display enhanced corticospinal tract (CST) regeneration passing through a spinal cord lesion, accelerated regrowth of monoaminergic axons across a transection gap, and increased compensatory sprouting of uninjured CST. Notably, regenerated CST axons form functional synapses and promote motor functional recovery. Administration of the bioenergetic compound creatine boosts CST regenerative capacity in Snph-/- mice. Our study provides mechanistic insights into intrinsic regeneration failure in CNS and suggests that enhancing mitochondrial transport and cellular energetics are promising strategies to promote regeneration and functional restoration after CNS injuries.

Descending motor circuitry required for NT-3 mediated locomotor recovery after spinal cord injury in mice.

Locomotor function, mediated by lumbar neural circuitry, is modulated by descending spinal pathways. Spinal cord injury (SCI) interrupts descending projections and denervates lumbar motor neurons (MNs). We previously reported that retrogradely transported neurotrophin-3 (NT-3) to lumbar MNs attenuated SCI-induced lumbar MN dendritic atrophy and enabled functional recovery after a rostral thoracic contusion. Here we functionally dissected the role of descending neural pathways in response to NT-3-mediated recovery after a T9 contusive SCI in mice. We find that residual projections to lumbar MNs are required to produce leg movements after SCI. Next, we show that the spared descending propriospinal pathway, rather than other pathways (including the corticospinal, rubrospinal, serotonergic, and dopaminergic pathways), accounts for NT-3-enhanced recovery. Lastly, we show that NT-3 induced propriospino-MN circuit reorganization after the T9 contusion via promotion of dendritic regrowth rather than prevention of dendritic atrophy.

Targeting of a Photosensitizer to the Mitochondrion Enhances the Potency of Photodynamic Therapy.

Photodynamic therapy (PDT) involves use of a photosensitizer, whose activation with light leads to the production of singlet oxygen (SOS), generation of reactive oxygen species (ROS), and initiation of associated cell toxicity. Because a cell's mitochondria constitute sites where oxygen levels are high, ROS can be readily produced, and apoptosis is commonly initiated. Therefore, an ideal PDT agent might be a potent photosensitizer that could naturally accumulate in mitochondria. Although a number of mitochondria-targeting moieties, including triphenylphosphine, guanidinium, and bisguanidium, have been identified, a quantitative comparison of their efficacies in targeting mitochondria has not been performed. In this study, we have prepared triphenylphosphine, guanidinium, and bisguanidium derivatives of the FDA-approved PDT agent verteporfin (Visudyne, benzoporphyrin derivative-monoacid ring A: BPD-MA) and compared their abilities to induce the intracellular perturbations common to potent PDT agents. Cellular parameters examined included subcellular localization of the verteporfin, real-time monitoring of SOS production, quantitation of reactive oxygen species (ROS) generation, analysis of mitochondria and chromatin integrity, characterization of cytoskeletal disruption and evaluation of cytochrome C release as a measure of apoptosis. An analysis of these parameters demonstrates that the triphenylphosphine derivative (0323) has better mitochondria-targeting efficacy, SOS production, and mitochondria membrane toxicity than either unmodified verteporfin or its guanidinium derivatives. Consistent with this potency, 0323 also induced the most prominent mitochondria swelling, actin depolymerization, pyknosis, and cytochrome C release. We conclude that triphenylphosphine has a better mitochondria-targeting moiety than guanidinium or bis-guanidinium and those PDT photosensitizers with improved cytotoxicities can be prepared by conjugating a mitochondria-targeting moiety to the desired photosensitizer.

Optogenetics and its application in neural degeneration and regeneration.

Neural degeneration and regeneration are important topics in neurological diseases. There are limited options for therapeutic interventions in neurological diseases that provide simultaneous spatial and temporal control of neurons. This drawback increases side effects due to non-specific targeting. Optogenetics is a technology that allows precise spatial and temporal control of cells. Therefore, this technique has high potential as a therapeutic strategy for neurological diseases. Even though the application of optogenetics in understanding brain functional organization and complex behaviour states have been elaborated, reviews of its therapeutic potential especially in neurodegeneration and regeneration are still limited. This short review presents representative work in optogenetics in disease models such as spinal cord injury, multiple sclerosis, epilepsy, Alzheimer's disease and Parkinson's disease. It is aimed to provide a broader perspective on optogenetic therapeutic potential in neurodegeneration and neural regeneration.

Toxicological effects of trichloroethylene exposure on immune disorders.

Trichloroethylene (TCE) is one of the most common ground water contaminants in USA. Even though recent regulation mandates restricted utilization of TCE, its use is not completely prohibited, especially in industrial and manufacturing processes. The risk of TCE on human health is an ongoing field of study and its implications on certain diseases such as cancer has been recognized and well-documented. However, the link between TCE and immune disorders is still an under-studied area. Studies on the risk of TCE on the immune system is usually focused on certain immune class disorders, but consensus on the impact of TCE on the immune system has not been established. This review presents representative work that investigates the effect of TCE on immune disorders and highlights future opportunities. We attempt to provide a broader perspective of the risks of TCE on the immune system and human health.