Diffuse intrinsic pontine glioma (DIPG): A review of current and emerging treatment strategies.

Diffuse intrinsic pontine glioma (DIPG) is a childhood malignancy of the brainstem with a dismal prognosis. Despite recent advances in its understanding at the molecular level, the prognosis of DIPG has remained unchanged. This article aims to review the current understanding of the genetic pathophysiology of DIPG and to highlight promising therapeutic targets. Various DIPG treatment strategies have been investigated in pre-clinical studies, several of which have shown promise and have been subsequently translated into ongoing clinical trials. Ultimately, a multifaceted therapeutic approach that targets cell-intrinsic alterations, the micro-environment, and augments the immune system will likely be necessary to eradicate DIPG.

Overcoming the challenge of a thin skull in a 2-year-old patient undergoing laser interstitial thermal therapy using an individualized stereotactic platform: illustrative case.

BACKGROUND: Ependymoma is the third most common pediatric brain tumor that can present with headaches, cranial nerve deficits, nausea, vomiting, and ataxia. Current treatment is maximal safe resection followed by radiation therapy. More recently, laser interstitial thermal therapy (LITT) has become an alternative to traditional resection. In this report, the authors describe the utilization of a single-use, patient-specific stereotactic platform for the treatment of supratentorial ependymoma with LITT. OBSERVATIONS: A 2-year-old female had a complex history of supratentorial ependymoma after multiple craniotomies for repeated tumor progression and ventriculoperitoneal shunt placement. Imaging demonstrated an enlarging, complex, enhancing mass in the right occipital region. LITT was decided on for treatment. Given the thinness of the patient's skull, which precluded traditional means of stereotaxy, the authors elected to use a personalized stereotactic platform. Immediate postoperative imaging captured complete laser ablation of the tumor, with long-term imaging demonstrating a decreased tumor size. LESSONS: Individualized stereotactic platforms are increasingly used in adult populations, but pediatric use continues to be infrequent. In this report, the authors present the youngest reported case using a personalized stereotactic platform and show the effectiveness of this system for performing LITT in the youngest of populations with very thin skulls.

Cost-effectiveness of invasive monitoring strategies in epilepsy surgery.

OBJECTIVE: Drug-resistant epilepsy occurs in up to 40% of patients with epilepsy who may be considered for epilepsy surgery. For drug-resistant focal epilepsy, up to 50% of patients require invasive monitoring prior to surgery. Of the most common invasive monitoring strategies (subdural electrodes [SDEs] and stereo-electroencephalography [sEEG]), the most cost-effective strategy is unknown despite substantial differences in morbidity profiles. METHODS: Using data collected from an internationally representative sample published in available systematic reviews and meta-analyses, this economic evaluation study employs a decision analysis model to simulate the risks and benefits of SDE and sEEG invasive monitoring strategies. In this model, patients faced differing risks of morbidity, mortality, resection, and seizure freedom depending on which invasive monitoring strategy they underwent. A range of cost values was obtained from a recently published single-center cost-utility analysis. The model considers a base case simulation of a characteristic patient with drug-resistant epilepsy using clinical parameters obtained from systematic reviews of invasive monitoring available in the literature. The main outcome measure was the probability of a positive outcome after invasive monitoring, which was defined as improvement in seizures without a complication. Cost-effectiveness was measured using an incremental cost-effectiveness ratio (ICER). RESULTS: Invasive monitoring with sEEG had an increased cost of $274 and increased probability of effectiveness of 0.02 compared with SDEs, yielding an ICER of $12,630 per positive outcome obtained. Sensitivity analyses varied parameters widely and revealed consistent model results across the range of clinical parameters reported in the literature. One-way sensitivity analyses revealed that invasive monitoring strategy costs were the most influential parameter for model outcome. CONCLUSIONS: In this analysis, based on available observational data and estimates of complication costs, invasive monitoring with either SDEs or sEEG was nearly equivalent in terms of cost-effectiveness.

MRI-guided laser interstitial thermal therapy for deep-seated gliomas in children with neurofibromatosis type 1: report of two cases.

PURPOSE: Nearly a quarter of neurofibromatosis type 1 (NF 1)- associated diencephalic low-grade tumors are refractory to chemotherapy. Addition of alternative treatment options with laser interstitial thermal therapy will have a positive impact on the outcome of these patients. METHODS: We report on two illustrated cases of pediatric NF1- associated, chemoresistant, WHO grade 1 pilocytic astrocytomas treated with laser interstitial thermal therapy (LITT). RESULTS: Both tumors responded favorably to LITT. CONCLUSION: LITT should be considered as a treatment option for chemoresistant deep-seated NF1-associated low-grade gliomas.

Child Neurology: Functional Evaluation of the Dominant Hemisphere Using Magnetoencephalography Prior to Hemispherectomy.

Rasmussen encephalitis is a devastating progressive inflammatory disorder that leads to debilitating neurologic deficits and intractable epilepsy. Surgical treatment of the dominant hemisphere has been attempted with hesitation, given the lack of effective diagnostic tools to determine the potential functional deficits from disconnection procedures.

Single-center cost comparison analysis of stereoelectroencephalography with subdural grid and strip implantation.

OBJECTIVE: Use of invasive stereoelectroencephalography (SEEG) has gained traction recently. However, scant research has investigated the costs and resource utilization of SEEG compared with subdural grid (SDG)-based techniques in pediatric patients. Here, the authors have presented a retrospective analysis of charges associated with SEEG and SDG monitoring at a single institution. METHODS: The authors performed a retrospective case series analysis of pediatric patients with similar characteristics in terms of age, sex, seizure etiology, and epilepsy treatment strategy who underwent SEEG or SDG monitoring and subsequent craniotomy for resection of epileptogenic focus at St. Louis Children Hospital, St. Louis, Missouri, between 2013 and 2020. Financial data, including hospital charges, supplies, and professional fees (i.e., those related to anesthesia, neurology, neurosurgery, and critical care), were adjusted for inflation to 2020 US dollars. RESULTS: The authors identified 18 patients (9 underwent SEEG and 9 underwent SDG) with similar characteristics in terms of age (mean [range] 13.6 [1.9-21.8] years for SDG patients vs 11.9 [2.4-19.6] years for SEEG patients, p = 0.607), sex (4 females underwent SDG vs 6 females underwent SEEG, p = 0.637), and presence of lesion (5 patients with a lesion underwent SDG vs 8 underwent SEEG, p = 0.294). All patients underwent subsequent craniotomy for resection of epileptogenic focus. SEEG patients were more likely to have a history of status epilepticus (p = 0.029). Across 1 hospitalization for each SDG patient and 2 hospitalizations for each SEEG patient, SEEG patients had a significantly shorter mean operating room time (288 vs 356 minutes, p = 0.015), mean length of stay in the ICU (1.0 vs 2.1 days, p < 0.001), and tended to have a shorter overall length of stay in the hospital (8.4 vs 10.6 days, p = 0.086). Both groups underwent invasive monitoring for similar lengths of time (5.2 days for SEEG patients vs 6.4 days for SDG patients, p = 0.257). Time to treatment from the initial invasive monitoring evaluation was significantly longer in SEEG patients (64.6 vs 6.4 days, p < 0.001). Neither group underwent readmission within the first 30 days after hospital discharge. Seizure outcomes and complication rates were similar. After adjustment for inflation, the average total perioperative charges were $104,442 for SDG and $106,291 for SEEG (p = 0.800). CONCLUSIONS: Even though 2 hospitalizations were required for SEEG and 1 hospitalization was required for SDG monitoring, patients who underwent SEEG had a significantly shorter average length of stay in the ICU and operating room time. Surgical morbidity and outcomes were similar. Total perioperative charges for invasive monitoring and resection were approximately 2% higher for SEEG patients when corrected for inflation, but this difference was not statistically significant.

Competitive binding of E3 ligases TRIM26 and WWP2 controls SOX2 in glioblastoma.

The pluripotency transcription factor SOX2 is essential for the maintenance of glioblastoma stem cells (GSC), which are thought to underlie tumor growth, treatment resistance, and recurrence. To understand how SOX2 is regulated in GSCs, we utilized a proteomic approach and identified the E3 ubiquitin ligase TRIM26 as a direct SOX2-interacting protein. Unexpectedly, we found TRIM26 depletion decreased SOX2 protein levels and increased SOX2 polyubiquitination in patient-derived GSCs, suggesting TRIM26 promotes SOX2 protein stability. Accordingly, TRIM26 knockdown disrupted the SOX2 gene network and inhibited both self-renewal capacity as well as in vivo tumorigenicity in multiple GSC lines. Mechanistically, we found TRIM26, via its C-terminal PRYSPRY domain, but independent of its RING domain, stabilizes SOX2 protein by directly inhibiting the interaction of SOX2 with WWP2, which we identify as a bona fide SOX2 E3 ligase in GSCs. Our work identifies E3 ligase competition as a critical mechanism of SOX2 regulation, with functional consequences for GSC identity and maintenance.

Therapeutic enhancement of blood-brain and blood-tumor barriers permeability by laser interstitial thermal therapy.

BACKGROUND: The blood-brain and blood-tumor barriers (BBB and BTB), which restrict the entry of most drugs into the brain and tumor, respectively, are a significant challenge in the treatment of glioblastoma. Laser interstitial thermal therapy (LITT) is a minimally invasive surgical technique increasingly used clinically for tumor cell ablation. Recent evidence suggests that LITT might locally disrupt BBB integrity, creating a potential therapeutic window of opportunity to deliver otherwise brain-impermeant agents. METHODS: We established a LITT mouse model to test if laser therapy can increase BBB/BTB permeability in vivo. Mice underwent orthotopic glioblastoma tumor implantation followed by LITT in combination with BBB tracers or the anticancer drug doxorubicin. BBB/BTB permeability was measured using fluorimetry, microscopy, and immunofluorescence. An in vitro endothelial cell model was also used to corroborate findings. RESULTS: LITT substantially disrupted the BBB and BTB locally, with increased permeability up to 30 days after the intervention. Remarkably, molecules as large as human immunoglobulin extravasated through blood vessels and permeated laser-treated brain tissue and tumors. Mechanistically, LITT decreased tight junction integrity and increased brain endothelial cell transcytosis. Treatment of mice bearing glioblastoma tumors with LITT and adjuvant doxorubicin, which is typically brain-impermeant, significantly increased animal survival. CONCLUSIONS: Together, these results suggest that LITT can locally disrupt the BBB and BTB, enabling the targeted delivery of systemic therapies, including, potentially, antibody-based agents.

Corpus callosotomy performed with laser interstitial thermal therapy.

OBJECTIVE: Corpus callosotomy is a palliative procedure that is effective at reducing seizure burden in patients with medically refractory epilepsy. The procedure is traditionally performed via open craniotomy with interhemispheric microdissection to divide the corpus callosum. Concerns for morbidity associated with craniotomy can be a deterrent to patients, families, and referring physicians for surgical treatment of epilepsy. Laser interstitial thermal therapy (LITT) is a less invasive procedure that has been widely adopted in neurosurgery for the treatment of tumors. In this study, the authors investigated LITT as a less invasive approach for corpus callosotomy. METHODS: The authors retrospectively reviewed all patients treated for medically refractory epilepsy by corpus callosotomy, either partial or completion, with LITT. Chart records were analyzed to summarize procedural metrics, length of stay, adverse events, seizure outcomes, and time to follow-up. In select cases, resting-state functional MRI was performed to qualitatively support effective functional disconnection of the cerebral hemispheres. RESULTS: Ten patients underwent 11 LITT procedures. Five patients received an anterior two-thirds LITT callosotomy as their first procedure. One patient returned after LITT partial callosotomy for completion of callosotomy by LITT. The median hospital stay was 2 days (IQR 1.5-3 days), and the mean follow-up time was 1.0 year (range 1 month to 2.86 years). Functional outcomes are similar to those of open callosotomy, with the greatest effect in patients with a significant component of drop attacks in their seizure semiology. One patient achieved an Engel class II outcome after anterior two-thirds callosotomy resulting in only rare seizures at the 18-month follow-up. Four others were in Engel class III and 5 were Engel class IV. Hemorrhage occurred in 1 patient at the time of removal of the laser fiber, which was placed through the bone flap of a prior open partial callosotomy. CONCLUSIONS: LITT appears to be a safe and effective means for performing corpus callosotomy. Additional data are needed to confirm equipoise between open craniotomy and LITT for corpus callosotomy.

Onyx embolization of a ruptured anterior inferior cerebellar artery in a neonate.

Aneurysmal subarachnoid hemorrhage (SAH) is rare in neonates. The authors present a unique report of a neonate with SAH from anterior inferior cerebellar artery (AICA) aneurysm rupture that was successfully treated with Onyx embolization. This case report demonstrates the utility of Onyx embolization for posterior circulation aneurysms in neonates and the successful management of SAH in this population.

Management of Intracranial Metastatic Disease With Laser Interstitial Thermal Therapy.

Treatment approaches for metastatic brain tumors continue to evolve, with increasing recent emphasis on focal therapies whenever possible. MRI-guided Laser Interstitial Thermal Therapy (LITT) is a minimally invasive surgical option that has broadened the capability of the neurosurgeon in treating difficult-to-treat intracranial lesions. This technology uses image-guided delivery of laser to the target lesion to generate heat and thereby ablate pathological tissue and has expanded the neurosurgical armamentarium for surgical treatment of brain metastases. In this study, we describe the indications for LITT in the management of intracranial metastatic disease and report our institutional experience with LITT.

Widely Metastatic Choroid Plexus Carcinoma Associated with Novel TP53 Somatic Mutation.

BACKGROUND: Choroid plexus carcinoma (CPC) is a rare, malignant tumor occurring more commonly in children than adults. This case report describes the clinical course of a 3-year-old boy with a rare case of metastatic CPC with a novel TP53 mutation. CASE DESCRIPTION: A 3-year-old boy presented with postconcussive symptoms after a fall. Computed tomography and magnetic resonance imaging revealed lesions in the suprasellar cistern, left lateral ventricle, and cauda equina. The tumor was diagnosed as choroid plexus carcinoma with a novel TP53 V216M somatic mutation. The patient underwent resection of the left lateral ventricle lesion. CONCLUSION: We describe a case of CPC with highly metastatic characteristics and a novel TP53 mutation. Our report implicates TP53 in the pathogenesis of pediatric CPC, and we emphasize that CPC in children should prompt careful consideration of TP53 status to inform prognosis and clinical treatment.

Applications of a robotic stereotactic arm for pediatric epilepsy and neurooncology surgery.

OBJECTIVE The ROSA device is a robotic stereotactic arm that uses a laser system to register the patient's head or spine with MR or CT images. In this study, the authors analyze their experience with this system in pediatric neurosurgical applications and present selected cases that exemplify the usefulness of this system. METHODS The authors reviewed all cases that utilized the ROSA system at their institution. Patient demographics, pathology, complications, electrode placement, laser ablation, and biopsy accuracy were analyzed. Patient disposition and condition at follow-up were also analyzed. RESULTS Seventeen patients underwent 23 procedures using the ROSA system. A total of 87 electroencephalography electrodes were placed, with 13% deviating more than 3 mm from target. Six patients underwent stereotactic needle biopsy, and 9 underwent laser interstitial thermotherapy (LITT). One patient who underwent LITT required a subsequent craniotomy for tumor resection. Another patient experienced an asymptomatic extraaxial hematoma that spontaneously resolved. No patient suffered neurological complications during follow-up. Follow-up from the last procedure averaged 180 days in epilepsy patients and 309 days in oncology patients. CONCLUSIONS The precision, ease of use, and versatility of the ROSA system make it well suited for pediatric neurosurgical practice. Further work, including long-term analysis of results and cost-effectiveness, will help determine the utility of this system and if its applications can be expanded.

Detection of Bendiocarb and Carbaryl Resistance Mechanisms among German Cockroach Blattella germanica (Blattaria: Blattellidae) Collected from Tabriz Hospitals, East Azerbaijan Province, Iran in 2013.

BACKGROUND: Insecticide resistance is one of the serious problems for German cockroach control program. This study was conducted to determine the bendiocarb and Carbaryl resistance mechanisms in German cockroaches using the piperonyl butoxide (PBO). METHODS: Bioassay tests were conducted with 4 to 6 different concentrations of both insecticides with four replicates of 10 susceptible strain cockroaches per concentration to determine of discriminative concentration. After determining discriminative concentration, the result was compared to wild strain. The levels of susceptibility and resistance ratio (RR) and synergism ratio (SR) were calculated for each five wild strains. Moreover resistance mechanisms in wild strains were determined using PBO synergist in vivo. RESULTS: Hospital strains showed different levels of resistance to bendiocarb and carbaryl compared to susceptible strain. The bendiocarb and carbaryl resistance ratios ranged from 2.11 to 7.97 and 1.67 to 2 at LD50 levels, respectively. The synergist PBO significantly enhanced the toxicity of bendiocarb and carbaryl to all strains with different degrees of synergist ratio, 1.31, 1.39, 3.61, 1.78, 1.62 and 2.1 fold for bendiocarb, 1.19, 1.18, 1.12. 1.29, 1.45 and 1.11-fold for carbaryl, suggesting monooxygenase involvement in bendiocarb and carbaryl resistance. CONCLUSION: The synergetic effect of PBO had the highest effect on bendiocarb and resistance level was significantly reduced, which indicates the important role of monoxidase enzyme in creating resistance to Bendiocarb. Piperonyl butoxide did not have a significant synergistic effect on carbaryl and did not significantly break the resistance.

Neosuture formation after endoscope-assisted craniosynostosis repair.

OBJECTIVE The goal of this study was to identify the rate of neosuture formation in patients with craniosynostosis treated with endoscope-assisted strip craniectomy and investigate whether neosuture formation in sagittal craniosynostosis has an effect on postoperative calvarial shape. METHODS The authors retrospectively reviewed 166 cases of nonsyndromic craniosynostosis that underwent endoscope-assisted repair between 2006 and 2014. Preoperative and 1-year postoperative head CT scans were evaluated, and the rate of neosuture formation was calculated. Three-dimensional reconstructions of the CT data were used to measure cephalic index (CI) (ratio of head width and length) of patients with sagittal synostosis. Regression analysis was used to calculate significant differences between patients with and without neosuture accounting for age at surgery and preoperative CI. RESULTS Review of 96 patients revealed that some degree of neosuture development occurred in 23 patients (23.9%): 16 sagittal, 2 bilateral coronal, 4 unilateral coronal, and 1 lambdoid synostosis. Complete neosuture formation was seen in 14 of those 23 patients (9 of 16 sagittal, 1 of 2 bilateral coronal, 3 of 4 unilateral coronal, and 1 of 1 lambdoid). Mean pre- and postoperative CI in the complete sagittal neosuture group was 67.4% and 75.5%, respectively, and in the non-neosuture group was 69.8% and 74.4%, respectively. There was no statistically significant difference in the CI between the neosuture and fused suture groups preoperatively or 17 months postoperatively in patients with sagittal synostosis. CONCLUSIONS Neosuture development can occur after endoscope-assisted strip craniectomy and molding helmet therapy for patients with craniosynostosis. Although the authors did not detect a significant difference in calvarial shape postoperatively in the group with sagittal synostosis, the relevance of neosuture formation remains to be determined. Further studies are required to discover long-term outcomes comparing patients with and without neosuture formation.

RNA expression patterns in serum microvesicles from patients with glioblastoma multiforme and controls.

BACKGROUND: RNA from exosomes and other microvesicles contain transcripts of tumour origin. In this study we sought to identify biomarkers of glioblastoma multiforme in microvesicle RNA from serum of affected patients. METHODS: Microvesicle RNA from serum from patients with de-novo primary glioblastoma multiforme (N = 9) and normal controls (N = 7) were analyzed by microarray analysis. Samples were collected according to protocols approved by the Institutional Review Board. Differential expressions were validated by qRT-PCR in a separate set of samples (N = 10 in both groups). RESULTS: Expression profiles of microvesicle RNA correctly separated individuals in two groups by unsupervised clustering. The most significant differences pertained to down-regulated genes (121 genes > 2-fold down) in the glioblastoma multiforme patient microvesicle RNA, validated by qRT-PCR on several genes. Overall, yields of microvesicle RNA from patients was higher than from normal controls, but the additional RNA was primarily of size < 500 nt. Gene ontology of the down-regulated genes indicated these are coding for ribosomal proteins and genes related to ribosome production. CONCLUSIONS: Serum microvesicle RNA from patients with glioblastoma multiforme has significantly down-regulated levels of RNAs coding for ribosome production, compared to normal healthy controls, but a large overabundance of RNA of unknown origin with size < 500 nt.

Regulation of synaptic structure by ubiquitin C-terminal hydrolase L1.

Ubiquitin C-terminal hydrolase L1 (UCH-L1) is a deubiquitinating enzyme that is selectively and abundantly expressed in the brain, and its activity is required for normal synaptic function. Here, we show that UCH-L1 functions in maintaining normal synaptic structure in hippocampal neurons. We found that UCH-L1 activity is rapidly upregulated by NMDA receptor activation, which leads to an increase in the levels of free monomeric ubiquitin. Conversely, pharmacological inhibition of UCH-L1 significantly reduces monomeric ubiquitin levels and causes dramatic alterations in synaptic protein distribution and spine morphology. Inhibition of UCH-L1 activity increases spine size while decreasing spine density. Furthermore, there is a concomitant increase in the size of presynaptic and postsynaptic protein clusters. Interestingly, however, ectopic expression of ubiquitin restores normal synaptic structure in UCH-L1-inhibited neurons. These findings point to a significant role of UCH-L1 in synaptic remodeling, most likely by modulating free monomeric ubiquitin levels in an activity-dependent manner.