The Surgical Resection of Brainstem Glioma: Outcomes and Prognostic Factors.

BACKGROUND: The management of brainstem glioma remains controversial, with increasing evidence supporting surgical resection as the primary treatment for a select subgroup of tumors. However, there remains no consensus on the specific benefits and risks, the selection of surgical candidates, and prognostic factors that may further refine surgical indications. METHODS: A retrospective single-surgeon chart review was performed for all patients who underwent surgical treatment for radiographically suspected brainstem glioma between 2000 and 2017. Preoperative and postoperative radiographic evaluations on magnetic resonance imaging were conducted. Survival outcomes were collected, and machine-learning techniques were used for multivariate analysis. RESULTS: Seventy-seven patients with surgical treatment of brainstem glioma were identified, with a median age of 9 years (range, 0-58 years). The cohort included 64% low-grade (I and II) and 36% high-grade (III and IV) tumors. For all patients, the 1-year and 5-year overall survival were 76.4% and 62.3%, respectively. Transient neurologic deficit was present in 34% of cases, and permanent deficit in a further 29%. CONCLUSIONS: The radical surgical resection of brainstem gliomas can be performed with acceptable risk in well-selected cases and likely confers survival advantage for what is otherwise a rapidly and universally fatal disease. Various radiographic features are useful during patient selection and may guide treatment selection.

Central nervous system hemangioblastomas in the elderly (over 65 years): Clinical characteristics and outcome analysis.

OBJECTIVES: Hemangioblastomas (HBs) in the elderly are very uncommon and have rarely been studied. This retrospective study aimed to identify clinical features, optimal treatment, surgical outcomes and long-term prognostic factors in these rare lesions. PATIENTS AND METHODS: We performed a retrospective analysis of HBs patients over 65 years old who underwent surgery from 2008 to 2018 at our department. Clinical data was retrospectively reviewed and statistically analyzed. RESULTS: Thirty-three elderly patients with a mean age of 68.76 years were included in this study. Cerebellum, brainstem, and spinal cord locations accounted for 72.7 %, 18.2 % and 9.1 %. Two patients (6.1 %) were diagnosed as von Hippel-Lindau (VHL) syndrome. After mean follow-up of 37.95 ± 22.12 months, clinical symptoms improved in 22 patients (67 %), unchanged in seven patients (21 %) and aggravated in 4 patients (12 %). Only 1(3 %) patient experienced local recurrence during follow-up. Univariate analysis showed tumor size (P = 0.044) and tumor characteristic (cystic or solid) (P = 0.034) were significantly related to long-term outcomes, while multiple logistic regression analysis depicted tumor characteristics were exclusively correlated with outcomes (P = 0.04). CONCLUSIONS: Our study suggests elderly hemangioblastomas may be different from their younger counterparts in that they often display solid configuration with large size and include more cerebellar tumors. HBs should be included in the differential diagnosis of elderly patients presenting with cerebellar mass. Despite many challenges involved, surgical removal of HBs in this age group is a safe procedure with acceptable risks. They may do not require as frequent follow-up as younger counterparts due to the low associations with VHL disease and tumor recurrence rate.

Abnormal Neural Activity in Children With Diffuse Intrinsic Pontine Glioma Had Manifested Deficit in Behavioral Inhibition: A Resting-State Functional MRI Study.

PURPOSE: The purpose of this study was to investigate whether alterations of regional neural function in children with diffuse intrinsic pontine glioma (DIPG) had manifested deficit in behavioral inhibition using resting-state functional MRI (rs-fMRI). METHODS: There were 17 participants with DIPG who took part in the study. Eight children were with deficit in behavioral inhibition, whereas the other 9 children did not obtain deficit in behavioral inhibition. Five healthy children with age, sex, and education matched to the study group also participated as the control group. These 3 groups underwent rs-fMRI, and the results were then converted to amplitude of low-frequency fluctuation (ALFF) data. Amplitude of low-frequency fluctuation data were further analyzed by single-factor analysis of variance comparing among 3 groups based on the whole brain levels. Amplitude of low-frequency fluctuation results were subjected to t test of voxel-wised comparison to derive the rs-fMRI brain function differences between the 2 DIPG groups. The Pearson correlation between ALFF values of abnormal regions found in 3 groups and the scores obtained according to the Child Behavior Checklist were analyzed. RESULTS: The 3 groups had shown significant differences in terms of the ALFF results, with the ALFF increased in several brain regions (P < 0.05, corrected with AlphaSim, clusters >59 voxels), which include left supramarginal gyrus, left dorsolateral superior frontal gyrus, right precentral gyrus, and right middle frontal gyrus. Participants with deficit in behavioral inhibition had shown significant differences (ALFF decreased) in several brain regions, including left dorsolateral superior frontal gyrus and right fusiform gyrus (P < 0.05, corrected with AlphaSim, clusters >123 voxels), whereas other brain regions had shown ALFF increased, including left supramarginal gyrus, left middle frontal gyrus, and right medial superior frontal gyrus (P < 0.05, corrected with AlphaSim, clusters >123 voxels). There was no significant correlation between ALFF values and Child Behavior Checklist scores (P > 0.05). CONCLUSIONS: These findings of focal spontaneous hyperfunction and hypofunction, which correlate with deficit in behavioral inhibition processing, and the abnormal brain regions are considered to be inefficient (in regions of the brain that may relate to compensatory brain and behavioral functioning, and it may be that the brain region needs to exert extra energy to perform a task to the same degree as the control group) or inability (inability in a certain region, or underpowered), pointing to a pathophysiologic process in executive dysfunction.

Microsurgical Management of Midbrain Cavernous Malformations: Predictors of Outcome and Lesion Classification in 72 Patients.

BACKGROUND: Due to the complex segmental organization of the brainstem, it is preferable to study midbrain cavernous malformations (MCMs) separately from pontine and medullary lesions. OBJECTIVE: To evaluate clinical results after microsurgical removal of MCMs, assess predictors for outcome and introduce a topographical classification of MCMs. METHODS: A retrospective study was conducted on consecutive patients who underwent MCM resection. Clinical parameters before and after surgery, morphological CM features, surgical approaches and outcomes were analyzed. MCMs were classified according to their exact location within the midbrain and their axial and sagittal extension. RESULTS: The authors reviewed 72 patients (35 male). Lesions varied in size between 4 and 55 mm. The vast majority of patients benefited from surgery. The mean modified Rankin Scale (mRS) decreased significantly from 1.6 at admission to 1.3 at discharge and to 0.7 at follow-up (6-247 mo postoperatively). Five patients (6.9%) suffered from delayed hypertrophic olivary degeneration as visualized on magnetic resonance imaging. One male suffered from early postoperative re-bleeding that required surgical hematoma evacuation. There were no severe long tract impairment or other disabling complications, no delayed re-bleedings, and no surgical mortality. CONCLUSION: We present a new topographic classification of MCMs that may be useful for predicting the occurrence of postoperative eye movement disorders. Other predictors of persistent oculomotor disturbances are time interval between onset of symptoms and surgery, and patient's age over 40 yr. Early surgery is recommendable in patients with oculomotor disturbances. MCM size over 18 mm, patient age over 40 yr, and poor mRS at admission are important predictors for the long-term outcome.

Intraoperative facial motor evoked potential monitoring for pontine cavernous malformation resection.

OBJECTIVE: The aim of this study was to predict postoperative facial nerve function during pontine cavernous malformation surgery by monitoring facial motor evoked potentials (FMEPs). METHODS: From 2008 to 2017, 10 patients with pontine cavernous malformations underwent total resection via the trans-fourth ventricle floor approach with FMEP monitoring. House-Brackmann grades and Karnofsky Performance Scale (KPS) scores were obtained pre- and postoperatively. The surgeries were performed using one of 2 safe entry zones into the brainstem: the suprafacial triangle and infrafacial triangle approaches. Six patients underwent the suprafacial triangle approach, and 4 patients underwent the infrafacial triangle approach. A cranial peg screw electrode was used to deliver electrical stimulation for FMEP by a train of 4 or 5 pulse anodal constant current stimulation. FMEP was recorded from needle electrodes on the ipsilateral facial muscles and monitored throughout surgery by using a threshold-level stimulation method. RESULTS: FMEPs were recorded and analyzed in 8 patients; they were not recorded in 2 patients who had severe preoperative facial palsy and underwent an infrafacial triangle approach. Warning signs appeared in all patients who underwent the suprafacial triangle approach. However, after temporarily stopping the procedures, FMEP findings during surgery showed recovery of the thresholds. FMEPs in patients who underwent the infrafacial triangle approach were stable during the surgery. House-Brackmann grades were unchanged postoperatively in all patients. Postoperative KPS scores improved in 3 patients, decreased in 1, and remained the same in 6 patients. CONCLUSIONS: FMEPs can be used to monitor facial nerve function during surgery for pontine cavernous malformations, especially when the suprafacial triangle approach is performed.

International experience in the development of patient-derived xenograft models of diffuse intrinsic pontine glioma.

PURPOSE: Diffuse intrinsic pontine glioma is the most aggressive form of high grade glioma in children with no effective therapies. There have been no improvements in survival in part due poor understanding of underlying biology, and lack of representative in vitro and in vivo models. Recently, it has been found feasible to use both biopsy and autopsy tumors to generate cultures and xenograft models. METHODS: To further model development, we evaluated the collective international experience from 8 collaborating centers to develop DIPG pre-clinical models from patient-derived autopsies and biopsies. Univariate and multivariate analysis was performed to determine key factors associated with the success of in vitro and in vivo PDX development. RESULTS: In vitro cultures were successfully established from 57% of samples (84.2% of biopsies and 38.2% of autopsies). Samples transferred in DMEM media were more likely to establish successful culture than those transported in Hibernate A. In vitro cultures were more successful from biopsies (84.2%) compared with autopsies (38.2%) and as monolayer on laminin-coated plates than as neurospheres. Primary cultures successfully established from autopsy samples were more likely to engraft in animal models than cultures established from biopsies (86.7% vs. 47.4%). Collectively, tumor engraftment was more successful when DIPG samples were directly implanted in mice (68%), rather than after culturing (40.7%). CONCLUSION: This multi-center study provides valuable information on the success rate of establishing patient-derived pre-clinical models of DIPG. The results can lead to further optimization of DIPG model development and ultimately assist in the investigation of new therapies for this aggressive pediatric brain tumor.

Neuronavigation-Guided Corticospinal Tract Mapping in Brainstem Tumor Surgery: Better Preservation of Motor Function.

OBJECTIVE: To evaluate a new technique in brainstem surgery, neuronavigation (NN)-guided corticospinal tract (CST) mapping, in a retrospective study of patients undergoing brainstem tumor surgery. METHODS: We studied 40 patients with a brainstem tumor who were enrolled in this study. Patients whose worst preoperative muscle strength of the 4 limbs was greater than 3 levels from normal on the Lovett scale were divided into 2 groups: a treatment group of 21 patients who underwent NN-guided CST mapping and routine intraoperative neurophysiology monitoring (IONM) and a control group of 19 patients who underwent routine NN and IONM. Preoperative muscle strength and postoperative (day 90 postsurgery) muscle strength were assessed and compared between the 2 groups. RESULTS: In the NN-guided CST mapping group, 3 patients (14.3%) had a decrease in muscle strength by 1 level postoperatively, and no patient experienced a decrease of >1 level. In the control group, 4 patients (21.1%) had a 1-level decrease in muscle strength, and 5 (26.3%) had a decrease of >1 level. Patients in the NN-guided CST mapping group had significantly better surgical outcomes compared with those in the control group (P = 0.018, Fisher exact test). CONCLUSIONS: Brainstem tumor resection using NN-guided CST mapping achieved better preservation of motor function compared with routine NN and IONM. NN-guided CST mapping not only decreased the difficulty of the surgery, but also significantly improved the efficiency of surgery.

Surgical outcome of motor deficits and neurological status in brainstem cavernous malformations based on preoperative diffusion tensor imaging: a prospective randomized clinical trial.

OBJECTIVE: Surgical management of brainstem lesions is challenging due to the highly compact, eloquent anatomy of the brainstem. This study aimed to evaluate the safety and efficacy of preoperative diffusion tensor imaging (DTI) and diffusion tensor tractography (DTT) in brainstem cavernous malformations (CMs). METHODS: A prospective randomized controlled clinical trial was performed by using stratified blocked randomization. The primary eligibility criterion of the study was being a surgical candidate for brainstem CMs (with informed consent). The study enrolled 23 patients who underwent preoperative DTI/DTT and 24 patients who did not (the control group). The pre- and postoperative muscle strength of both limbs and modified Rankin Scale (mRS) scores were evaluated. Muscle strength of any limb at 12 months after surgery at the clinic visit was the primary outcome; worsened muscle strength was considered to be a poor outcome. Outcome assessors were blinded to patient management. This study reports the preliminary results of the interim analysis. RESULTS: The cohort included 47 patients (22 women) with a mean age of 35.7 years. The clinical baselines between these 2 groups were not significantly different. In the DTI/DTT group, the corticospinal tract was affected in 17 patients (73.9%): it was displaced, deformed/partially interrupted, or completely interrupted in 6, 7, and 4 patients, respectively. The surgical approach and brainstem entry point were adjusted in 3 patients (13.0%) based on DTI/DTT data. The surgical morbidity of the DTI/DTT group (7/23, 30.4%) was significantly lower than that of the control group (19/24, 79.2%, p = 0.001). At 12 months, the mean mRS score (1.1, p = 0.034) and percentage of patients with worsened motor deficits (4.3%, p = 0.006) were significantly lower in the DTI/DTT group than in the control group (1.7% and 37.5%). Multivariate logistic regression identified the absence of preoperative DTI/DTT (OR 0.06, 95% CI 0.01-0.73, p = 0.028) and use of the 2-point method (OR 4.15, 95% CI 1.38-12.49, p = 0.011) as independent adverse factors for a worsened motor deficit. The multivariate model found a significant correlation between poor mRS score and both an increased preoperative mRS score (t = 3.559, p = 0.001) and absence of preoperative DTI/DTT (t = -2.747, p = 0.009). CONCLUSIONS: DTI/DTT noninvasively allowed for visualization of the anatomical relationship between vital tracts and pathologies as well as facilitated the brainstem surgical approach and entry-point decision making. The technique was valuable for complex neurosurgical planning to reduce morbidity. Nonetheless, DTI/DTT data should be interpreted cautiously.■ CLASSIFICATION OF EVIDENCE Type of question: therapeutic; study design: randomized controlled trial; evidence: class I. Clinical trial registration no.: NCT01758211 (ClinicalTrials.gov).

Neurophysiological Monitoring and Awake Craniotomy for Resection of Intracranial Gliomas.

Aggressive resection of intracranial gliomas has a positive impact on patients' prognosis, but is associated with a risk of neurological complications. For preservation of brain functions and avoidance of major postoperative morbidity various methods of intraoperative neurophysiological monitoring have been introduced into clinical practice. At present, somatosensory evoked potentials (SSEP), motor evoked potentials (MEP), visual evoked potentials (VEP), brainstem auditory evoked potentials (BAEP), and electrocorticography (ECoG) are used routinely during neurosurgical procedures. To maximize the efficacy of these neurophysiological techniques, it is most preferable to apply total intravenous anesthesia with continuous infusion of propofol and opioids and avoidance of long-acting muscle relaxants. Surgery for brainstem gliomas requires specific mapping with direct electrical stimulation (DES), corticobulbar tract MEP monitoring, and free-running electromyography (EMG) of the various muscles innervated by the cranial nerves. Awake craniotomy and intraoperative mapping of language and sensorimotor functions with DES allow precise identification of the functionally important neuronal structures and have become standard techniques for removal of cerebral neoplasms affecting eloquent cortical areas and subcortical pathways. Overall, contemporary neurophysiology plays a very important role in guidance of brain tumor surgery, in which it helps to maximize the extent of resection and to minimize the risk of permanent neurological morbidity.

Diffuse Intrinsic Pontine Glioma: New Pathophysiological Insights and Emerging Therapeutic Targets.

BACKGROUND: Diffuse Intrinsic Pontine Glioma (DIPG) is the leading cause of brain tumor-related death in children, with median survival of less than one year. Despite decades of clinical trials, there has been no improvement in prognosis since the introduction of radiotherapy over thirty years ago. OBJECTIVE: To review the clinical features and current treatment challenges of DIPG, and discuss emerging insights into the unique genomic and epigenomic mechanisms driving DIPG pathogenesis that present new opportunities for the identification of therapeutic targets. CONCLUSION: In recent years, an increased availability of biopsy and rapid autopsy tissue samples for preclinical investigation has combined with the advent of new genomic and epigenomic profiling tools to yield remarkable advancements in our understanding of DIPG disease mechanisms. As well, a deeper understanding of the developmental context of DIPG is shedding light on therapeutic targets in the microenvironment of the childhood brain.

Child Neurology: Diencephalic syndrome-like presentation of a cervicomedullary brainstem tumor.

Diencephalic syndrome is a rare clinical entity, traditionally encompassing severe failure to thrive, nystagmus, and hyperkinesis, secondary to an intracranial neoplasm that is classically located in the hypothalamic region and its vicinity. However, the presenting features can be variable, often resulting in delayed diagnosis, which may worsen prognosis. This case report describes the atypical presentation of a posterior fossa tumor with features reminiscent of diencephalic syndrome that have not previously been reported in the literature. We report a 21-month-old girl with a cervicomedullary brainstem astrocytoma, who presented with isolated gross motor developmental delay, decreased growth velocity, and stridor. The neurologic signs frequently reported in patients with diencephalic syndrome were absent; however, severe failure to thrive was present. This case broadens the etiologic differential diagnosis of diencephalic syndrome in addition to the traditional hypothalamic region tumor location. This case urges physicians to consider central neurologic processes in the differential diagnosis of children with refractory failure to thrive with or without classical features of diencephalic syndrome, in whom etiology is not identified by routine investigations, given its importance in determining prognosis and management.

Pathological crying and emotional vasovagal syncope as symptoms of a dorsally exophytic medullary tumor.

A 3-year-old boy with a dorsally exophytic tumor arising from the rostral medulla presented with a chief complaint of a change in his emotional behavior, most notably anxiety and paroxysmal crying often followed by syncope. Magnetic resonance imaging revealed that the tumor pushed on the dorsal surface of the medulla and displaced the medulla anteriorly, and also displaced the cerebellar vermis upward and slightly posteriorly. Tissue from a partial resection was diagnosed as a pilocytic astrocytoma. The symptoms did not improved after surgery, but did improve clinically after chemotherapy with vincristine and carboplatin, at which time MR showed a reduction in tumor size. We diagnosed the paroxysmal crying as 'pathological crying' and the syncope with increased anxiety as 'emotional vasovagal syncope'. This case stresses the importance of recognition of this rare presentation as an indication of a medullary tumor.

Pediatric brainstem abscess with hemorrhage mimicking diffuse intrinsic pontine glioma: a case report.

PURPOSE: We report a rare case of brainstem abscess with hemorrhage mimicking diffuse intrinsic pontine glioma (DIPG). METHODS: A 7-month-old baby girl presented with lethargy and poor oral feeding. She had the mild fever for 1 month. Brain computed tomography revealed the hypodense lesion in the pons. Brain magnetic resonance images (MRI) showed around 1.4-cm-sized rim-enhanced mass with perilesional edema and internal hemorrhage in the pons. The cerebral blood volume was increased in the rim-enhanced area. The provisional diagnosis was DIPG, but the mass did not show the expansile mass with encasement of the basilar artery on the ventral pons. RESULTS: The biopsy was done via the floor of the fourth ventricle, and the pathologic findings showed the many inflammatory cells and CD68-immunopositive macrophage which were compatible with abscess. The antibiotics with ceftriaxone and metronidazole were administrated for 11 weeks, and the follow-up MRI showed the slightly small enhanced lesion without central necrotic area. Three years later, follow-up MRI revealed the encephalomalacic change and atrophy of the pons. She had the stable neurologic deficit of left facial palsy and right hemiparesis. CONCLUSION: The biopsy could be necessary for pontine lesions without typical radiologic findings of DIPG.

Citrate concentrations increase with hypoperfusion in pediatric diffuse intrinsic pontine glioma.

Citrate, a tricarboxylic acid cycle intermediate, is present in high concentrations in pediatric diffuse intrinsic pontine gliomas (DIPG). Since citrate increases during hypoxia in animal studies, we hypothesized that it accumulates in DIPG when hypoperfused. Relative tumor blood volumes (rTBV) were determined, using dynamic susceptibility contrast-enhanced magnetic resonance imaging, in twelve children [median age 8.2 (range 3.2-14.5) years] with DIPG and compared to citrate concentrations measured with in vivo proton magnetic resonance spectroscopy ((1)H MRS). Tissue perfusion and metabolite concentration were assessed at initial presentation and over the clinical course, yielding 36 and 46 perfusion and MR spectroscopy datasets, respectively. At presentation, DIPG blood volume was 60 ± 27 % of that measured for normal cerebellum. Citrate, which is not detectable in normal brain tissue, was present in DIPG at concentrations of 3.81 ± 1.44 mmol/kg tissue. Over the course of the disease and treatment, rTBV increased and citrate decreased (both p < 0.05) with an inverse correlation (p = 0.028). Citrate accumulation is associated with tissue hypoperfusion in DIPG.

Diffuse intrinsic pontine glioma: time for therapeutic optimism.

Diffuse intrinsic pontine glioma (DIPG) is an aggressive tumor that is universally fatal, and to-date we are at a virtual standstill in improving its grim prognosis. Dearth of tissue due to rarity of biopsy has precluded understanding the elusive biology and frustration continues in reproducing faithful animal models for translational research. Furthermore the intricate anatomy of the pons has forestalled locoregional therapy and drug penetration. Over the last few years, biopsy-driven targeted therapy, development of vitro and xenograft animal models for therapeutic testing, profiling immunotherapeutic strategies and locoregional infusion of drugs in brain stem tumors, now provide a sense of hope in the years ahead. This review aims to discuss current status and advances in the management of these tumors.

Pax3 expression enhances PDGF-B-induced brainstem gliomagenesis and characterizes a subset of brainstem glioma.

High-grade Brainstem Glioma (BSG), also known as Diffuse Intrinsic Pontine Glioma (DIPG), is an incurable pediatric brain cancer. Increasing evidence supports the existence of regional differences in gliomagenesis such that BSG is considered a distinct disease from glioma of the cerebral cortex (CG). In an effort to elucidate unique characteristics of BSG, we conducted expression analysis of mouse PDGF-B-driven BSG and CG initiated in Nestin progenitor cells and identified a short list of expression changes specific to the brainstem gliomagenesis process, including abnormal upregulation of paired box 3 (Pax3). In the neonatal mouse brain, Pax3 expression marks a subset of brainstem progenitor cells, while it is absent from the cerebral cortex, mirroring its regional expression in glioma. Ectopic expression of Pax3 in normal brainstem progenitors in vitro shows that Pax3 inhibits apoptosis. Pax3-induced inhibition of apoptosis is p53-dependent, however, and in the absence of p53, Pax3 promotes proliferation of brainstem progenitors. In vivo, Pax3 enhances PDGF-B-driven gliomagenesis by shortening tumor latency and increasing tumor penetrance and grade, in a region-specific manner, while loss of Pax3 function extends survival of PDGF-B-driven;p53-deficient BSG-bearing mice by 33%. Importantly, Pax3 is regionally expressed in human glioma as well, with high PAX3 mRNA characterizing 40% of human BSG, revealing a subset of tumors that significantly associates with PDGFRA alterations, amplifications of cell cycle regulatory genes, and is exclusive of ACVR1 mutations. Collectively, these data suggest that regional Pax3 expression not only marks a novel subset of BSG but also contributes to PDGF-B-induced brainstem gliomagenesis.

Convection enhanced delivery of carmustine to the murine brainstem: a feasibility study.

BACKGROUND: Systemic delivery of therapeutic agents remains ineffective against diffuse intrinsic pontine glioma (DIPG), possibly due to an intact blood-brain-barrier (BBB) and to dose-limiting toxicity of systemic chemotherapeutic agents. Convection-enhanced delivery (CED) into the brainstem may provide an effective local delivery alternative for DIPG patients. NEW METHOD: The aim of this study is to develop a method to perform CED into the murine brainstem and to test this method using the chemotherapeutic agent carmustine (BiCNU). To this end, a newly designed murine CED catheter was tested in vitro and in vivo. After determination of safety and distribution, mice bearing VUMC-DIPG-3 and E98FM-DIPG brainstem tumors were treated with carmustine dissolved in DW 5% or carmustine dissolved in 10% ethanol. RESULTS: Our results show that CED into the murine brainstem is feasible and well tolerated by mice with and without brainstem tumors. CED of carmustine dissolved in 5% DW increased median survival of mice with VUMC-DIPG-3 and E98FM-DIPG tumors with 35% and 25% respectively. Dissolving carmustine in 10% ethanol further improved survival to 45% in mice with E98FM-DIPG tumors. COMPARISON WITH EXISTING METHODS: Since genetically engineered and primary DIPG models are currently only available in mice, murine CED studies have clear advantages over CED studies in other animals. CONCLUSION: CED in the murine brainstem can be performed safely, is well tolerated and can be used to study efficacy of chemotherapeutic agents orthotopically. These results set the foundation for more CED studies in murine DIPG models.

Pediatric posterior fossa ganglioglioma: unique MRI features and correlation with BRAF V600E mutation status.

Ganglioglioma (GG) is a rare pediatric brain tumor (1-4 %) with neoplastic glial and neuronal cells. Posterior fossa GGs (PF GGs) occur less frequently than supratentorial GGs (ST GGs). The BRAF V600E mutation has been reported in GGs and carries therapeutic implications. We compare the presenting symptoms, magnetic resonance imaging, BRAF V600E mutation status, treatment, and prognosis in children with ST and PF GGs. The neuro-oncology database at a tertiary care Children's Hospital was retrospectively reviewed from 1995 to 2010 for patients with ST and PF GG. All available imaging was reviewed. Symptoms, BRAF V600E mutation status, treatment, and survival data were collected from the electronic medical record and analyzed. Our series consisted of 11 PF GG and 20 ST GG. Children with PF GG presented with ataxia, cranial nerve deficits and long tract signs whereas the majority with ST GGs presented with seizures. On imaging, PF GGs were infiltrative and expansile solid masses with dorsal predominant "paintbrush" enhancement whereas ST GGs were well circumscribed mixed solid and cystic masses with heterogeneous enhancement. Five of 11 (45%) PF GGs and 6 of 9 (67%) ST GGs expressed the BRAF V600E mutation. No unique imaging features were identified in BRAF V600E mutation positive tumors. The majority of ST GGs were treated with surgery alone, whereas the majority of PF GGs required multimodality therapy. PF GGs had worse progression-free survival and a higher mortality rate compared with ST GGs. Unlike ST GGs, PF GGs are expansile, infiltrative, show dorsal predominant "paintbrush" enhancement, are not amenable to gross total resection, and have worse progression-free survival and mortality.

Human pontine glioma cells can induce murine tumors.

Diffuse intrinsic pontine glioma (DIPG), with a median survival of only 9 months, is the leading cause of pediatric brain cancer mortality. Dearth of tumor tissue for research has limited progress in this disease until recently. New experimental models for DIPG research are now emerging. To develop preclinical models of DIPG, two different methods were adopted: cells obtained at autopsy (1) were directly xenografted orthotopically into the pons of immunodeficient mice without an intervening cell culture step or (2) were first cultured in vitro and, upon successful expansion, injected in vivo. Both strategies resulted in pontine tumors histopathologically similar to the original human DIPG tumors. However, following the direct transplantation method all tumors proved to be composed of murine and not of human cells. This is in contrast to the indirect method that included initial in vitro culture and resulted in xenografts comprising human cells. Of note, direct injection of cells obtained postmortem from the pons and frontal lobe of human brains not affected by cancer did not give rise to neoplasms. The murine pontine tumors exhibited an immunophenotype similar to human DIPG, but were also positive for microglia/macrophage markers, such as CD45, CD68 and CD11b. Serial orthotopic injection of these murine cells results in lethal tumors in recipient mice. Direct injection of human DIPG cells in vivo can give rise to malignant murine tumors. This represents an important caveat for xenotransplantation models of DIPG. In contrast, an initial in vitro culture step can allow establishment of human orthotopic xenografts. The mechanism underlying this phenomenon observed with direct xenotransplantation remains an open question.