Brainstem Glioma Research Articles

Lagophthalmos- A Rare Presenting Sign in a Case of Childhood Pontine Glioma

Brain stem glioma is a rare central nervous system tumour arising from glial cells which occur mostly in children. Diffuse Intrinsic Pontine Gliomas (DIPG) and Focal glioma are the two types of pontine glioma. DIPGs are highly aggressive. The clinical features are not the same in every child. It commonly has a grave prognosis as most children die within 18 months of diagnosis. Hereby, Authors present a case of 10-year-old male child complaining of watering from the left eye for four days. There was no history suggesting involvement of any other cranial nerves and there was no episode of any seizure or similar history. On examination patient was found to have left lagophthalmos. Magnetic Resonance Imaging (MRI) of brain showed features of pontine glioma with mass effect. To prevent exposure keratopathy, the child was started on lubricating drops/gel and lid taping and referred immediately to a cancer centre for further management. Patients with pontine gliomas usually complain of gait disturbance, headache, limb weakness and double vision. To Authors’ knowledge no other documented case has presented with lagophthalmos. This case is presented for the rarity of the presenting symptom and to stress the importance of picking early ophthalmic signs.

Role of gamma knife radiosurgery in the management of intracranial gliomas.

Gamma knife for gliomas is a relatively obscure treatment modality with few reports and small series available on the same. An extensive search of English Language literature yields no comprehensive reviews of the same. We here, attempt to review the available literature on gamma knife for all types of gliomas: Low grade, High grade, recurrent, and also for pediatric populations. We used keywords such as "Gamma Knife Glioma," "Stereotactic Radiosurgery Glioma," "Gamma Knife," "Adjuvant therapy Glioma" "Recurrent Glioma" on PubMed search engine, and articles were selected with respect to their use of gamma Knife for Gliomas and outcome for the same. These were then analyzed and salient findings were elucidated. This was combined with National Comprehensive Cancer Network guidelines for the same and also included our own initial experience with these tumors. Gamma-knife improved long term survival and quality of life in patients with low grade gliomas. In pediatric low grade gliomas, it may be considered as a treatment modality with a marginal dose of 12-14 Gy, especially in eloquent structures such as brain stem glioma, anterior optic pathway hypothalamic glioma. However, in newly diagnosed high-grade glioma gamma knife radiosurgery (GKRS) is not recommended because of a lack of definitive evidence in tumor control and quality of life. GKRS may find its role in palliative care of recurrent gliomas irrespective of type and grade. Inspite of growing experience with GKRS for gliomas, there is no Level I evidence in support of GKRS, hence better designed randomized controlled trials with long term outcomes are warranted. Although this modality is not a "one size fits all' therapy, it has its moments when chosen correctly and applied wisely. Gliomas being the most common tumors operated in any neurosurgical setting, knowledge about this modality and its application is essential and useful.

The Spectrum of Underlying Diseases in Children with Torticollis.

To investigate the underlying conditions in children with torticollis. Between May 2016 and December 2019, 24 patients (10 girls and 14 boys; mean age, 8 years) presenting with twisted neck, neck pain, weakness of extremities, imbalance, and gait disorder were evaluated retrospectively. Five of the patients had cranial pathologies (cerebellar anaplastic ependymoma and medulloblastoma, brain stem glioma, atypical teratoid rhabdoid tumor, and acute disseminated encephalomyelitis), and five of the patients had spinal pathologies (idiopathic intervertebral disc calcification, vertebral hemangiomatosis, compression fracture, multiple hereditary exostoses, and Langerhans cell histiocytosis at C4). Six of the patients had ocular pathologies (strabismus, Duane syndrome, and Brown syndrome each in two patients). Four patients had otorhinolaryngological infections (Sandifer syndrome, esophageal atresia, reflux, and spasmus nutans, with one patient each). Detailed clinical physical examination and necessary laboratory investigation were performed for all patients. Torticollis is a sign that is not always innocent and may herald an underlying severe disease. Misdiagnosis can lead to wrong and unnecessary surgical procedures and treatments, and sometimes, the results can be damaging due to underlying severe conditions if diagnosed late. In addition, we first report a case of vertebral hemangiomatosis and temporomandibular joint ankylosis that presented with torticollis in the English medical literature.

Phase I trial of convection-enhanced delivery of nimustine hydrochloride (ACNU) for brainstem recurrent glioma.

BackgroundTreatment options for patients suffering brainstem gliomas are quite limited as surgery is not an option against intrinsic tumors at brainstem and chemotherapy generally failed to demonstrate its efficacy. Intracerebral convection-enhanced delivery (CED) is a novel approach for administering chemotherapy to patients with brain tumors. We present the results of phase I trial of CED of nimustine hydrochloride (ACNU), designed to determine the maximum tolerable concentration of ACNU, for patients with recurrent brainstem gliomas.MethodsSixteen patients, aged 3–81 years old, suffering from recurrent brainstem gliomas, including diffuse intrinsic pontine glioma patients as well as patients with recurrent gliomas that originated from non‐brainstem sites, were enrolled in this trial between February 2011 and April 2016. The dose/concentration escalation trial included 3 dose/concentration groups (0.25, 0.5, and 0.75 mg/mL, all at 7 mL) to determine the safety and tolerability of CED of ACNU. Real-time monitoring of drug distribution was performed by mixing gadolinium-tetraazacyclododecanetetraacetic acid (Gd-DOTA) in the infusion solution. CED of ACNU was given in combination with oral or intravenous temozolomide chemotherapy.ResultsCED of ACNU demonstrated antitumor activity, as assessed by radiographic changes and prolonged overall survival. The recommended dosage was 0.75 mg/mL. Drug-associated toxicity was minimal.ConclusionsIntracerebral CED of ACNU under real-time monitoring of drug distribution, in combination with systemic temozolomide, was well tolerated among patients with recurrent brainstem gliomas. The safety and efficacy observed suggest the clinical benefits of this strategy against this devastating disease. Based on this phase I study, further clinical development of ACNU is warranted.

A Position-Adjustable Multi-Point Synchronizing Biopsy Tool for Intratumor Heterogeneity: A Proof-of-Principle Study

A biopsy needle is a tool employed to fetch a portion of tissue at a point in the volume of diseased tissue, i.e., a Single Sample with a Single Spoon (SS-SS). Using this tool, the pathological status of the unhealthy tissue is generally represented by that of the specimen. However, for the tumor growing heterogeneously, like brainstem glioma, its inner constituent is heterogeneous. Therefore, the histological status of the specimen cannot precisely represent that of other points except the sampled point itself. The common principle of the existing solutions to this problem is to design the needle that fulfills biopsy operation by obtaining Multiple Samples with a Single Spoon at different points (MS-SS). The drawback of the designs following this principle is that during one biopsy operation, the latter samples are contaminated by their formers. The reason for the shortcoming is that the same spoon grabs all samples. To solve this problem, we design a novel biopsy tool that implements a single insertion to obtain Multiple Samples in multiple desired points with Multiple Spoons (MS-MS). The detailed system structure design, the motion procedure of the needle spoon, and the critical stress on the crucial mechanical parts are explicitly presented. Experiments using a built prototype is carried out on agar phantom and ex vivo porcine tissue, respectively. The results demonstrate the feasibility of the novel position-adjustable multi-point synchronizing biopsy tool for investigating intratumoral heterogeneity.

Role of magnetic resonance imaging in diagnosis of pediatric posterior fossa tumors

Objective The aim was to study the role of MRI in diagnosis of pediatric posterior fossa tumors. Background Brain tumors represent the most common solid neoplasms in children and the second most common pediatric malignancy following leukemia. Patients and methods A retrospective study was conducted on 25 pediatric patients with known brain posterior fossa masses, who ranged in age from 1 to 15 years and had suspected posterior fossa tumor by computed tomography. All participants attended the MR unit of Radiology Department, Menoufia University, Menoufia Governorate, during the period from October 2016 to November 2017. Complete history taking, clinical examination, and MR data were compared with histopathology obtained from all patients. Results The mean age of the cases was 7.2 ± 3.9 years. The most common tumors were medulloblastoma (MB) and pilocytic astrocytoma. MB showed restricted diffusion with low apparent diffusion coefficient value, and pilocytic astrocytoma showed free diffusion with higher apparent diffusion coefficient value. High-grade tumors such as MB and brain stem glioma showed elevated choline and reduced N-acetyl aspartate in magnetic resonance spectroscopy curve. Low-grade tumors such as low-grade glioma showed mild rise of choline and mild reduction of creatine in magnetic resonance spectroscopy curve. Conclusion Conventional MRI provided limited information regarding tumor type and grade, falling short as a definitive diagnostic examination. Advanced brain MRI techniques provided incremental diagnostic value over conventional MRI. However, no single advanced technique was perfect, but different techniques typically complement one another.

The role of radiation and chemotherapy in adult patients with high-grade brainstem gliomas: results from the National Cancer Database.

Surgical resection of high-grade brainstem gliomas is challenging and treatment mostly involves radiation and chemotherapy. In this study, we utilized registry data to determine prognostic features and impact of chemotherapy and radiation on overall survival. The National Cancer Database was queried from 2006 to 2015 for adult cases with histologically confirmed high-grade brainstem glioma. Covariates including patient demographics, comorbidities, tumor characteristics and treatment parameters were captured. Multivariable Cox proportional hazards regression was performed to identify predictors of survival. A total of 422 patients were analyzed. Most patients (66.6%) underwent postoperative radiation with chemotherapy, 9.2% underwent radiation alone, while the remaining had no postoperative treatment (24.2%). Overall median survival was 9.8months (95% CI 8.8-12). Survival was longer (p < 0.001) in the radiation + chemotherapy group (median: 14.2months, 95% CI 11.7-17.1) compared to radiation alone (median: 5.7months, 95% CI 3.7-12) and no postoperative treatment (median: 1.8months, 95% CI 1.4-4) groups. In multivariable analysis, increasing age was associated with worse survival (HR: 1.87, 95% CI 1.47-2.37, p < 0.001), whereas radiation + chemotherapy was associated with lower mortality compared to radiation alone (HR: 0.67, 95% CI 0.46-0.98, p = 0.038). In subgroup analysis, postoperative chemotherapy with radiation was associated with significant survival benefit compared to radiation alone for grade IV (HR: 0.46, 95% CI 0.28-0.76, p = 0.003), but not for grade III tumors (HR: 0.87, 95% CI 0.48-1.58, p = 0.65). Analysis from a national registry illustrated the effectiveness of radiation with chemotherapy for adult patients with high-grade brainstem gliomas, particularly grade IV. Further research should identify specific patient profiles and molecular subgroups that are more likely to benefit from multimodality therapy.

Pediatric Brainstem Gliomas: An Institutional Experience.

Objective:The aim of this study was to analyze the clinical profiles and outcomes of pediatric brainstem gliomas treated at our institute.Methodology:We reviewed the files of 18 pediatric age group patients diagnosed with brainstem glioma at our institution. The following variables were recorded: age, sex, duration of symptoms, date of diagnosis, main clinical symptoms, Karnofsky performance status score, magnetic resonance imaging findings, histopathology findings, details of the treatment given, disease progression, and date of mortality/last follow-up. This data were then transferred to SPSS version 23 which was used for further analysis.Results:The mean age of our cohort was 8.6 years (range 3–15). There were 11 (61.1%) males and 7 (38.9%) females. There were 16 (88.9%) patients with diffuse intrinsic pontine gliomas (DIPGs), 1 (5.6%) patients with exophytic medullary gliomas, and 1 (5.6%) patient with midbrain/tectal glioma. Mean overall survival (OS) was 9.7 months. Mean progression-free survival (PFS) was 6.3 months. All patients with DIPG eventually passed away from their disease. Patients with DIPG who received radiotherapy had a longer OS and PFS than those who did not (9.8 and 6 months vs. 3.4 and 2.4 months). Diagnostic latency >1 month was found to have a statistically significant longer progression-free interval.Conclusion:DIPGs in the pediatric population have a poor prognosis. Radiotherapy serves to increase survival time but is not curative.

Favorable prognosis in pediatric brainstem low-grade glioma: Report from the German SIOP-LGG 2004 cohort.

Reports on pediatric low-grade glioma (LGG) of the caudal brainstem are retrospective with heterogeneous cohorts, variable treatments and inconsistent outcome data. We analyzed their natural history and asked whether brainstem location proved unfavorable for survival within the framework of the comprehensive SIOP-LGG 2004 management strategy. Within the prospectively registered, population-based German SIOP-LGG 2004 cohort 116 patients (age 0.2-16.5 years, 10% Neurofibromatosis NF1) were diagnosed with LGG of the pons (27%) and medulla oblongata (73%). After biopsy (23%), variable resection (63%) or radiologic diagnosis only (14%), 59 patients received no adjuvant treatment. Radiologic progression or severe neurologic symptoms prompted chemo- (n = 39) or radiotherapy (n = 18). After further progression (28/57), salvage treatments included multiple treatment lines for 12/28 patients. Five-years event-free survival dropped to 0.40, while 5-years overall survival was 0.95 (median observation time 6.8 years). Higher extent of resection yielded lower progression rate (p = 0.001), but at a cost of 21/100 patients suffering from new postsurgical complications including respiratory insufficiency. Central review confirmed pilocytic astrocytoma (56%), diffuse astrocytoma (8%) or glioneuronal histology (16%) (others 4%, no histology 17%). Malignant evolution was documented in five patients associated with Histone3 mutation in 2/5. Our treatment algorithm conveyed high overall survival for pediatric brainstem LGG. Extensive neurosurgical resection did increase additional postoperative neurologic deficits but not overall survival in this often-chronic disease. More than half of all patients can be safely followed by observation, while multimodal adjuvant treatment can control progressive tumors. Molecular assessment should confirm low-grade diagnosis and may detect patterns prognostic for malignant evolution.

RARE-53. THE ROLE OF RADIATION AND CHEMOTHERAPY IN ADULT PATIENTS WITH HIGH-GRADE BRAINSTEM GLIOMAS

Abstract BACKGROUND High-grade gliomas (HGGs) of the brainstem represent a rarer subtype of central nervous system tumors compared to their supratentorial counterpart. Predictors of survival and patterns of care have not yet been established on a national, multi-institutional scale. METHODS The National Cancer Database was queried for adult cases surgically diagnosed with brainstem high-grade glioma. An array of patient demographics, comorbidities, tumor characteristics and treatment parameters were captured. Predictors of survival were investigated using multivariable Cox proportional hazards regression analysis adjusting for age, insurance status, Charlson comorbidity score, tumor grade, tumor size and type of treatment. RESULTS A total of 422 patients (median 51 years, 60% males) were analyzed. Two hundred eighty one received postoperative radiation with chemotherapy (66.6%), thirty-nine had radiation alone (9.2%), while the remaining had no adjuvant treatment (24.2%). Median radiation dosage was 54Gy. Overall median survival was 9.8 months (95% CI 8.8–12). Survival was significantly longer (p&lt; .001) in the chemotherapy+radiation group (median: 14.2 months, 95% CI 11.7–17.1) compared to radiation alone (median: 5.7 months, 95% CI 3.7–12) and no adjuvant treatment (median:1.8 months, 95% CI 1.4–4). In multivariable analysis, increasing age (HR 1.87, 95% CI 1.47–2.37, p&lt; .001) was associated with worse survival, whereas radiation with chemotherapy (HR 0.67, 95% CI 0.46–0.98, p=0.038) were associated with lower hazards of death compared to radiation alone. In subgroup analysis, the effect of adjuvant chemotherapy with radiation remained significant for grade IV (HR 0.46, 95% CI 0.28–0.76, p=0.003), but not for grade III tumors (HR 0.87, 95% CI 0.48–1.58, p=0.65). CONCLUSION Findings of the present analysis demonstrate the effectiveness of radiation with chemotherapy for adult patients with high-grade brainstem gliomas, particularly grade IV. Further research should aim on identifying specific patient profiles and molecular subgroups that are more likely to benefit from multimodality therapy.

ACVR1 Function in Health and Disease.

Activin A receptor type I (ACVR1) encodes for a bone morphogenetic protein type I receptor of the TGFβ receptor superfamily. It is involved in a wide variety of biological processes, including bone, heart, cartilage, nervous, and reproductive system development and regulation. Moreover, ACVR1 has been extensively studied for its causal role in fibrodysplasia ossificans progressiva (FOP), a rare genetic disorder characterised by progressive heterotopic ossification. ACVR1 is linked to different pathologies, including cardiac malformations and alterations in the reproductive system. More recently, ACVR1 has been experimentally validated as a cancer driver gene in diffuse intrinsic pontine glioma (DIPG), a malignant childhood brainstem glioma, and its function is being studied in other cancer types. Here, we review ACVR1 receptor function and signalling in physiological and pathological processes and its regulation according to cell type and mutational status. Learning from different functions and alterations linked to ACVR1 is a key step in the development of interdisciplinary research towards the identification of novel treatments for these pathologies.

Generation of diffuse intrinsic pontine glioma mouse models by brainstem-targeted in utero electroporation.

Diffuse intrinsic pontine gliomas (DIPGs) are highly lethal childhood brain tumors. Their unique genetic makeup, pathological heterogeneity, and brainstem location all present challenges to treatment. Developing mouse models that accurately reflect each of these distinct features will be critical to advance our understanding of DIPG development, progression, and therapeutic resistance. The aims of this study were to generate new mouse models of DIPG and characterize the role of specific oncogenic combinations in DIPG pathogenesis. We used in utero electroporation (IUE) to transfect neural stem cells in the developing brainstem with PiggyBac DNA transposon plasmids. Combinations of platelet-derived growth factor B (PDGFB), PdgfraD842V, or PdgfraWT, combined with dominant negative Trp53 (DNp53) and H3.3K27M expression, induced fully penetrant brainstem gliomas. IUE enabled the targeted transfection of brainstem neural stem cells. PDGFB + DNp53 + H3.3K27M induced the rapid development of grade IV gliomas. PdgfraD842V + DNp53 + H3.3K27M produced slower forming grade III gliomas. PdgfraWT + DNp53 + H3.3K27M produced high- and low-grade gliomas with extended latencies. PDGFB, PdgfraD842V, and PdgfraWT DIPG models display unique histopathological and molecular features found in human DIPGs. H3.3K27M induced both overlapping and unique gene expression changes in PDGFB and PdgfraD842V tumors. Paracrine effects of PDGFB promote disruption of pericyte-endothelial interactions and angiogenesis in PDGFB DIPG mouse models. Brainstem-targeted IUE provides a rapid and flexible system to generate diverse DIPG mouse models. Using IUE to investigate mutation and pathohistological heterogeneity of DIPG will provide a valuable tool for future genetic and preclinical studies.

Reply to ‘The complex tale of Mantiqueira and Juiz de Fora: A comment on “Eoarchean to Neoproterozoic crustal evolution of the Mantiqueira and the Juiz de Fora Complexes, SE Brazil: Petrology, geochemistry, zircon U-Pb geochronology and Lu-Hf isotopes”’ by K. Cutts and C. Lana

The radiological signs of intracranial dural arteriovenous fistulas (ICDAVFs) are heterogenous. While it is commonly accepted that hyper intense T2 wedge magnetic resonance imaging of the brainstem and cervical cord mainly concern gliomas, it is so far uncommon and probably unknown that ICDAVFs can imitate similar radiological pattern, especially with gadolinium contrast enhancement and cord enlargement. Thus the angiography is poorly documented in the diagnostic workup. We report the unusual history of ICDAVFs, revealed by clinical and radiological features that mimicked a medulla or cervical spinal cord glioma. This observation provides information on the management of atypical lesions mimicking medulla or cervical cord glioma and arguments for a careful radiological study. Looking for dilated veins around the brainstem and the cord is mandatory in the workup of a supposed infiltrating brainstem or spinal cord lesion, in order to rule out an ICDAVF. Even if the hyperintense T2 images associated with contrast enhancement is in favor of a brainstem or spinal cord glioma, additional cerebral angiography should be mandatory. Moreover, this clinical case highlights the need for a multidisciplinary approach including neuroradiologist, oncologist and neurosurgeon.

P14.33 Adult brainstem gliomas in neurofibromatosis type 1 (NF1)

Abstract BACKGROUND The brainstem is the second location of brain tumors after optic pathways in NF1. In NF1 children, brainstem gliomas are usually indolent and have a better prognosis than their counterparts in non NF1 children. In contrast, the natural history and prognosis of adult brainstem gliomas in NF1 are nearly unknown. MATERIAL AND METHODS We conducted a retrospective analysis of medical records and MRI of adult NF1 patients followed for a brainstem glioma in 8 centers over a 17 years period (2000–2017). Clinical and imaging characteristics, management and outcome were analyzed. RESULTS Twenty five patients were included in the study (13 males and 12 females) with a median age of 32 (range 17–58). The epicenter of the tumor was located into the pons n=13 (52%), the mesencephalon n=7 (28%), the medulla oblongata n=5 (20%). On MRI, contrast enhancement was seen in 19 tumors (76%). Pathological examination was available in 13 tumors (52%) and showed a high grade astrocytoma (III or IV) in 9 tumors. Five patients were asymptomatic, 3 remained asymptomatic during the follow-up (median follow-up: 86 months, range 22–124). Twenty patients were symptomatic with a median duration of symptom of 2.5 months (range 1–10) before diagnosis. Among these symptomatic patients, 15 died from tumor progression despite treatment with radiation therapy and or chemotherapy. The median overall survival of symptomatic patients was 36 months. CONCLUSION Brainstem gliomas are rare tumors in adults with NF1. Unlike children, adult brainstem gliomas seem to have an unexpected poor prognosis, suggesting the disease may be different in adulthood.

Liquid biopsy for diffuse intrinsic pontine glioma: an update.

Diffuse intrinsic pontine glioma (DIPG), otherwise known as diffuse midline glioma with H3K27M mutation, is a devastating brainstem glioma without a cure. Efforts are currently underway to better optimize molecular diagnoses through biological sampling, which today remains largely limited to surgical biopsy sampling. Surgical intervention is not without its risks, and therefore a preference remains for a less invasive modality that can provide biological information about the tumor. There is emerging evidence to suggest that a liquid biopsy, targeting biofluids such as CSF and blood plasma, presents an attractive alternative for brain tumors in general. In this update, the authors provide a summary of the progress made to date regarding the use of liquid biopsy to diagnose and monitor DIPG, and they also propose future development and applications of this technique moving forward, given its unique histone biology.

Glioblastoma in the Cerebellopontine Angle in a Patient with Neurofibromatosis Type I: A Case Report and Review of the Literature

Abstract Introduction Glioblastoma multiforme (GBM) is the most common primary brain malignancy in adults and is typically in the supratentorial cerebral hemispheres. It has been reported to occur in the posterior fossa at the cerebellopontine angle (CPA), but the incidence is extremely rare. Case Report We report a case of a patient with a history of neurofibromatosis type I (NFI) diagnosed with a GBM arising in the CPA after presenting with facial numbness and pain. Patients with NFI are known to have an increased risk of developing both benign and malignant tumors, including a propensity for brainstem gliomas. However, there is no known association between NFI and tumors of the CPA. We believe this is the first reported case of a GBM of the CPA in a patient with NFI. Conclusion Although rare, GBM should be included in the differential diagnosis of a patient with a CPA tumor, especially in patients with increased risk of malignant pathology.

The application value of diffusion tensor imaging in surgical management of patients with brainstem gliomas

Objective To explore the role of diffusion tensor imaging (DTI) in brainstem glioma surgery. Methods A retrospective analysis was performed on 57 patients with brainstem gliomas who had undertaken surgery from January 2014 to December 2018 at Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University. All patients underwent preoperative DTI and tumor resection with the assistance of neuronavigation and electrophysiological monitoring. Radiological and clinical data were collected, including conventional MRI and DTI, corticospinal tract (CST) score, tumor-to-CST distance (TCD), muscle strength and Karnofsky performance status (KPS) before and after surgery. Kruskal-Wallis H test was used to evaluate postoperative motor deficit and KPS of patients with different CST scores. Spearman's correlation was performed to assess the relationship of both CST score and TCD with postoperative motor deficits and KPS, respectively. Multiple linear regression was used to investigate the influence of CST score and TCD on postoperative muscle strength and KPS. Results Among the 57 patients, 51 patients had at least one CST compromised. The most common changes of the CST were deviation (30/114, 26.3%) and deformation (30/114, 26.3%). The surgical approaches were adjusted after evaluation of the DTI results in 21 (36.8%) cases. Postoperative muscle strength and KPS were significantly different between different CST score groups (χ2=16.011; χ2=9.576, all P<0.05). Preoperative CST scores were negatively correlated with postoperative muscle strength and KPS (r=-0.362; r=-0.354, both P<0.05) whereas TCD had positive correlation with both postoperative muscle strength and KPS (r=0.305, r=0.339, both P<0.05). CST score could independently influence postoperative muscle strength (t=-2.438, P=0.016). However, CST score could not independently influence postoperative KPS (t=-0.523, P=0.603). Conclusion DTI plays an important role in surgical management of brainstem gliomas and could help optimize the surgical strategy and predict postoperative motor deficits. Key words: Diffusion tensor imaging; Brainstem glioma; Neurosurgical procedures; Application value

Abstract 4430: Simulating delivery of TTFields to the infratentorium in patients with brainstem gliomas

Abstract Purpose/Objective(s): TTFields are FDA-approved for the treatment of recurrent and newly diagnosed Glioblastoma (GBM) in the supratentorial brain. The EF-14 trial showed that combining TTFields with adjuvant chemo-radiation leads to a significant increase in overall survival compared to adjuvant chemo-radiation alone. High-grade gliomas also occur in the infratentorium and brainstem of pediatric and adult patients. Brainstem gliomas have a median survival of 9 to 11 months, necessitating the exploration of novel treatment combinations, such as delivering TTFields to the infratentorial brain. We recently showed in a simulation-based study that TTFields can be successfully delivered to the infratentorium. Effective delivery was achieved by placement of the arrays on the vertex, bilateral posterolateral occiput, and superior-posterior neck; the array placement results in TTFields at therapeutic intensities throughout the brainstem and cerebellum of realistic computational head models. The previous simulation-based study was performed using realistic computational models of healthy individuals; it did not provide detailed insight into field distributions within tumor tissue located in the infratentorium. Here, we aim to expand the results of this previous study, by simulating the delivery of TTFields to the infratentorium of adult and pediatric patients with high-grade brainstem gliomas. Materials/Methods: A realistic computational model was created using MRI data of adult and pediatric patients with high-grade brainstem gliomas. Transducer arrays were placed on the model and the delivery of TTFields to the infratentorial brain was then simulated using a commercial numerical solver. The electric field distribution in the supratentorium, infratentorium, and within the tumor were derived from the simulations, and the dose in the tumor analyzed. Results: The distribution of calculated isofield lines demonstrates effective delivery of TTFields to infratentorial brain tumors. Conclusion: Our results provides rationale for clinically investigating the utility of TTFields in treating infratentorial high-grade gliomas. Citation Format: Marigdalia K. Ramirez-Fort, Brittany Cross, Ariel Naveh, Shearwood McClelland III, Melissa Mendez, Roberto Santiago, Sean S. Mahase, Jaime Matta, Ze'ev Bomzon, Christopher S. Lange. Simulating delivery of TTFields to the infratentorium in patients with brainstem gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4430.

Abstract 3920: Differential effects of Jumonji family demethylase and EZH2 H3K27 methyltransferase inhibition on radiation sensitivity of H3K27M mutant DIPG

Abstract Diffuse intrinsic pontine glioma (DIPG) is an aggressive pediatric brainstem tumor with a 5-year survival of &amp;lt;1% (1). Up to 80% of DIPG tumors contain a specific K27M mutation in one of two genes encoding histone H3 (H3K27M). 60-75% of H3K27M mutations occur in gene encoding histone variant H3.3, which has been linked to reduced overall survival and poor response to first line radiation therapy (1). Recent evidence indicates that H3K27M inhibits the enzymatic activity of Polycomb Repressive Complex 2 through interaction with the EZH2 histone methyl transferase (2). A specific inhibitor of Jumonji family histone demethylase GSK-J4 was recently reported to restore H3K27 tri-methylation patterns in human DIPG cells and improve survival of H3K27M mutant orthotopic xenograft brainstem tumor models (3). Furthermore, a genetic deletion of EZH2 had also been shown to improve survival of H3K27M mouse model of DIPG, suggesting that EZH2 may be a potential therapeutic target (4). Given these data, we investigated the effects of Jumonji demethylase inhibitor GSK-J4 and EZH2 inhibitor tazemetostat on radiosensitization of human H3K27M DIPG cells. We found that GSK-J4 inhibitor had a growth inhibitory effect on H3K27M mutant DIPG cells as a single agent (96% growth inhibition at 1.5 micro-molar concentration, P&amp;lt;0.0001). Strikingly, GSK-J4 inhibitor also displayed radiosensitizing effects when combined with ionizing radiation at sub-micromolar concentrations of the drug (34.4% growth inhibition at 0.37 micro-molar concentration when combined with 4 Gy XRT vs 23.3% with XRT alone, P&amp;lt;0.0001 for both; no significant growth inhibition as single agent). Contrary to previously reported results with EZH2 inhibition in H3K27M neural stem cell model of DIPG, EZH2 inhibitor tazemetostat had no effect on human H3K27M DIPG cells as a single agent or when combined with ionizing radiation. This result is, however, not unexpected, given the proposed inhibitory effect of H3K27M mutation on EZH2 activity in DIPG disease pathogenesis. In conclusion, Jumonji family methyltransferase inhibitor GSK-4J sensitizes H3K27M DIPG cells to ionizing radiation, while EZH2 methyltransferase inhibitor has no effect. This result appears to be consistent with the recently proposed epigenetic mechanism of DIPG pathogenesis (1, 2). 1. Johung TB, et al. Diffuse intrinsic pontine glioma: new pathophysiological insights and emerging therapeutic targets. Curr Neuropharmacol. 2017;15:88-97. 2. Lewis PW, et al. Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma. Science. 2013;340:857-61. 3. Hashizume R, et al. Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma. Nat Med. 2014;20:1394-6. 4. Mohammad F, et al. EZH2 is a potential therapeutic target for H3K27M-mutant pediatric gliomas. Nat Med. 2017;23:483-492. Citation Format: Anatoly Y. Nikolaev, John B. Fiveash, Eddy S. Yang. Differential effects of Jumonji family demethylase and EZH2 H3K27 methyltransferase inhibition on radiation sensitivity of H3K27M mutant DIPG [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3920.

Delayed Radiation-Induced Stroke Mimics Recurrent Tumor in an Adolescent With Remote History of Low-Grade Brainstem Glioma

Delayed Radiation-Induced Stroke Mimics Recurrent Tumor in an Adolescent With Remote History of Low-Grade Brainstem Glioma