Thalamic Glioma Research Articles

BIOM-34. GENOMIC PROFILING IDENTIFIED COPY NUMBER VARIATIONS OF CDK4/6 AS A NOVEL PROGNOSTIC BIOMARKER FOR THALAMIC GLIOMA

Abstract BACKGROUND Thalamic glioma is a rare tumor, which is poorly understood in adults. The genetic variation of this tumor is still unknown. In this study, we investigated the mutation landscape of thalamic glioma and compared the clinical outcomes between different mutation situations in thalamic glioma. METHODS Next-generation sequencing targeting 425 cancer-relevant genes was performed with 34 thalamic glioma tissue samples. Gene mutations and copy number variations were investigated for prognostic effect with overall survival data. RESULTS Several diagnostic and prognostic biomarkers appeared in our thalamic glioma cohort, including TP53 (56%), EGFR (41%), TERT (35%), M CL1 (26%), PDGFRA (26%), PTEN (26%), CDK4/6 (24%), POLE (24%), PIK3CA (24%), NF1 (21%), ATR (21%), ATRX (18%), BRAF (15%), and ROS1 (12%). Among all genetic aberrations with a more than 10% occurrence rate, two mutations (TERT and PTEN) were associated with poor overall survival and one copy number variation (CDK4/6) was associated with favorable overall survival (univariate P < 0.1). Among these genes, CDK4/6 copy number variations (hazard ratio [HR], 0.16; 95% confidence interval [CI], 0.035–0.704; P = 0.016) remained significant survival associated in multivariate analyses. Copy number variations of CDK4/6 was seldom reported as a prognostic biomarker for glioma, especially for thalamic glioma in public databases. Besides, several gene mutations (BRIP1, MRE11A, MAP2K1, ROS1, MUTYH, JARID2, CTCF, and EGFR) were found positively associated with CDK4/6 copy number variations. Gene enrichment analysis demonstrated that those genes were related to astrocyte differentiation. CONCLUSIONS In our study, CDK4/6 copy number variation was determined as a favorable overall survival biomarker for thalamic glioma, and CDK4/6 copy number variation associated mutant genes were related to astrocyte differentiation, which could be the potential therapeutic targets for thalamic glioma.

PATH-19. TERT PROMOTER MUTATION, NOT H3K27M MUTATION IS A PROGNOSTIC FACTOR FOR ADULT THALAMIC GLIOMAS

Abstract Purpose Thalamic diffuse glioma is classified as WHO grade 4 as Diffuse midline glioma, H3K27M mutation if H3K27M mutation was found regardless of its histological findings, but the significance of H3K27M mutation is not clear compared with pediatric cases. We aimed to find genetic prognostic factors in adult thalamic diffuse gliomas. METHODS Pathological diagnosis, genetic abnormalities, and clinical course of adult newly diagnosed thalamic gliomas diagnosed and treated at our institution from July 2007 to March 2020 were retrospectively analyzed. RESULTS The number of cases was 41 (24 males, 17 females), median age was 47 years (20-75 years). Tumor localization was 20 cases on the left, 14 cases on the right, and 7 cases on both sides. The pathological diagnosis was GBM 15 cases, DMG 15 cases, AA-IDH WT 7 cases, DA-IDH WT 4 cases, all of which were IDH wild type, and none of them had IDH mutation and 1p/19q co-deletion. H3K27M mutations were found in 15 cases and TERT promoter mutations were found in 12 cases, both of which were completely mutually exclusive. Tumor resection and biopsy was performed in 33 and 8 cases, respectively, and the median removal rate was 95% for those who underwent tumor resection. The median PFS and OS of all cases were 14.3 months and 38 months, respectively, and the median OS by pathological diagnosis was GBM 12.4 months, DMG 47.4 months, AA-IDH WT 37.3 months, DA-IDH WT not reached. The median OS in the H3K27M mutant group (47.4 months) was significantly better (p=0.02) than that in the TERT promoter mutation group (13.5 months). CONCLUSION There was no IDH mutation in adult thalamic gliomas, the H3K27M mutation and the TERT promoter mutation were mutually exclusive. The H3K27M mutation was not a prognostic factor, but the TERT promoter mutation was the strongest prognostic factor.

Spinal Cord Diffuse Midline Gliomas With H3 K27m-Mutant: Clinicopathological Features and Prognosis.

"Diffuse midline glioma, H3 K27M-mutant" (DMG) mainly arises within the pontine, thalamic, and spinal cord regions. Because of the rarity of spinal cord gliomas, the general knowledge surrounding DMGs is mainly based on pontine and thalamic gliomas, whereas tumor location tends to influence the clinicopathological features and prognosis. To determine the clinicopathological characteristics and molecular profiles of DMGs located in the spinal cord. The clinical and molecular pathologic features and prognosis were comprehensively analyzed in a series of 44 patients with spinal cord DMGs. The median age was 36 yr, and 88.7% of patients (39/44) were adults (≥18 yr). Histopathologically, malignant grades included grade II (16 cases), grade III (20 cases), and grade IV (8 cases). Compared with patients with histological grade IV, patients with lower histological grade (grade II/III) were older (37vs 24 yr, P=.020) and were associated with longer overall survival (24.1vs 8.6 mo, P=.007). All 30 tested tumors were isocitrate dehydrogenase (IDH) wild type, and 96% of cases (22/23) presented with unmethylated O6-methylguanine-DNA methyltransferase. Univariate and multivariate analyses showed that histological grade and presurgery McCormick Scale scores were independent prognostic factors for overall survival, whereas extensive surgical resection and chemoradiotherapy were not significantly associated with improved survival. The most frequent anatomic locations were the cervical enlargement (C4-T1, n=16) and conus medullaris (T12-L1, n=13), which exhibited distinctive clinical characteristics and molecular features. The findings provide guidelines for the evidence-based practice of the specialized management of spinal cord DMGs.

Clinical Findings of Thalamic and Brainstem Glioma Including Diffuse Midline Glioma, H3K27M Mutant:A Clinical Study

Diffuse midline glioma, H3K27M mutant is a glioma located in the thalamus, brainstem, or spine with the H3K27M mutation, which is a new entity in the 2016 revised WHO classification. The treatment of thalamic glioma(TG)and brainstem glioma(BSG), which includes diffuse midline gliomas, the H3K27M mutant is challenging, and there are no standard therapeutic strategies. It is important to determine the characteristics of these brain tumors. Here, we retrospectively reviewed 31 consecutive patients with TG and BSG who were treated at our institute between January 1994 and May 2018, including methionine-positron emission tomography(MET-PET)data. Fourteen patients had TG, while 17 patients had BSG. Six patients were children, and 25 were adults. Nine patients with TGs and seven with BSG were enhanced by gadolinium. Twenty-seven patients were treated with radiotherapy, and 20 patients were treated with chemotherapy. All 21 tumors that underwent surgery showed wild-type IDH. The H3K27M mutation was present in four TG and two BSG. There was no statistically significant association between methionine uptake and gadolinium contrast enhancement and tumor grade. The median overall survival period(OS)of all cases was 16.9 months, whereas those of TG and BSG were 22.8 and 10.0 months, respectively. Because TG and BSG still have poor prognoses, it is necessary to elucidate the pathology of the disease and establish its standard therapy.

Case series of diffuse extraneural metastasis in H3F3A mutant high-grade gliomas: Clinical, molecular phenotype and literature review

H3K27M and H3.3G34R/V mutations have been identified in pediatric high-grade gliomas (pHGG), though extraneural metastases are rarely reported and poorly characterized. Three pHGG patients from two institutions were identified with extraneural metastasis, harboring histone mutations. Their clinical, imaging and molecular characteristics are reported here. A 17-year old female presented with supratentorial H3.3G34R-mutant glioma with metastatic osseous lesions in the spine, pelvis, bone marrow, pleural effusion and soft tissue of pelvis. Bone marrow biopsy and soft tissue of pelvis biopsy showed neoplastic cells positive for P53. A 20-year old female was diagnosed with H3F3A H3K27M–mutant thalamic glioma. She developed diffuse sclerotic osseous lesions. Biopsy of an osseous lesion was non-diagnostic. A 17-year old female presented with a H3F3A H3K27M-mutant diffuse midline glioma with diffuse spinal cord metastasis. She further developed multifocal chest lymphadenopathy, pleural effusions, and a soft tissue mass in the abdominal wall. The latter was positive for H3K27M mutation. We present the first case series of pHGG with H3F3A mutation and diffuse extraneural dissemination, describing their clinical and molecular profile.

High prevalence of developmental venous anomaly in adult patients with midline thalamic diffuse gliomas

ObjectiveThis study aimed to assess the prevalence of developmental venous anomaly (DVA) in patients with thalamic glioma. Furthermore, we explored the association between DVA and some important biomarkers, such as IDH1 mutation, and H3K27M mutation. Patients and MethodsPatients who received tumor resection in West China Hospital between August 2009 and October 2017 were enrolled. Propensity score matching was conducted based on a logistic regression model and 1:1 matching for case and control was used to generate a new cohort from patients with meningioma. Chi-square test, t-test, univariate and multivariate analyses were employed to assess the prevalence of DVA in thalamic glioma and meningioma and to identify risk factors associated with DVA. ResultsNinety-nine patients with thalamic glioma were enrolled in the current study (male, n = 54; female, n = 45). The mean age was 42.9 ± 15.3 years old. We identified a higher prevalence of DVA in 99 patients with thalamic glioma when compared with 99 patients with meningioma (18.18% vs. 7.07%), which was slightly lower than the prevalence of DVA in glioma reported in previous studies. Furthermore, the distribution of gender, age, and tumor grade in DVA did not reach statistical significance. Chi-square test, univariate and multivariate analyses showed that IDH1 mutation, ATRX mutation, MGMT promoter methylation, p53 mutation, MMP9, EGFR, and Top II positive expression, TERT mutation, and H3K27M mutation were not associated with the development of DVA in thalamic glioma. ConclusionA higher prevalence of DVA was found in thalamic glioma compared with meningioma.

Molecular Characteristics of Thalamic Gliomas in Adults.

The 2016 World Health Organization classification of central nervous system tumor firstly introduces molecular diagnosis to glioma, while the molecular features of adult thalamic gliomas (ATGs) in a relatively large sample have not been reported. We aimed at exploring molecular characteristics in ATGs. The data of 97 and 575 newly diagnosed ATGs and superficial gliomas (SGs) patients were collected, and we performed a comparative analysis of molecular characteristics between them. We analyzed expressions of molecules as follow: H3 K27M, isocitrate dehydrogenase1 (IDH1), Ki-67, O6-Methylguanine-DNA methyltransferase (MGMT) promoter, EGFR, p53, ATRX, GFAP, Oligo2, PTEN, MGMT, and MMP9 by immunohistochemistry. Direct gene sequencing was performed to test the H3 K27M, IDH1, and TERT promoter mutation. The median age at diagnosis of ATGs was 36.0years, and majority of them were high-grade glioma. We found a significant difference in H3 K27M mutation (P = 0.003), IDH1 mutation (P < 0.001), MGMT promoter methylation (P = 0.005), and Ki67 > 0.1 (P < 0.001) between ATGs and SGs. The statuses of IDH1 (P < 0.001), MGMT promoter (P < 0.001), and Ki67 (P < 0.001) were significantly different between these two groups in lower-grade gliomas. And statuses of IDH1 (P < 0.001), Ki67 (P < 0.001), and EGFR (P = 0.032) were different between these two groups in high-grade gliomas. Only Ki67 > 0.1 was differentially expressed between lower- and high-grade gliomas in ATGs (P = 0.014). The high occurrence of H3 K27M mutation and Ki67 > 0.1, rare occurrence of IDH1 mutation, and MGMT promoter methylation in ATGs suggested that ATGs may be a distinct type of glioma entity.

The concept of \u201cFour Walls, Two Poles\u201d in the lesions of the thalamus and ganglion regions: case report and literature review

BackgroundThere are few articles about the surgical techniques of thalamic glioma and the lesions in the basal ganglia area. According to three existing cases and the literature review (Twelve articles were summarized which mainly described the surgical techniques), we discuss the surgical characteristics of lesions of the thalamus and basal ganglia area and summarize the relevant surgical skills.Case presentationOf the three cases, two were thalamic gliomas and one was brain abscess in basal ganglia. According to the three-dimensional concept of the “Four Walls, Two Poles”, lesions of the thalamus and basal ganglia were surgically removed, and the operative effect was analysed by relevant surgical techniques. Surgical resection of the lesions of the thalamus and basal ganglia area according to the three-dimensional concept of the “Four Walls, Two Poles” has achieved good surgical results. Relevant surgical techniques, such as the use of retractors, the use of aspirators, the choice of surgical approaches, and the haemostasis strategy, also played an important role in the operation process.ConclusionsIn the presented three cases the three-dimensional concept of the “Four Walls, Two Poles” allowed for safe surgical resection of lesions of the thalamus and basal ganglia.

A subset of pediatric-type thalamic gliomas share a distinct DNA methylation profile, H3K27me3 loss and frequent alteration of EGFR.

Malignant astrocytic gliomas in children show a remarkable biological and clinical diversity. Small in-frame insertions or missense mutations in the epidermal growth factor receptor gene (EGFR) have recently been identified in a distinct subset of pediatric-type bithalamic gliomas with a unique DNA methylation pattern. Here, we investigated an epigenetically homogeneous cohort of malignant gliomas (n = 58) distinct from other subtypes and enriched for pediatric cases and thalamic location, in comparison with this recently identified subtype of pediatric bithalamic gliomas. EGFR gene amplification was detected in 16/58 (27%) tumors, and missense mutations or small in-frame insertions in EGFR were found in 20/30 tumors with available sequencing data (67%; 5 of them co-occurring with EGFR amplification). Additionally, 8 of the 30 tumors (27%) harbored an H3.1 or H3.3 K27M mutation (6 of them with a concomitant EGFR alteration). All tumors tested showed loss of H3K27me3 staining, with evidence of overexpression of the EZH inhibitory protein (EZHIP) in the H3 wildtype cases. Although some tumors indeed showed a bithalamic growth pattern, a significant proportion of tumors occurred in the unilateral thalamus or in other (predominantly midline) locations. Our findings present a distinct molecular class of pediatric-type malignant gliomas largely overlapping with the recently reported bithalamic gliomas characterized by EGFR alteration, but additionally showing a broader spectrum of EGFR alterations and tumor localization. Global H3K27me3 loss in this group appears to be mediated by either H3 K27 mutation or EZHIP overexpression. EGFR inhibition may represent a potential therapeutic strategy in these highly aggressive gliomas.

Infiltrative gliomas of the thalamus in children: the role of surgery in the era of H3 K27M mutant midline gliomas

BackgroundThe role of surgery in the management of pediatric non-pilocytic infiltrative thalamic gliomas needs to be revisited specifically with regard to molecularly defined subtypes.MethodsA retrospective review of a consecutive series of children operated on a thalamic tumor between 1992 and May 2018 was performed. Neuroimaging data were reviewed for localization and extent of resection; pathology was re-reviewed according to the current WHO classification, including assessment of histone H3 K27 mutational status.ResultsForty-nine patients with a thalamic tumor aged < 18 years at diagnosis were identified. Twenty-five patients (51%) had a non-pilocytic infiltrative glioma, of which the H3 K27M status was available in 22. Fourteen patients were diagnosed as diffuse midline glioma (DMG) H3 K27M mutant. There was no statistically significant difference in survival between patients harboring the H3 K27M mutation and wildtype. Resection (“any resection > 50%” vs “biopsy”) and histological tumor grade (“°II” vs “°III+°IV”) were statistically significant predictors of survival (univariate: p = 0.044 and p = 0.013, respectively). These results remained significant on multivariate analysis (HR 0.371/p = 0.048, HR 9.433/p = 0.035).ConclusionWe advocate to still consider an attempt at maximal safe resection in the multidisciplinary treatment of unilateral thalamic non-pilocytic gliomas irrespective of their H3 K27-mutational status.

Endoscope-Assisted Contralateral Perimedian Supracerebellar Suprapineal Approach to Third Ventricle Surface of the Thalamus: 3-Dimensional Operative Video.

In managing thalamic gliomas, total surgical removal is the most effective way of increasing overall survival. However, the thalamus is a difficult target because of surrounding neurovascular structures. According to the lesion's size/location/growth pattern, relation to neighboring structures, and surgeon's experience, most thalamic lesions can be reached through one of the 4 free surfaces: lateral ventricle, velar, cisternal, and third ventricle surfaces of the thalamus (3VsT).1-3 Approaching the thalamic lesions through the lateral side disrupts the integrity of internal capsule and corona radiata; thus, we never prefer this approach. For the removal of the lesions on the 3VsT, a transcallosal approach can be considered, but with this approach, we cannot reach 3VsT without harming the velar surface. In this 3-dimensional video, we demonstrate an endoscope-assisted contralateral perimedian supracerebellar suprapineal (CPeSS) approach to a glioma on the 3VsT. The patient, a 49-yr-old man, had progressive dizziness for a month. With the patient in a semisitting position, total resection was achieved via the endoscope-assisted CPeSS approach. This approach is entirely transcisternal-transventricular and is a natural route to the 3VsT. Although the route is longer than the ipsilateral approach, it requires no retraction and provides more direct and wider visualization. It allows complete visualization of the lateral border of the lesion. A perimedian approach also avoids the major tentorial bridging veins, which are mostly at the midline. High-definition neuroendoscope was a great adjunct that helped to visualize residual tumors at hidden corners. We suggest this approach for thalamic lesions on the third ventricle surface of the thalamus. The patient consented to the publication of his images and a written consent was obtained.

Clinical efficacy of ONC201 in thalamic H3 K27M-mutant glioma.

3617 Background: Diffuse midline gliomas, H3 K27M-mutant are associated with a poor prognosis compared to H3 wild-type gliomas and have no effective therapy following first-line radiation. ONC201 is a bitopic DRD2 antagonist and allosteric ClpP agonist that has shown encouraging single agent efficacy in recurrent H3 K27M-mutant gliomas located in various midline structures of the brain. In addition to tumor and immune cells, the pharmacodynamics of ONC201 extend to stromal cells that can mediate a bystander antitumor response in preclinical models. Given this observation and that the thalamus has the highest extrastriatal expression of DRD2, we report the clinical experience of ONC201 in a subgroup of H3 K27M-mutant glioma patients with primary tumors located in the thalamus. Methods: We analyzed 29 thalamic H3 K27M-mutant glioma patients treated with ONC201 in clinical trials enrolled as of 5/22/19. Nineteen enrolled with recurrent disease whereas 10 enrolled following radiation prior to recurrence. Twelve patients enrolled on NCT03295396, 10 NCT03416530, 4 NCT02525692, and 3 expanded access. Median age was 22 years old (range: 5-70) and baseline KPS was 80 (range: 60-90). Median time from radiation to start of ONC201 was 1.8 months (range: 0.2-8.7) for non-recurrent patients and 7.2 months (range: 1.4-102.0) for recurrent patients. Results: As of 12/18/2019, PFS6 and OS12 measured relative to initiation of ONC201 are 26.3% and 36.8%, respectively, in the recurrent group. For patients initiating ONC201 post-radiation prior to recurrence, median PFS or OS have not been reached with a median follow up of 21.9 months (8.6-26.6) from diagnosis, which surpass historical OS of 13.5 months. Best response for evaluable recurrent patients by RANO: 1 CR, 3 PR, 4 SD, 8 PD, 3 not reported; for non-recurrent patients: 2 PR, 4 SD, 1 PD, 3 not reported. Median duration of response for recurrent patients is 14.0 months (2.0-33.1). ONC201 was well tolerated and no dose-limiting toxicities or treatment discontinuations due to toxicity occurred. Furthermore, H3 K27M cell-free tumor DNA in plasma and CSF correlated with MRI response. Conclusions: In summary, single agent ONC201 administered at recurrence or following radiation, demonstrates promising clinical efficacy in thalamic H3 K27M-mutant glioma patients. Investigations are ongoing to assess whether micro-environmental DRD2 expression correlates with responses of thalamic H3 K27M-mutant glioma to ONC201. Clinical trial information: NCT03295396, NCT03416530, NCT02525692 .

Long term follow-up and outcomes in adult patients with thalamic gliomas

ObjectivesTo investigate the optimal treatment and prognosis of thalamic glioma in adult patients. Patients and methodsWe retrospectively analyzed the adult patients with thalamic glioma admitted to our hospital from May 2005 to September 2016. Patients were divided into two groups according to their treatment: surgery-based combined treatment and intensity modulated radiation therapy (IMRT)-based treatment. Univariate chi-square test and multivariate logistic regression were used to identify independent factors for the treatment modality. A log-rank test, adjusting for propensity score, was used to compare the overall survival (OS) and progression-free survival (PFS) of patients between the two groups. ResultsFifty-eight adult patients with thalamic gliomas were included in the analysis. Of them, 31 were treated with surgery-based treatment, and 27 were treated with IMRT-based treatment. The overall survival (OS) and progression-free survival (PFS) of patients between the two groups were not significantly different (median OS 16.0 (range 1.0–163.0) months vs. 10.0 (range 1.0–118.0) months, p = 0.344 and median PFS 10.0 (range 1.0–163.0) months vs. 6.0 (range 1.0–118.0) months, p = 0.464, respectively) even after adjusting for potential confounding factors. ConclusionsThe OS and PFS of adult patients with thalamic glioma were not significantly different between patients in the surgical group and in the IMRT group. IMRT might be an acceptable alternative to surgery for adult patients with unresectable thalamic glioma.

Expression and clinical significance of microchromosome maintenance protein 10 in thalamic gliomas

Objective To investigate the expression of microchromosome maintenance protein 10(MCM10) in thalamic gliomas and its prognostic value. Methods A retrospective analysis was conducted on the clinical data of 48 patients with thalamic glioma who underwent tumor resection at Neurosurgery Department of Beijing Tiantan Hospital, Capital Medical University from September 2016 to September 2017. At 1 week post operation, the degree of tumor resection was determined according to cranial MRI. After discharge, all patients underwent follow-up by outpatient clinic visits or telephone, which included reexamination of skull enhanced MRI and assessment of Karnofsky performance scale(KPS) score. All tumor tissues were reserved during operation for immunohistochemical staining analysis of MCM10. According to the positive rate of MCM10 expression and comprehensive score of staining intensity, the lower expression of MCM10 was decided as less than 6 points, and the higher expression of MCM10 as at least 6 points. The expression of MCM10 in different grade thalamic gliomas was analyzed. We then compared the clinical data of MCM10 low expression group and high expression group. The survival of two groups was further analyzed using Kaplan-Meier method. Finally, the univariate and multivariate Cox regression analysis methods were used to determine whether MCM10 was an independent risk factor affecting the total survival of thalamic glioma patients. Results In 48 patients, 1 week after surgery, the cranial MRI showed that total resection was achieved in 13 cases (27.1%), near-total resection in 29 cases (60.4%) and partial resection in 6 cases (12.5%). The median follow-up time was 22.6 months (0.3-34.2 months) in 48 patients. Three months after surgery, the median KPS score was 60 points(0-100 points). By the end of the follow-up period, 31 of the 48 patients survived and 17 died. The results of immunohistochemistry showed that the tumor tissue in 48 patients expressed MCM10, of which 23 (47.9%) were low expression and 25 (52.1%) were high expression. Immunohistochemistry analysis in the 48 patients of thalamic gliomas with various World Health Organization (WHO) grades showed that MCM10 had the lowest staining points (3.7±1.2) in grade Ⅰ glioma, middle-level in grade Ⅱ (5.8±2.3) and grade Ⅲ(7.5±3.5), and the highest in grade Ⅳ (7.9±2.8). The difference between groups was statistically significant (P=0.021). The differences in age, sex, WHO grade, preoperative KPS score and postoperative recurrence of MCM10 high expression group and low expression group were not statistically significant (all P>0.05). The survival rate and KPS score improvement were significantly higher in the patients of MCM10 low expression group than those in the high expression group (both P<0.05). The results of univariate and multivariate Cox regression analysis showed that MCM10 high expression was one of the independent risk factors affecting the outcome of patients with thalamic glioma (HR=0.129, 95% CI: 0.024-0.685, P=0.016). Conclusions MCM10 is expressed in thalamic glioma with the lowest level in WHO Ⅰ grade tumor and the highest in grade Ⅳ. Longer survival is associated with low expression of MCM10, which can be used as an indicator of the prognosis judgment of thalamic glioma. Key words: Thalamus; Glioma; Prognosis; Microchromosome maintenance protein 10

Primary bilateral thalamic glioma with bipeduncle involvement of midbrain

Primary bilateral thalamic glioma with bipeduncle involvement of midbrain

Lateral or Medial Surgical Approaches for Thalamic Gliomas Resection?

This study aimed to investigate the selection, safety, and prognosis of medial (transcorpus callosal) and lateral (translateral brain gyrus) approaches for adult thalamic glioma resection. The medical records of adult patients with thalamic glioma between March 2006 and March 2016 in Huashan Hospital were reviewed. The probabilistic map of the gliomas was shown in Montreal Neurological Institute (MNI) space, and a paralleling midline was delineated to decide the approach. The extent of resection, complications, adjuvant treatment, and survival data were analyzed. A literature review was also conducted. Fifty-three patients with thalamic glioma were enrolled. Eighteen patients received tumor resection by a medial approach and 35 by a lateral approach. The probabilistic map based on 20 patients showed that 9 gliomas with ≥45% located in the medial side were treated medially and the other 11 gliomas were treated laterally. Both approaches achieved adequate extent of resection with similar morbidity. Kaplan-Meier analysis showed no significant difference of overall survival by a transcorpus callosal or translateral brain gyrus approach. Total resection (TR) or subtotal resection (STR) (P= 0.0003), radiochemotherapy (P < 0.0001), and low-grade glioma (P= 0.031) were correlated with better OS. Multivariate Cox regression analysis showed that TR/STR (P= 0.007; 95% confidence interval, 1.345-6.287) and radiochemotherapy (P < 0.0001; 95% confidence interval, 4.740-71.569) were independent prognostic factors for adult thalamic gliomas. Both medial and lateral approaches are feasible and adequate for resection of thalamic gliomas. The paramidline paralleling midline crossing the genu of the internal capsule could help make the choice. TR/STR, radiochemotherapy, and low-grade glioma could benefit the prognosis.

PDTM-10. USE OF A NOVEL, HAND-HELD, ELECTRONIC DNA ANALYSIS PLATFORM TO QUANTIFY MULTI-GENE MOLECULAR RESPONSE IN CSF OF PATIENTS WITH HIGH-GRADE GLIOMA

Abstract BACKGROUND For midline tumors, surgical biopsy risks neurological injury. Non-invasive methods for diagnosis and surveillance are greatly needed. Tumors release DNA into cerebrospinal fluid (CSF-ctDNA), allowing for potential detection and serial monitoring of tumor-associated genetic mutations by CSF sampling. Current detection platforms are limited by their requirement for assay development for each mutation (digital droplet PCR), or cost and timeliness (Illumina sequencing). We hypothesized that direct, electronic analysis of CSF-ctDNA with a novel, hand-held platform (Oxford Nanopore MinION) could provide real-time, ultra-deep sequencing of patient-specific alterations in CSF-ctDNA. METHODS We established multiple clinical trials for pediatric high-grade glioma with required multi-time point (0, 2, and 6 month) correlate lumbar puncture (LP) at time of MRI, with accrual ongoing. We performed amplicon-based PCR on CSF-ctDNA for recurrent mutations and sequenced patient samples (tumor tissue n=8, tumor CSF n=60) and normal controls (tissue n=5, CSF n=24) using NanoPore technology. Variant allele fractions (VAF) were determined via MinKNOW, Guppy, MiniMap2, and Integrated Genome Browser. RESULTS Sensitivity was 79% and specificity 100% by NanoPore. Time from LP to results was 12 hours. A 17-year-old female presented with a biopsy-proven grade IV thalamic glioma with clonal mutations in H3F3A K27M, PIK3CA E545G, TP53 R158G, and TP53 R248Q. After failing standard treatment, she was enrolled in the ONC201 clinical trial and underwent serial LPs. MRI showed stable tumor at 2 months and 40% decrease at 6 months of treatment. H3K27M VAF increased from baseline at 2 months, but decreased to 1% at 6 months of treatment, results that were confirmed by ddPCR. PIK3CA E545G, TP53 R158G, and TP53 R248Q demonstrated the same decrease in VAF, with p-value of &lt; 0.0001. CONCLUSIONS We demonstrate a rapid, reliable method to detect tumor mutations in CSF, and further show molecular remission of H3K27M glioma by CSF sampling.

Pulvinar Locus is Highly Relevant to Patients' Outcomes in Surgically Resected Thalamic Gliomas in Children

Thalamic gliomas in children are less suitable for surgical resection because of their location. In cases of unavoidable resection, careful surgical planning in addition to histology and extent of resection affects prognosis. A cohort of 10 pediatric patients with thalamic glioma underwent surgical resection at our department. The predominant location of tumor origins in the thalamus was defined in imaging studies. Histopathology was determined (retrospectively in a subset) according to the World Health Organization classification 2016, including the newly established type of "diffuse midline glioma, H3 K27M-mutant." Three low-grade gliomas (grade I/II) and 7 high-grade gliomas (grade III/IV) were identified. The mean follow-up period was 49.8 months. All 3 low-grade gliomas did not recur (progression-free survival, 58.3 months). Six of 7 high-grade gliomas recurred, and the patients died of the primary disease (overall survival, 28.1 months). Poor outcomes, especially when located at the pulvinar region, were noticeable, with strong predictive power for poor prognosis (P= 0.0018). The presence of H3 K27M mutation and pulvinar location were closely associated (P= 0.0036). Four of 5 patients with pulvinar region tumors developed dissemination and died of the primary disease. Pulvinar location is specifically associated with a high rate of malignancy in histology, the presence of H3 K27M mutation, and dissemination at an early disease stage. This association suggests that a distinct biological profile affects prognosis depending on location within the thalamus, especially the pulvinar. We report that tumor location is highly relevant to prognosis and should be taken into consideration when planning treatment.

Case Report of a High Grade Bilateral Thalamic Glioma in an 8Year Old Child Presenting in Psychiatry OPD

Case Report of a High Grade Bilateral Thalamic Glioma in an 8Year Old Child Presenting in Psychiatry OPD

High frequency of H3K27M immunopositivity in adult thalamic glioblastoma.

Adult thalamic glioblastomas (GBM) are uncommon tumors with limited available molecular data. One of the reported molecular alterations in these tumors is the H3K27M mutation. It has been documented that H3K27M mutation is found in a high proportion of pediatric thalamic gliomas. In this study, we have analyzed the molecular alterations exclusive to adult thalamic GBM. This is a 6 years retrospective study of adult thalamic GBM patients who underwent surgical decompression of the tumor. Clinical data were obtained from the case records. Immunohistochemistry (IHC) was performed on the tumors using antibodies directed against the gene products of R132H mutant isocitrate dehydrogenase 1 (IDH1), alpha-thalassemia/mental retardation X-linked (ATRX), p53, H3K27M, H3K27me3, and V600E mutant BRAF. Molecular analyses were carried out to detect other IDH1 and IDH2 mutations, O6 -methylguanine-DNA-methyltransferase gene (MGMT) promoter methylation, and epidermal growth factor gene (EGFR) and telomerase reverse transcriptase gene (TERT) promoter mutations. A total of 42 cases of adult thalamic GBM were studied. The mean age of presentation was 42 years with age range of 19-58 years. Male predominance was noted. All the tumors were IDH wild-type, BRAF (V600E)-immunonegative and unmethylated for MGMT promoter. H3K27M immunopositivity was noted in 60% of tumors. Of these 33.3% were from older adults above the age of 50 years. Of the H3K27M-immunopositive cases, ATRX loss of expression was seen in 32%, p53 immunopositivity in 24% and EGFR amplification in 12%. Higher frequency of TERT promoter mutations was noted in H3K27M-immunonegative cases (58.8%) compared to immunopositive cases (20%). Ours is one of the few studies elucidating the molecular alterations exclusive to adult thalamic GBM. We show a high frequency of H3K27M immunopositivity, suggestive of its mutational status in these tumors, including in older adults.