Epithelioid Glioblastoma Research Articles

P16.10.A UNRAVELING THE CLINICAL IMPLICATIONS OF TRIM24::NTRK2 FUSION GENE IN PEDIATRIC HIGH-GRADE GLIOMA: A CASE STUDY

Abstract BACKGROUND High-grade gliomas are among the deadliest of all childhood cancers and the leading cause of cancer-related mortality in children. The standard treatment is resection followed by chemotherapy, most often temozolomide and radiation therapy. Unfortunately, there is no evidence that temozolomide influences survival in pediatric patients and only a limited number of new drugs have been identified for specific subgroups of tumors. The identification of fusion genes as possible drivers of the disease offers an opportunity for targeted therapies. We present a case of a six-year-old patient with a novel TRIM24::NTRK2 fusion positive epithelioid glioblastoma with subsequent relapses. METHODS We investigated the ramification of this fusion and evolution of the tumor through whole genome sequencing, RNA-sequencing and DNA methylation profiling, and studied the effect of the patient’s treatment using patient-derived cell cultures. RESULTS Our studies show that the TRIM24::NTRK2 fusion has oncogenic abilities but loses its importance as the tumor evolves. In addition, we demonstrate an increased drug resistance over time, further indicating the diminished driver function of the fusion. CONCLUSION The use of resequencing revealed parallel development of tumor subclones with different genomic alterations, highlighting the importance of genomic profiling from various parts of the tumor. FUNDING This work was supported by the Swedish Research Council, the Swedish Childhood Cancer Foundation, and the Swedish Cancer Society

Clinicopathological, immunohistochemical and therapeutic approaches on survival in patients with epithelioid glioblastoma: Institutional experience in the management of 58 patients

Epithelioid glioblastoma (Ep-GBM) is a rare variant of glioblastoma characterized by a high recurrence rate and poor prognosis. Currently, there is no established standard treatment for Ep-GBM. Therefore, we identified 58 Ep-GBM cases to investigate these characteristics and identify the possible prognostic factors of survival. There were 30 male and 28 female patients with a median age of 39 years. Headaches and dizziness were the most common clinical symptom. The tumor is most frequently located in the temporal lobe (36.2%). The positivity rate for BRAF-V600E is 56.9% (33/58), for MGMT is 56.9% (33/58), and for INI-1 is 75% (30/40). Tumor recurrence was observed in 39 patients. The median progression-free survival (PFS) of all patients was 12.7 months, while the median overall survival (OS) was 29.1 months. Additionally, the median survival time after recurrence was 14.3 months. Both univariate and multivariate COX regression analyses revealed that individuals who received more than six cycles of adjuvant oral temozolomide experienced a longer median PFS compared to those who received fewer cycles. Characteristics associated with poorer PFS included tumor dissemination prior to initial surgery. Additionally, both analyses identified tumor dissemination, radiotherapy and adjuvant oral temozolomide as predictors of OS. Notably, for patients with recurrent Ep-GBM, reoperation was shown to significantly increase survival time after recurrence. In conclusion, the standard Stupp regimen is also applicable to patients with Ep-GBM, extending adjuvant oral temozolomide could further improve survival for Ep-GBM patients, reoperation may also prolong survival for recurrent Ep-GBM.

Clinical Outcome of Patients with Epithelioid Glioblastoma Harboring BRAFV600E Mutation; A Single Institution Experience

Purpose Epithelioid glioblastoma (GBM) is a rare variant of GBM. The study aimed to look into clinicopathological details and outcomes of patients with epithelioid GBM harboring BRAFV600E mutation from a single institution. Methods Ten cases of epithelioid GBM diagnosed over the past 5 years were reviewed. All patients underwent surgical resection followed by adjuvant treatment as per protocol after initial diagnosis. Of these, seven patients were planned to redo surgery, reradiation, BRAF with MEK inhibitors, and bevacizumab based on clinical condition, magnetic resonance imaging findings, and progression-free survival after their recurrence. Four recurrent patients had received dabrafenib and trametinib. Results All tumor locations were supratentorial. The median follow-up was 2.3 years and the median time to recurrence was 19 months from the diagnosis (range 4–36 months). Four recurrent patients received BRAF + MEK inhibitors. One patient who started dabrafenib and trametinib experienced local progression after 33 months, followed by lung and bone metastasis. One patient died due to multiple subacute hemorrhages, who was a known case of congenital vascular malformations, and two patients remained disease-free after a year and 2 years. Conclusion Epithelioid GBM is a very rare, but well-documented entity. Therefore, careful preoperative imaging and detailed evaluation of genetic studies including BRAF V600E mutation are necessary for accurate diagnosis and appropriate selection of treatment for epithelioid GBM. Dabrafenib plus trametinib showed clinically meaningful activity in patients with BRAF V600E mutation-positive recurrent high-grade glioma.

Efficacy of BRAF/MEK-inhibitor therapy for epithelioid glioblastoma with a novel BRAFV600 mutation

Epithelioid glioblastoma (eGB), a very aggressive and rare brain tumour, is associated with a dismal median overall survival. Effective therapies for patients with eGB, particularly with leptomeningeal dissemination, are still lacking. Here, we describe a case of a 25-year-old male diagnosed with an intramedullary cervical tumour with subsequent leptomeningeal disease. Histopathology identified a highly necrotising, epithelioid-type tumour with high cell density, most compatible with the diagnosis of an eGB. DNA analysis revealed an unprecedented B-Raf protooncogene, serine/threonine kinase (BRAF) gene variant in exon 15 (ENST00000288602.6, c.1799_1810delinsATG, p.(V600_W604delinsDG)), triggering activation of the mitogen-activated protein kinase (MAPK) pathway. Consequently, we initiated MAPK inhibitor (MAPKi) therapy, utilizing a combination of BRAF and mitogen-activated protein kinase kinase (MEK) inhibitors. Liquid chromatography–tandem mass spectrometry analysis confirmed the drugs’ presence in the patient’s cerebrospinal fluid, indicating their capacity to cross the blood-brain barrier. Remarkably, the patient responded very well to therapy and transitioned from a near-comatose state to significantly improved health, sustained for over three months. This study highlights that MAPKi, particularly targeted towards novel BRAFV600 mutations, might offer promising advancements in eGB treatment strategies.

Successful treatment of pediatric patients with high-grade gliomas featuring leptomeningeal metastases by targeting BRAF V600E mutations with dabrafenib plus trametinib: two illustrative cases.

A combination of BRAF and MEK inhibitors is reported to be effective for gliomas with the BRAF V600E mutation; however, its efficacy in gliomas with leptomeningeal metastases (LMM) is still unknown. In this report, we describe two pediatric patients with high-grade glioma featuring the BRAF V600E mutation who were treated with dabrafenib and trametinib for LMM. Both 2 cases underwent craniotomy for primary intracranial lesions and were diagnosed as a high-grade glioma with BRAF V600E mutation; one case was consistent with anaplastic pleomorphic xanthoastorocytoma, the other was epithelioid glioblastoma. They received standard treatment for the lesions but subsequently were found to have new lesions including multiple spinal dissemination. We started administering dabrafenib and trametinib. Within a few days of starting treatment, the symptoms improved dramatically and MRI performed one month after the prescription of the two drugs demonstrated remission of both brain and spinal lesions. This report shows that dabrafenib and trametinib are effective not only for recurrent lesions but also for LMM in pediatric patients.

Adult epithelioid glioblastoma exhibits an extremely poor prognosis and high frequency of SWI/SNF complex mutation: Insights from a retrospective study.

Epithelioid glioblastoma (eGBM) is a rare subtype of GBM. Given the update of the definition of GBM, the understanding of the molecular characteristics and prognosis of "true" adult eGBM remains limited. Herein, we retrospectively analyzed the clinicopathological data of 39 adult eGBM cases. Adult eGBM primarily affected females, with a male-to-female ratio of 1:2.3. The average age of diagnosis was 53 years, and the tumor affected the temporal lobe in 41% of cases (16/39, 41%). Microscopically, the tumors consisted mainly or entirely of epithelioid cells. Perivascular infiltration (10/39, 25.6%) and leptomeningeal dissemination (7/39, 17.9%) were not uncommon. BRAF V600E mutation was detected in 40.9% of cases (n = 9/22). Next-generation sequencing revealed that CDKN2A/B homogeneous deletion was the most frequently mutated gene (8/10, 80%), followed by TERT promoter mutation (7/10, 70%), Cyclin-dependent kinases 4 or 6 (CDK4/6) amplification (5/10, 50%) and BRAF V600E mutation (50%, 5/10). Notably, the incidence of ARID1B mutation in eGBM was 50% (5/10), representing the first report of such a mutation in this subtype of GBM. ARID1B was known to be a subunit of the SWI/SNF chromatin remodeler. Chromosome analysis showed a 7+/10- signature in 90% (9/10) cases. Adult eGBM carried a dismal prognosis compared to GBM with IDH and H3 wild-type (typical GBM) (OS: 13.89 vs 24.30 months; P = .003) and even typical GBM without MGMT promoter methylation (OS: 13.89 vs 22.08 months; P = .036). Based on these findings, it can be concluded that adult eGBM harbors a high frequency of the 7+/10- signature and alterations in the MAPK pathway, SWI/SNF complex and cyclin-related genes and portends an extremely poor prognosis.

A patient-derived xenograft mouse platform from epithelioid glioblastoma provides possible druggable screening and translational study

A patient-derived xenograft mouse platform from epithelioid glioblastoma provides possible druggable screening and translational study

Analysis of Histomorphologic/Molecular Association and Immune Checkpoint Regulators in Epithelioid Glioblastoma and Pleomorphic Xanthoastrocytoma: Are These Tumors Potential Candidates for Immune Checkpoint Blockade?

Accurate diagnosis of Epithelioid glioblastoma (eGB) and pleomorphic xanthoastrocytoma (PXA) is sometimes challenging owing to overlapping histologic and genetic features. There are limited reports on the immune profile of these tumors. In this study, we assessed 21 PXA [15 PXA Grade 2 (PXAG2); 6 PXA Grade 3 (PXAG3)] and 14 eGB for their histopathological and molecular association. Further, their immune profile was compared with GB, IDH1 wild-type (wt) (n-18). Morphologically, PXAG2 mostly differed from eGB; however, it was occasionally difficult to differentiate PXAG3 from eGB due to their epithelioid pattern and less obvious degenerative features. PXAG2 showed predominantly diffuse, whereas variable positivity for epithelial and glial markers was seen in PXAG3 and eGB. All cases showed retained nuclear ATRX and INI-1 . H3K27M or IDH1 mutation was seen in none. P53 mutation was more common in eGB, followed by PXAG3, and least common in PXAG2. BRAF V600E mutation was observed in 66.67% PXAG2, 33.33% PXAG3, and 50% eGB, with 100% concordance between immunohistochemistry (IHC) and sequencing. Thirty-six percent eGB, 33% PXAG3, and 61% PXAG2 harbored CDKN2A homozygous deletion. EGFR amplification was observed in 14% eGB and 66% of GB, IDH wt. PDL1 and CTLA-4 expression was higher in eGB (71.4% and 57.1%), PXAG3 (66.6% and100%), and PXAG2 (60% & 66.7%) as compared with GB, IDH wt (38.8% and 16.7%). Tumor-infiltrating lymphocytes were also observed in a majority of eGB and PXA (90% to 100%) in contrast to GB, IDH wt (66%). This analysis highlights the homogenous molecular and immune profile of eGB and PXA, suggesting the possibility that histologically and molecularly, these two entities represent 2 ends of a continuous spectrum with PXAG3 lying in between. Higher upregulation of PDL1, CTLA-4, and increased tumor infiltrating lymphocytes in these tumors as compared with GB, IDH wt suggests potential candidature for immunotherapy.

BIOM-04. IMPROVEMENT OF LEPTOMENINGEAL DISEASE (LMD) WITH MEK AND BRAF INHIBITORS, CRANIOSPINAL IRRADIATION (CSI), AND INTRATHECAL (IT) CHEMOTHERAPY IN ANAPLASTIC PLEOMORPHIC XANTHOASTROCYTOMA (PXA)

Abstract Anaplastic pleomorphic xanthoastrocytomas (aPXA) are rare gliomas with a five-year survival of 57%. Standard treatment involves maximal safe resection followed by radiotherapy. BRAF mutation is frequently seen in these patients and is a promising target with concurrent BRAF and MEK inhibitors. However, there is no standard treatment for patients with aPXA and leptomeningeal disease (LMD). Literature review identified four cases with overall survivals (OS) of 3, 4, 18, and 66 months, respectively. We report a 23-year-old female who presented with headache, nausea, vomiting, and aphasia with MRI evidence of a left temporal lobe enhancing mass. Her tumor was initially diagnosed as epithelioid glioblastoma, WHO grade IV after craniotomy. She received concurrent radiation and temozolomide with subsequent 12 cycles of TMZ. After identification of BRAF V600E mutation by next generation sequencing, we revisited her diagnosis, and it was changed to aPXA. Three years later, she presented to the ER with aphasia, headache, weakness, nausea, and vomiting with MRI evidence of hydrocephalus and LMD by brain and spine MRI as well as cerebrospinal fluid analysis. Her treatment regimen consisted of the MEK inhibitor cobimetinib, the BRAF inhibitor vemurafenib, partial craniospinal irradiation (CSI), and intrathecal (IT) chemotherapy with methotrexate, topotecan, cytarabine, and thiotepa sequentially. She is currently doing well with mild bilateral leg weakness. She continues on therapy with BRAF and MEK inhibitors. Her OS is 56 months. Adverse events (AE) were tabulated according to the Common Terminology Criteria for Adverse Events Version 5.0 and included grade IV neutropenia, grade III anemia, grade II rash acneiform, and grade II nausea/vomiting. All AEs were manageable and reversible. Despite the limitations of a case report and retrospective review, our findings suggest that MEK and BRAF inhibitors, CSI, and IT chemotherapy may be effective treatment options for patients with aPXA and LMD.

CTNI-76. EFFICACY OF BRAF INHIBITOR PLIXORAFENIB (FORE8394) IN RECURRENT, PRIMARY CENTRAL NERVOUS SYSTEM TUMORS (PCNST)

Abstract Plixorafenib, a selective potent BRAFi, is uniquely designed to disrupt BRAF dimers and evade paradoxical MAPK pathway activation. Thus, it inhibits both V600 and non-V600 BRAF alterations and may be less prone to toxicities and resistance typical of approved BRAFi. An approved BRAFi, when used with MEKi, has ORR 33% with mDOR 13.6=months and ORR=50% with DOR of 6-29 months in V600+ HGG and LGG, respectively (dabrafenib US Prescribing Information, 2023). Phase 1/2a is a single-arm study (NCT02428712) in patients (n=113) with BRAF-altered advanced tumors to assess safety, PK, and efficacy of oral plixorafenib 900-3600 mg/day alone or with cobicistat (CYP3A4/P-gp inhibitor). Symptomatic TEAEs (rash, pyrexia, myalgia) were low grade and infrequent relative to approved BRAFi. This pre-specified analysis (31Mar2023) was in MAPKi-naïve adults with BRAFV600+ PCNST. 22 patients with PCNST received plixorafenib: 9 LGG, 1 glioneuronal tumor (LGG/GNT; 5 V600+), 12 HGG (10 V600+). Treatment-emergent AEs (TEAEs, ≥ 20%) were limited to LFT changes, G1 increased creatinine, fatigue, headache, and nausea. Only one G3 event (increased ALT) occurred at the RP2D (n=7) showing better tolerability than dabrafenib. 10 BRAFV600+ MAPKi-naïve adults with PCNST (median age 45 yrs, 6 females, 9 non-Hispanic) were efficacy evaluable: 6 HGG (4 glioblastoma, 1 epithelioid glioblastoma, 1 anaplastic astrocytoma); 4 LGG/GNT (1 each: ganglioglioma, pilocytic astrocytoma, xanthoastrocytoma, neuroepithelial tumor). Prior anti-cancer treatments included surgery (8/10), radiotherapy (8/10), and systemic therapy (8/10, including temozolomide [n=8], bevacizumab [n=2], carboplatin [n=1], dendritic cell vaccine [n=1]). 1 was treatment-naïve (unresectable; declined radiation/chemotherapy). ORR=60% (6/10) including HGG=67% (4/6), LGG/GNT=50% (2/4); median time to response=1.94 months; 4/6 responders with DOR > 9 months; mPFS=34.1 months; median follow-up=10.3 months; 4/10 ongoing. Plixorafenib has a benign safety profile and leads to a high ORR and durable response in MAPKi-naïve BRAFV600+ PCNST. A phase 2 study is ongoing to confirm these findings (NCT05503797).

An unusual distant metastases of epithelioid glioblastoma detected by 18-F FDG PET/CT

Epithelioid glioblastoma is a rare, aggressive subtype of glioblastoma, which was officially recognized by the World Health Organization classification of the central nervous system in 2016. Here, we represent the case of a 19-year-old female with epithelioid glioblastoma whose extracranial metastasis was detected on 18F 2-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (18-F FDG PET/CT).

The Significance of BRAF Mutation in the Epithelioid Glioblastoma Subtype: A Systematic Literature Review and a Case Report with a Unique Intraventricular Topography.

Epithelioid glioblastoma (E-GBM) is an exceedingly rare subtype of isocitrate dehydrogenase (IDH)-wildtype glioblastoma, first included in the WHO 2016 classification and characterized by a dominant population of epithelioid cells. Its histological and molecular defining features remain troublesome. The significance of BRAF mutations to pathological diagnosis and surgical outcome has drawn increasing attention given their promising potential for future adjuvant therapies. Herein, we describe a unique case of an E-GBM in the atrium of the left lateral ventricle and comprehensively analyze the importance of BRAF status in a cohort of 211 E-GBMs from the literature. Our patient was a 40-year-old man with occipital pain. His brain MRI revealed a large intraventricular tumor at the same location as a signal change found 10 years earlier with no additional follow-up. He underwent gross total tumor removal followed by conventional adjuvant treatment. Histopathological diagnosis was consistent with IDH-wildtype E-GBM WHO grade 4 with pleomorphic xanthoastrocytoma-like areas. BRAF p.V600 mutation was demonstrated in the tumoral genetic study. In the cohort analyzed, male patients predominated (63%), the median age was 32 years old, and the 5-year survival rate following diagnosis was 4.2%. BRAF mutations were found in 60.3% of the tumors overall, with this rate increasing to 78.3% in young adults (19-49 years, P < .001). Presence of BRAF mutations associated with tumor progression (P = .001), the event usually leading to death (P < .001). In conclusion, our study supports the importance of genetic BRAF p.V600 mutation analysis because its presence not only points to an E-GBM diagnosis but may also promote tumor progression.

P07.03.A COMPLETE LONG-LASTING RESPONSE TO MULTIMODAL THIRD LINE TREATMENT WITH NEUROSURGICAL RESECTION, CARMUSTINE WAFER IMPLANTATION AND DABRAFENIB PLUS TRAMETINIB IN A BRAFV600E MUTATED HIGH-GRADE GLIOMA

Abstract BACKGROUND BRAF mutations are drivers of oncogenesis in a variety of tumors and they can be successfully targeted with small molecule inhibitors. In primary central nervous system tumors, BRAFV600E mutations are most frequently found in pleomorphic xanthoastrocytoma, ganglioglioma, pilocytic astrocytoma and epithelioid glioblastoma. Dabrafenib is a potent and selective inhibitor of BRAF-mutant kinase that was approved, as monotherapy or in combination with trametinib (mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor), for unresectable or metastatic BRAF-mutated melanoma, advanced non-small cell lung cancer and anaplastic thyroid cancer harboring BRAFV600E mutation. MATERIAL AND METHODS In February 2016, a 21-year-old female was admitted to our Unit for seizures. A brain magnetic resonance imaging (MRI) revealed a frontal contrast enhanced lesion. Neurosurgical resection was performed. The histological analysis diagnosed anaplastic pleomorphic xanthoastrocytoma (PXA) WHO grade III. A volumetric modulated radiotherapy course was delivered for a total dose of 59,4 Gy in 33 fractions with concomitant and adjuvant temozolomide therapy (Stupp protocol). In October 2017, a brain MRI showed relapsing disease. Six courses of chemotherapy with procarbazine, lomustine and vincristine (PCV) were administered, and then neurosurgical partial removal and carmustine wafer implantation were performed. The histological analysis confirmed BRAF V600E mutated anaplastic PXA. RESULTS In April 2019 the 24-year-old female patient with BRAF mutated anaplastic PXA started her third-line therapy with dabrafenib. The well-known tumor residue was less evident on the subsequent MRIs performed every three/four months. Given the literature data of the most effectiveness and the best control of the side effects, in August 2020 the patient was put on combined treatment with dabrafenib plus trametinib. Since December 2021 the residual tumor has not been longer visible. Last MRI evaluation, performed on January 26th 2023, showed no recurrence of the disease, four years after BRAF inhibitor treatment beginning. CONCLUSION Dabrafenib plus trametinib is a promising new therapy for patients affected by BRAFV600E-mutant glioma, with high overall response and manageable toxicity. Due to very poor prognosis, there are a few described cases of high-grade glioma (HGG) patients in third-line therapy, showing complete response and for such a long time. The emergence of optimized sequencing strategies and targeted agents, including multimodal treatment and systemic therapy with dabrafenib plus trametinib, will continue to broaden personalized therapy in HGG and to improve patient outcomes.

Epithelioid Glioblastoma in A 15-Year-Old Boy: A Rare Case Report

Epithelioid glioblastoma (E-GBM), one of the rarest intrusive forms of Glioblastoma multiforme (GBM), was consigned in the World Health Organization (WHO) categorization of the Central nervous system (CNS) in the year 2016. The current article reports a rare epithelioid glioblastoma described for its histomorphological character and clinical finding for its medical rarity. The present case deals with a 15-year-old boy complaining of headaches and multiple episodes of vomiting. The investigatory procedures revealed hypo-intense multiple lesions in the left medial frontal lobe extending to a Sylvian fissure. The case is being discussed to distinguish the development of secondary glioblastomas, which usually occur due to pre-existing lesions, which were not present in our discussed case. The patient had come from a rural background with no previous investigations, ophthalmological examination revealed the presence of bilateral papilledema, and the hematological reports were within normal range. The patient was managed with magnetic resonance imaging (MRI) and computed tomography (CT), which depicted a multifocal tumor. Further left fronto temporal craniotomy and ablation of the lesion were done. The surgical procedure upshot divulged that the patient was conscious with improved right side weakness but a remnant motor aphasia, but within a short span, he could walk with support. The incidence of E-GBM that too in adolescent children is minuscule, and due to its poor prognosis, it's very crucial to acknowledge the attributable features of epithelioid glioblastoma, inclusive of functional outset, neuro-imaging, and the hazards of surgical measures.

Acquired PTEN Loss May Mediate Dabrafenib and Trametinib Resistance in BRAF V600E-Mutated Epithelioid Glioblastoma: A Case Report and Literature Review

Epithelioid glioblastoma is a rare and aggressive variant of glioblastoma that is common in children and young adults. This variant frequently has a BRAF V600E mutation, and in recent years, this is often treated with BRAF and mitogen-activated protein kinase kinase inhibitors. An 18-year-old female initially presented with headaches and vomiting. They were diagnosed with an epithelioid glioblastoma and treated with temozolomide chemoradiotherapy. Upon progression, they had to redo surgery and then received dabrafenib and trametinib. They had one last surgery shortly before fatal tumour progression. Retrospective molecular analysis of three tumour specimens showed a PTEN mutation that arose upon first progression, but was not there initially. There were no new tumour mutations after initiation of dabrafenib and trametinib. The acquired PTEN mutation may have conferred resistance to dabrafenib and trametinib. This case highlights the potential importance of early treatment with BRAF and mitogen-activated protein kinase kinase inhibitors in high-grade BRAF V600E-mutated gliomas, ideally before the tumour develops resistance to targeted therapy.

ACQUIRED PTEN LOSS MAY MEDIATE DABRAFENIB AND TRAMETINIB RESISTANCE IN BRAF V600E–MUTATED EPITHELIOID GLIOBLASTOMA: A CASE REPORT

Abstract Epithelioid glioblastoma is a rare variant of glioblastoma that primarily affects children and young adults. This commonly has a BRAF V600E mutation and can be treated with BRAF and MEK inhibitors. CASE DESCRIPTION: An 18-year-old woman was diagnosed with an epithelioid glioblastoma. She received temozolomide chemoradiotherapy. Upon progression she had redo surgery and received dabrafenib and trametinib. The patient developed a drop metastasis to the cervical spine, and consequently received focal radiotherapy, 20 Gy in five fractions. Treatments were halted six months after her second resection due to further disease progression. She developed uncal herniation, requiring her to have a third resection approximately six months after her second resection. She passed away after this, 12 months following her initial diagnosis. Retrospective genetic analysis of three tumor specimens showed a novel PTEN mutation that arose after her first surgery. We suspect that the acquired PTEN mutation conferred resistance to dabrafenib and trametinib. DISCUSSION: This case offers teaching points and research questions. Firstly, early treatment with BRAF and MEK inhibitors in high grade BRAF V600E–mutated gliomas may be optimal as the patient may have stabilized with earlier treatment on dabrafenib and trametinib. Secondly, further studies are required to investigate whether the addition of PTEN mutation to BRAF V600E leads to aggressive tumor behavior. Lastly, there is a need for investigation into potential benefits of treating similar patients by co-targeting the BRAF and PI3K/AKT pathways.

TTFields Prolonged the PFS of Epithelioid Glioblastoma Patient: A Case Report

Epithelioid glioblastoma (EGBM, classified as glioblastoma, IDH wild type, grade 4 according to the fifth edition of the World Health Organization (WHO) Classification of Tumors of the Central Nervous System (CNS) (WHO CNS5)) is a highly aggressive malignancy, with a median progression-free survival (mPFS) of about 6 months in adults. The application of tumor-treating fields (TTFields, possessing anti-cancer capabilities via anti-mitotic effects) in the maintenance of temozolomide (TMZ) chemotherapy showed a benefit for prolonging the mPFS of newly diagnosed glioblastoma (GBM) for patients for up to 6.9 months in the EF-14 clinical trial (NCT00916409). However, studies focusing on the effect of TTFields in EGBM treatment are very limited due to the rarity of EGBM. Here, we have reported a case of a 28-year-old male (recurrent left-sided limb twitching for 1 month and dizziness for 1 week) diagnosed with EGBM. A right frontal lobe occupancy was detected by magnetic resonance imaging (MRI), and a total tumor resection was performed. Meanwhile, a postoperative histopathology test, including immunohistochemistry and molecular characterization, was conducted, and the results revealed a BRAF V600E mutation, no co-deletion of 1p and 19q, and negative O-6-methylguanine DNA methyltransferase (MGMT) promoter methylation. Then, chemoradiotherapy was conducted, and TTFields and TMZ were performed sequentially. Notably, a long-term PFS of 34 months and a Karnofsky Performance Scale (KPS) of 90 were achieved by the patient on TTFields combined with TMZ, whose average daily usage of TTFields was higher than 90%.

Abstract 3224: TTFields-prolonged the PFS of epithelioid glioblastoma patient: a case report

Abstract Epithelioid glioblastoma (EGBM, classified as glioblastoma, wild type, grade IV according to 2021 WHO CNS5 classification of neurological malignancies) is a highly aggressive malignancy, the median progression-free survival (mPFS) of which is about 4.0 months. Although, the introduction of tumor treating fields (TTFields, possessing anti-cancer capability via anti-mitotic effects) in the maintenance of TMZ chemotherapy was demonstrated beneficial for prolonging the mPFS of GBM patients to 6.9 months in the EF-14 clinical trial, studies centering on the significance of TTFields in EGBM treating are very limited due to the rarity of EGBM. Therefore, a 28-year-old patient (male, recurrent left-sided limb twitching for 1 month and dizziness for 1 week) was chosen as a clinical trial participant. A right frontal lobe occupancy was detected based on magnetic resonance imaging (MRI), and total tumor resection was performed on the patient. Meanwhile, postoperative histopathology test, including immunohistochemical and molecular characterization, was conducted and the results revealed a BRAF V600E mutation, no codeletion of 1p and 19q, and negative MGMT promoter methylation, which confirmed EGBM. In this context, chemoradiotherapy was conducted on the patient at first, and then concurrent TTFields and TMZ was performed. Notably, a long-term PFS of 33 months and KPS score of 90 were achieved over the patient upon TTFields combined TMZ, whose average daily usage of TTFields was higher than 90%. This clinical case corroborated the importance of TTFields in EGBM treating, and the higher compliance of TTFields is more beneficial for EGBM patient without additional side effect. YD, QW contributed equally to this work. Citation Format: Yuxuan Ding, Qiang Wang, Feijiang Wang, Nan Wu, Jianrui Li, Xia He, Hao Pan, Lijun Wang. TTFields-prolonged the PFS of epithelioid glioblastoma patient: a case report [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3224.

EPITHELIOID GLIOBLASTOMA OF BRAIN: A RARE CASE REPORT WITH REVIEW OF LITERATURE

A 52 year old female presented with complains of headache, dizziness and vomiting. Her MRI revealed a heterogenously enhancing tumor in right temporal lobe. She underwent gross total resection followed by chemoradiotherapy, but later succumbed to her illness. Histopathology showed highly pleomorphic tumor cells with eosinophillic cytoplasm and pleomorphic vesicular nuclei. A diagnosis of Epithelioid Glioblastoma was made. Epithelioid Glioblastoma is a rare pseudoepithelial form of glioblastoma. It usually presents in younger age group, is more malignant, difcult to differentiate from usual GBMs on radiology and needs aggressive management. No streamlined protocols exist for their diagnosis and treatment. The following communication discusses its epidemiology, pathology, diagnosis and management.

Dimorphic glioblastoma with glial and epithelioid phenotypes: Clonal evolution and immune selection.

Epithelioid glioblastoma is an unusual histologic variant of malignant glioma. The present study investigates both the genomic and transcriptomic determinants that may promote the development of this tumor. Whole-exome sequencing (WES) and whole-transcriptome sequencing (WTS) were performed on an epithelioid glioblastoma, along with a specific bioinformatic pipeline to generate electronic karyotyping and investigate the tumor immune microenvironment. Microdissected sections containing typical glioblastoma features and epithelioid morphology were analyzed separately using the same methodologies. An epithelioid glioblastoma, with immunopositivity for GFAP, Olig-2, and ATRX but negative for IDH-1 and p53, was identified. The tumor cell content from microdissection was estimated to be 85-90% for both histologic tumor components. WES revealed that both glioma and epithelioid sections contained identical point mutations in PTEN, RB1, TERT promoter, and TP53. Electronic karyotype analysis also revealed similar chromosomal copy number alterations, but the epithelioid component showed additional abnormalities that were not found in the glioblastoma component. The tumor immune microenvironments were strikingly different and WTS revealed high levels of transcripts from myeloid cells as well as M1 and M2 macrophages in the glioma section, while transcripts from CD4+ lymphocytes and NK cells predominated in the epithelioid section. Epithelioid glioblastoma may be genomically more unstable and oncogenically more advanced, harboring an increased number of mutations and karyotype abnormalities, compared to typical glioblastomas. The tumor immune microenvironment is also different.