Seizure characteristics and outcomes in patients with pleomorphic xanthoastrocytoma

Daniel J Zhou; Colin A Ellis; Kevin Xie; Nishant Sinha; Sharon X Xie; Kathryn A Davis; Joel M Stein; Tara Jennings; Stephen J Bagley; Arati Desai; Patrick Y Wen; David A Reardon; Steven Tobochnik

doi:10.1093/noajnl/vdaf134

. 2025 Jun 20;7(1):vdaf134. doi: 10.1093/noajnl/vdaf134

Seizure characteristics and outcomes in patients with pleomorphic xanthoastrocytoma

Daniel J Zhou ^1,^2,^✉, Colin A Ellis ^3,⁴, Kevin Xie ^5,⁶, Nishant Sinha ^7,⁸, Sharon X Xie ⁹, Kathryn A Davis ^10,¹¹, Joel M Stein ^12,¹³, Tara Jennings ¹⁴, Stephen J Bagley ¹⁵, Arati Desai ^16,¹⁷, Patrick Y Wen ¹⁸, David A Reardon ¹⁹, Steven Tobochnik ²⁰

¹ Center for Neuroengineering and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, USA

² Penn Epilepsy Center, Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA

³ Center for Neuroengineering and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, USA

⁴ Penn Epilepsy Center, Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA

⁵ Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA

⁶ Center for Neuroengineering and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, USA

⁷ Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA

⁸ Center for Neuroengineering and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, USA

⁹ Department of Biostatistics, Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, Pennsylvania, USA

¹⁰ Center for Neuroengineering and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, USA

¹¹ Penn Epilepsy Center, Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA

¹² Division of Neuroradiology, Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA

¹³ Center for Neuroengineering and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, USA

¹⁴ Penn Epilepsy Center, Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA

¹⁵ Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

¹⁶ Center for Neuro-Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA

¹⁷ Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

¹⁸ Center for Neuro-Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA

¹⁹ Center for Neuro-Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA

²⁰ Center for Neuro-Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA

^✉

Corresponding Author: Daniel Zhou, MD, MS, University of Pennsylvania, 301 Hayden Hall, 3320 Smith Walk, Philadelphia, PA 19104, USA (daniel.zhou@pennmedicine.upenn.edu).

PMCID: PMC12290447 PMID: 40718646

Abstract

Background

Pleomorphic xanthoastrocytomas (PXAs) are rare brain tumors that are often associated with seizures. There are limited data characterizing epilepsy phenotypes in relation to PXA tumor biology and survival outcomes.

Methods

This is a retrospective observational study of 35 patients with PXA who received treatment at the University of Pennsylvania or Dana-Farber Cancer Institute. Demographic and clinical features were assessed in PXA patients with or without seizures and with respect to seizure freedom following tumor resection.

Results

During their clinical course, 27 (77%) developed tumor-related epilepsy (TRE), with 25 (71%) initially presenting with a seizure. Compared to those without TRE, patients with TRE were more likely to have a BRAF-mutated PXA and less likely to have frontal lobe tumor localization. Patients with TRE who became seizure-free after the initial resection up to the time of progressive disease were found to have a lower age of seizure onset, smaller tumor diameter, and more likely to have BRAF-mutated tumors compared to those who were not seizure-free. However, following the last tumor resection and accounting for tumor recurrences, there were no significant differences in clinical features between those who were seizure-free and those who were not. Overall survival was 88% after 5 years and 59% after 10 years, with similar survival rates between patients with and without TRE.

Conclusion

These findings indicate that BRAF-mutated and BRAF-wildtype PXAs have distinct epilepsy phenotypes. Further investigation of the interplay between tumor biology and seizures may help guide counseling and targeted therapeutic strategies for PXA-related epilepsy.

Keywords: brain tumor, outcomes, pleomorphic xanthoastrocytoma, seizure, tumor-related epilepsy

Key Points.

BRAF-mutated PXAs are more strongly associated with tumor-related epilepsy than BRAF-wildtype PXAs.
BRAF mutation, earlier age of seizure onset, and smaller tumor size are associated with seizure freedom after initial resection prior to progressive disease.

Importance of the Study.

The management of tumor-related epilepsy (TRE) with pleomorphic xanthoastrocytomas (PXAs) remains an important aspect of patient care, yet predictive factors for seizure development and postoperative seizure freedom remain poorly understood, in part due to the rarity of the tumor. In this retrospective observational study based on two major academic hospitals, we evaluated the seizure-related characteristics and outcomes in a combined cohort of patients with PXA. Our findings underscore the need for further investigation into the interplay between tumor biology, surgical resection, and seizure outcomes for this rare tumor. Future studies, including prospective trials, should incorporate seizure-related outcomes, which could help guide counseling and management of PXA-related epilepsy.

Pleomorphic xanthoastrocytomas (PXAs) are rare, central nervous system tumors that can affect all age groups, with a reported mean age of onset in the late twenties.^1,2 Nearly all PXAs are supratentorial, and approximately half occur in the temporal lobe.^1,3 PXAs are classified as either grade 2 or 3 based on tissue pathology.⁴ The prognosis for PXA is considered to be favorable, with a 5-year overall survival of > 75% and progression-free survival of > 60%, although outcome can vary based on tumor grade, molecular profile, age, tumor size, and extent of resection.^2,5,6 Genetic alterations reported in PXAs include BRAF V600E mutation (38-80% cases), CDKN2A/B homozygous deletion (60-87%), and TERT promoter mutation (2-19%), while IDH1 or IDH2 mutations are not observed.^2,3,7–9BRAF mutations were found to be associated with increased overall survival, although results have been mixed.^10–13 In prior studies, CDKN2A/B deletion was not associated with survival, and TERT promoter mutations were associated with higher tumor grade and worse prognosis.^7,12–14

Seizures are commonly reported as the initial presenting symptom (30–71%).^1,3,5 One recent retrospective clinical study of PXA patients found that patients with BRAF mutation were younger and more often had a history of seizures compared to those without.¹³ Few studies investigating clinical outcomes of PXA patients reported seizure-related outcomes after resection. One study reported 5/28 patients continuing antiseizure medication (ASM) after resection.⁵ In a retrospective study of pediatric PXAs, 9/10 patients were seizure-free (follow-up > 8 months) following tumor resection.¹⁵ In a study of high-grade PXAs, 8 patients had preoperative seizures and were all seizure-free following gross total resection (follow-up 0.9-78.1 months).¹⁶ Two studies that evaluated epilepsy-related outcomes of long-term epilepsy-associated tumors (LEATs) reported 5/9 PXA patients with Engel 1A outcome,¹⁷ and 9/10 with Engel 1 outcome, although multivariate analyses were based on all brain tumor types, not specifically PXA.¹⁸ Seizure descriptions and epilepsy-related outcomes with PXA have otherwise mostly been limited to case reports and small case series, with mixed results mostly reporting seizure-freedom following resection.^19–24

PXAs have often been grouped together with glioneuronal tumors (eg, gangliogliomas, dysembryoplastic neuroepithelial tumors) in previous cohort studies. However, given a more recent understanding of genetically diverse signatures within and between these tumors, coupled with influences of hyperexcitability on tumor growth, a focused evaluation of seizure phenotyping of PXAs may improve understanding of tumor biology, prognostic predictions, and targeted management strategies.^25,26 In this retrospective observational study from two major academic cancer centers, we aimed to: (1) evaluate the clinical factors that may be associated with the presence of tumor-related epilepsy (TRE) in patients with PXA; (2) characterize TRE features, such as seizure type and ASM use, before and after surgical intervention; and (3) investigate the relationship between TRE and overall survival.

Materials and Methods

Patient Selection

This study was approved by the institutional review boards of the University of Pennsylvania (UPenn) and the Dana-Farber Cancer Institute (DFCI). Patients for the study were retrospectively identified by searching the electronic health records databases at UPenn from 2016-2024 and DFCI from 2013–2025, based on institutional data availability. Patients were included in the study if they had a diagnosis of PXA that was histologically confirmed from tissue pathology based on the World Health Organization (WHO) 2016 or 2021 criteria.

Variables

Demographic and clinical information were manually extracted by board-certified epileptologists (D.Z. and S.T.) at their respective medical centers. Demographic information included sex at birth and age during initial presentation and treatments. Tumor characteristics included size, laterality, location, grade, and genetic mutations. Tumor size was defined as the longest enhancing diameter with 2D measurements based on the Response Assessment in Neuro-Oncology (RANO) 2.0 criteria.^27,28 Tumor genetic features included the presence or absence of the BRAF V600E mutation, CDKN2A or CDKN2B mutation, TERT promoter mutation, copy number variations (CNV), and tumor mutational burden (TMB). Targeted exome sequencing, CNV, and TMB were performed using the OncoPanel at DFCI^29,30 and the in-house gene sequencing assay (PennSeq Solid Tumor Panel) at UPenn. Only broad CNV events defined as whole chromosome gain or loss were considered for this analysis. Treatments included surgical resection, chemotherapy, and radiation therapy. Surgical resection was classified as gross total when the entire enhancing tumor was surgically removed. Near gross total, subtotal, and partial resections were deemed not gross total.

Seizure characteristics recorded included the presence or absence of TRE, preoperative convulsive seizures, status epilepticus, and drug-resistant epilepsy. According to the International League Against Epilepsy (ILAE), drug-resistant epilepsy is defined as the failure of adequate trials of two tolerated and appropriately chosen and used ASMs to achieve sustained seizure freedom.³¹ Seizure-related outcomes were defined at both the latest time after the first resection and before the first tumor recurrence and at the most recent follow-up following the last tumor resection. In this study, a subject was considered to be seizure-free if they had both an Engel outcome of 1 or ILAE outcome of 1 or 2 at each timepoint.³² Overall survival was defined as from the date of first tumor resection to the date of death or latest follow-up.

Statistical Analyses

Statistical analyses were performed using SciPy and Lifelines in Python and reviewed with a biostatistician (S.X.) and data scientist (N.S.). Baseline demographic and clinical characteristics were summarized using median (range) or mean (standard deviation, SD) for continuous variables, and counts (percentages) for categorical variables. For group comparisons, categorical variables were analyzed using the chi-squared test when all expected group counts were ≥ 5; otherwise, Fisher’s exact test was used. Continuous variables were first assessed for normality using the Shapiro-Wilk test. Normally distributed variables were compared using a two-tailed t-test, while non-normally distributed variables were analyzed using the Mann–Whitney U test.

Survival analysis was conducted using the Kaplan–Meier method to estimate overall survival in patients with PXA. Patients were stratified into two groups: those with TRE and those without TRE. Survival probabilities were estimated using the Kaplan–Meier estimator and differences between groups were assessed using the log-rank test. To account for potential confounders, a Cox proportional hazards model was fitted to account for covariates and obtain an adjusted hazard ratio for survival differences between the two groups. The adjusted P-value for the group variable was extracted to assess statistical significance.

Results

Population Characteristics

From a database of 6805 patients with brain tumor ICD-10 codes excluding metastases, meningioma, or lymphoma at UPenn and 2202 unique patients with pathology-confirmed and sequenced glial brain tumors extracted from the Oncology Data Retrieval System (OncDRS) at DFCI, 20 (0.3%) and 15 (0.7%) patients with PXAs from each respective institution were included in this study. The combined cohort was 46% female and initially presented at a median age 21 years (range 1–50), including 24 (69%) adult cases and 11 (31%) pediatric cases. Both UPenn and DFCI had similar age and sex distributions, although UPenn’s cancer center is primarily dedicated to adults, several of whom had PXA resected during childhood before presenting to the UPenn Neuro-Oncology clinic. Initial presentations included seizure (25 cases, 71%), headache (8 cases, 23%), focal neurologic deficit (1 case, 3%), and behavioral change (1 case, 3%). Following the first resection, two additional patients (6%) developed new onset seizures. Thus, a total of 27 patients who had a seizure either at the presentation of the brain tumor or later during the clinical course were determined to have TRE. Notably, one other patient had a history of childhood epilepsy that resolved and did not develop recurrent seizures attributed to the brain tumor.

In all cases, the tumor had a supratentorial location in the brain, including the left hemisphere in 20 (57%) cases and the right hemisphere in 15 (43%). The tumor involved the temporal lobe in 18 (51%) cases. Histology demonstrated the tumor to be grade 2 in 19 (56%) cases and grade 3 in 15 (44%) cases (1 with missing information) following initial resection. All PXAs in this cohort were IDH-wildtype. All patients received at least one surgical resection, 25 (71%) of which were gross total resections and 1 (3%) which was an anterior temporal lobectomy with lesionectomy. In 21 (60%) cases, the tumor recurred at least once, at a median (range) time of 2 years (1 month—23 years), with 16 (76%) identified asymptomatically through surveillance imaging, 2 (10%) presenting as breakthrough seizure, 2 (10%) with headache, and 1 (5%) with a focal neurologic deficit. Of the cases of tumor recurrence, 10 (50%) were originally grade 3, and 4 (20%) additional cases transitioned from grade 2 to grade 3.

Factors Related to Presence of Tumor-Related Epilepsy

Table 1 describes the demographic and clinical characteristics compared between those who had an initial presentation of seizure and those who did not. In our cohort, patients with PXA without TRE were more likely to have frontal lobe involvement compared to those with TRE. Otherwise, both groups had similar distributions of tumor grades, laterality, lobar involvement, and size. Patients with a BRAF V600E mutation were more likely to present with a seizure compared to those without (P = .02). There was no significant difference in the proportions of patients with CDKN2A/CDKN2B deletion, TERT promoter mutations, or average TMB, although the sample sizes with these data were small.

Table 1.

Characteristics of PXA patients with and without an initial seizure or tumor-related epilepsy.

Characteristics	Initial seizure			Tumor-related epilepsy
Characteristics	Present	Absent	P-value	Present	Absent	P-value
Total patients, n	25	10		27	8
Age of initial presentation (years), median (range)	21 (1–44)	27.5 (17–50)	.07^a	21 (1–50)	23.5 (17–37)	.56^a
Sex at birth, female/male	11/14	5/5	1.0^b	13/14	3/5	.38^c
Tumor grade, grade 2/grade 3	14/10	5/5	.95^b	16/10	3/5	.42^c
Tumor laterality, L/R	15/10	5/5	.87^b	17/10	3/5	.25^c
Tumor location involvement^d,e
Frontal, n (%)	3 (12%)	5 (50%)	.03^c	3 (11%)	5 (62%)	.01^c
Temporal, n (%)	14 (56%)	4 (40%)	.47^c	15 (56%)	3 (38%)	.44^c
Parietal, n (%)	7 (28%)	1 (10%)	.39^c	8 (30%)	0 (0%)	.15^c
Occipital, n (%)	5 (20%)	0 (0%)	.29^c	5 (19%)	0 (0%)	.32^c
Insula, n (%)	2 (8%)	2 (20%)	.56^c	2 (7%)	2 (25%)	.22^c
Other subcortical/brainstem, n (%)	0 (0%)	2 (20%)	.08^c	2 (7%)	1 (12%)	.55^c
Greatest enhancing tumor diameter (cm), mean (SD)	2.7 ± 1.7	3.8 ± 2.2	.18^a	2.9 ± 1.7	3.7 ± 2.5	.38^a
BRAF V600E mutation, n (%)^e	21 (91%)	5 (50%)	.02^c	22 (88%)	4 (50%)	.04^c
CDKN2A or CDKN2B mutation, n (%)^e	12 (67%)	2 (29%)	.18^c	13 (65%)	1 (20%)	.13^c
TERT promoter mutation, n (%)^e	3 (25%)	1 (14%)	1.0^c	3 (23%)	1 (17%)	1.0^c
Tumor mutational burden, n (%)^e	3.3 ± 1.0	5.2 ± 2.5	.12^a	4.1 ± 2.0	5.3 ± 2.8	.35^a

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Abbreviations: L, left. PXA, pleomorphic xanthoastrocytoma. R, right. SD, standard deviation. Annotations: ^a t-test; ^b chi-square test; ^c Fisher’s exact test; ^d Each tumor can involve more than one lobe; ^e Percentage shown is based on total patients for the group specified in the corresponding column

CNV were tested in 21 (60%) patients and identified in 14/16 (88%) patients with TRE and in all 5 patients without TRE. Loss of chromosome 13 was seen in patients with TRE (19% cases) and without TRE (40% cases). Loss of chromosomes 1p and 19 were seen with TRE (25% cases for each) but not without TRE. Patients without TRE also had a gain of chromosomes 5 and 7 (60% cases for each) and loss of chromosomes 3 (20%) and 17 (40%), which was seen in 6%, 13%, 6%, and 13% of cases with TRE, respectively. Statistical testing for the correlation of these findings with outcome was deferred due to insufficient power.

Factors Related to Seizure Freedom after Resection

Of the 27 patients with PXA and TRE, 17 (65%, 1 case omitted due to missing information) became seizure-free (ie, free of disabling seizures) after the first resection and before the first tumor recurrence, and 18 (67%) were seizure-free after the last resection. Only 3 (9%) patients had their ASMs discontinued, while the others remained on at least one ASM by the last follow-up. When comparing seizure freedom initially and after the last resection, 2 patients who were initially not seizure-free later had tumor progression with subsequent repeat resection that resulted in improved seizure control, and 2 patients who were initially seizure-free had tumor progression with subsequent breakthrough seizures and drug-resistant epilepsy.

Table 2 compares the characteristics of patients with TRE who were seizure-free vs. not seizure-free at the latest follow-up before the first tumor recurrence and the latest follow-up overall. Following the first resection before tumor recurrence, a younger age at seizure onset, the presence of BRAF V600E mutation, and smaller tumor size correlated with a higher likelihood of seizure freedom. However, these associations were no longer observed when comparing between seizure-free and not seizure-free patients following the last tumor resection. Moreover, there was no significant difference in seizure-freedom rates either before the first tumor recurrence or after the last tumor resection associated with other clinical factors, including the presence of preoperative convulsive seizures, status epilepticus, or drug-resistant epilepsy, tumor grade, location, mutational burden, or CDKN2A, CDKN2B, or TERT promoter mutation, presence of gross total resection or a resection within 1 year of seizure onset, and the addition of chemotherapy or radiation therapy (Table 2).

Table 2.

Characteristics of PXA patients based on post-resective seizure freedom outcomes. .

Characteristic	Before first tumor recurrence^a			After last resection
Characteristic	Seizure-free	Not seizure-free	P-value	Seizure-free	Not seizure-free	P-value
Total patients, n	17	9		18	9
Duration from resection to follow-up (months), median (range)	43 (1–272)	17 (6–78)	.40^b	46 (4–364)	46 (11–131)	.58^b
Age of seizure onset (years), median (range)	21 (1–41)	37 (9–50)	.02^c	21.5 (1–44)	16 (5–50)	.66^c
Sex at birth, female/male	7/10	5/4	.03^d	8/10	5/4	.69^d
Preoperative convulsive seizure, n (%)^e	9 (53%)	5 (56%)	1.0^d	9 (50%)	6 (67%)	.68^d
Preoperative status epilepticus, n (%)^e	0 (0%)	1 (11%)	.35^d	0 (0%)	1 (11%)	.33^d
Preoperative drug-resistant epilepsy, n (%)^e	4 (24%)	4 (44%)	.38^d	4 (22%)	5 (56%)	.11^d
Tumor grade, initial, grade 2/grade 3	10/6	5/4	1.0^d
Tumor grade, final, grade 2/grade 3				10/8	4/4	1.0^d
Tumor laterality, L/R	8/9	8/1	.09^d	10/8	5/4	.41^d
Tumor location involvement^e,f
Frontal, n (%)	2 (12%)	1 (11%)	1.0^d	1 (6%)	2 (22%)	.25^d
Temporal, n (%)	9 (53%)	5 (56%)	1.0^d	10 (56%)	5 (57%)	1.0^d
Parietal, n (%)	7 (41%)	1 (11%)	.19^d	6 (33%)	2 (22%)	.68^d
Occipital, n (%)	4 (24%)	1 (11%)	.63^d	5 (28%)	0 (0%)	.14^d
Insula, n (%)	1 (6%)	1 (11%)	1.0^d	1 (6%)	1 (11%)	1.0^d
Other subcortical/brainstem, n (%)	0 (0%)	1 (11%)	.35^d	0 (0%)	1 (11%)	.33^d
Greatest enhancing tumor diameter (cm), mean ± SD	2.1 ± 1.2	4.3 ± 1.8	.01^c	2.7 ± 1.7	3.2 ± 2.1	.66^c
BRAF V600E mutation, n (%)^e	15 (100%)	6 (67%)	.04^d	15 (94%)	7 (78%)	.53^d
CDKN2A or CDKN2B mutation, n (%)^e	6 (55%)	7 (78%)	.37^d	8 (67%)	5 (62%)	1.0^d
TERT promoter mutation, n (%)^e	1 (14%)	2 (33%)	.56^d	1 (14%)	2 (33%)	.56^d
Tumor mutational burden, mean ± SD	4.0 ± 2.3	4.2 ± 1.9	.85^c	3.6 ± 2.4	4.8 ± 0.5	1.2^c
First resection, gross total / not gross total	16/1	6/3	.10^d
Initial resection within 1 year after seizure onset, n (%)^e	6 (35%)	6 (67%)	.22^d
Any tumor recurrence, n (%)^e				10 (56%)	6 (67%)	.69^d
Last resection, gross total / not gross total				14/4	6/3	.65^d
Last resection within 1 year after seizure onset, n (%)^e				4 (22%)	4 (44%)	.37^d
Add chemotherapy, n (%)^e	3 (18%)	4 (44%)	.19^d	8 (44%)	4 (44%)	1.0^d
Add radiation therapy, n (%)^e	4 (24%)	4 (44%)	.38^d	11 (61%)	5 (56%)	1.0^d

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Abbreviations: L, left. PXA, pleomorphic xanthoastrocytoma. R, right. SD, standard deviation. Annotations: ^a One patient did not have seizure freedom outcomes clearly described in the medical record before first tumor recurrence and was therefore excluded; ^b Mann-Whitney U test; ^c t-test; ^d Fisher’s exact test; ^e Percentage shown is based on total patients for the group specified in the corresponding column; ^f Each tumor can involve more than one lobe. One patient received an anterior temporal lobectomy with gross total lesionectomy, which resulted in seizure freedom; this patient was not included in comparing gross total vs. subtotal resection for seizure freedom.

Overall Survival Outcomes With and Without Tumor-Related Epilepsy

At the last available follow-up, 8/35 (23%) patients died, although one died as a direct result of a comorbid urologic malignancy. Overall, 100% of patients had an overall survival at > 1 year, 90% at > 3 years, 88% at > 5 years, and 59% at > 10 years. Figure 1 shows the Kaplan–Meier curve for patients who had TRE vs. patients who did not have TRE. In the unadjusted analysis, patients with TRE had a higher overall survival rate than those without TRE (P = .02). However, when adjusting for the covariates—age of initial presentation, tumor size, tumor laterality, sex at birth, tumor grade, tumor location (frontal, temporal, parietal, occipital, insula, other subcortical/brainstem), and presence of BRAF V600E mutation—there was no significant difference in survival (P = .99). Detailed analysis of Cox proportional hazards model is shown in Table 3. There was no significant difference in survival outcome when comparing between any individual covariate, including tumor grade. Notably, the model did not account for CDKN2A/B mutation, TERT promoter mutation, and tumor mutational burden due to low sample sizes.

Figure 1. — Kaplan–Meier survival curves comparing the overall survival of patients with PXA who experienced TRE (blue curve) versus those who did not (orange curve). The x-axis shows the time in months, and the y-axis shows the survival probability. The longest follow-up times available for PXA patients with TRE and without TRE were 407 and 127 months, respectively. Censored patients are marked with ticks on the curves. The shaded regions represent the 95% confidence intervals for the survival probabilities. The survival table below the plot lists the number of patients at risk, censored, and events at different time points for each group. Abbreviations: PXA, pleomorphic xanthoastrocytoma. TRE, tumor-related epilepsy.

Table 3.

Cox proportional hazards model for overall survival analysis of PXA with and without tumor-related epilepsy.

Features	HR	95% CI	P-value
TRE vs. no TRE (adjusted)	1.8	0 - 4.6E + 42	.99
Age at initial presentation	0.6	0.02 - 18.0	.77
Tumor size	3.9	0 - 2.5E + 14	.93
Tumor laterality (left)	5.5	0 - 4.4E + 19	.94
Sex at birth (female)	0.02	0 - 1.2E + 17	.86
Tumor grade (grade 2)	0	0 - 6.6E + 20	.83
Tumor localization Frontal lobe	0.08	0 - 3.0E + 25	.94
Temporal lobe	2.9E + 06	0.28 - 3.0E + 13	.07
Parietal lobe	3.2E + 05	0 - 2.6E + 27	.62
Occipital lobe	0.01	0 - 1.3E + 66	.96
Insula	8.9E + 03	0 - 6.0E + 31	.78
Subcortical	7.9E + 05	0 - 1.4E + 26	.57
BRAF V600E mutation	5.5	0 - 1.5E + 05	.43

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Abbreviations: CI, confidence interval. HR, hazard ratio, which represents the relative risk of an event (death) associated with each variable. PXA, pleomorphic xanthoastrocytoma.

Tumor-Directed Chemotherapy and Outcomes

After the initial diagnosis and resection, 11/35 (31%) of patients received adjuvant chemotherapy, all of which were temozolomide (TMZ)-containing regimens. In two cases, TMZ was followed by targeted therapy with BRAF-targeting therapy involving combination dabrafenib and trametinib. Over the course of disease, 18/35 (51%) received TMZ and 9/35 (26%) received BRAF-targeting therapy at any time. Using Fisher’s exact test, there was no association observed between administration of TMZ or BRAF-targeting therapy (TMZ 33% vs. no TMZ 56%, P = .41; BRAF-targeting therapy 33% vs. 22%, P = .67). Using Cox proportional hazards, there was no association observed between the administration of TMZ or BRAF-targeting therapy and overall survival (TMZ hazard ratio 7.8, P = .06; BRAF-targeting therapy hazard ratio 3.0, P = .17).

Discussion

Seizure-related outcomes have been extensively explored in a variety of brain tumors, as TRE can significantly impact patient quality of life.³³ With recent advances establishing direct neuron-glioma cell interactions driving hyperexcitability and impacting survival outcomes, there are even greater implications for determining the relationships between glioma molecular profiles and epileptogenicity.³⁴ Here, we demonstrate in PXAs, a rare subtype of LEATs, that preoperative epileptogenicity was associated with the presence of BRAF somatic mutations and that BRAF mutations were associated with seizure freedom after initial resection prior to progressive disease.

Similar to previous literature on PXAs, the majority of patients in this cohort presented initially with seizure, which led to their brain tumor diagnosis. BRAF V600E mutations were associated with an initial presentation of seizure. This is in line with growing evidence to suggest that mutationally activated BRAF may increase the epileptogenicity of low-grade gliomas and glioneuronal tumors, including gangliogliomas.^35,36 We also found that patients who were seizure-free before the first tumor recurrence were more likely to have BRAF-mutated PXAs, an earlier age of onset, and smaller PXA tumor size. These associations raise the possibility that BRAF-driven epileptogenicity to promote seizures may facilitate an earlier tumor diagnosis, thereby increasing the likelihood of gross total resection. Although the extent of resection was not significant in this analysis, the sample size was not sufficiently powered for this determination.

We found no association between PXA molecular profiles, including BRAF V600E mutation, and seizures after tumor recurrence. This is analogous to IDH mutations in diffuse gliomas, which were found to be much more strongly associated with preoperative than postoperative seizures.³⁷ These findings suggest that tumor resection and the administration of ASMs may help to mitigate intrinsic epileptogenicity over the tumor course.

The unadjusted survival analysis in this study showed that PXA patients with TRE had a longer overall survival than those without TRE, although this difference was no longer observed in the adjusted multivariate analysis. Therefore, tumor biology rather than the presence of TRE appears to determine PXA aggressiveness. Only 2/26 (8%) patients with BRAF-mutated PXAs received upfront adjuvant BRAF-targeting therapy after gross total resection, likely due to provider-specific practices in reserving the treatment for recurrent versus newly diagnosed tumors. With increasing evidence of epileptogenicity associated with BRAF mutations, future studies may explore early BRAF-targeting therapy as a possible treatment approach for TRE in patients with BRAF-mutated PXA. This targeted approach would be analogous to IDH-mutated gliomas in which early data suggests the potential for IDH inhibitors to ameliorate seizures.³⁸

Despite a combined dataset from two major academic cancer centers, this study was primarily limited by a relatively small sample size. Indeed, these datasets estimate that PXAs make up less than 1% of primary glial brain tumors. Nevertheless, these data support prior literature establishing a phenotypic difference between BRAF-mutated and BRAF-wildtype PXAs. An additional inherent limitation is the retrospective design with variability in clinical practice, particularly from two different medical centers. This could contribute to potential differences in the choice of testing, chemotherapy or radiation therapy, and epilepsy management. Methylation profiling was unavailable for most of the patients and not consistently used to support the diagnosis of PXA. More patients received testing for copy number variations and tumor mutational burden at DFCI than at UPenn, which may skew the analysis, although no significant associations were observed with these metrics. Finally, more granular details of seizure characteristics, such as preoperative and postoperative seizure frequency, could not reliably be captured from the retrospective chart review and were not included in the analyses.

In summary, these findings underscore the need for further investigation into the interplay between tumor biology, surgical intervention, tumor-directed therapy, and seizure outcomes for less common brain tumors. Future studies, including prospective trials, should incorporate seizure-related outcomes to guide individualized counseling and management of TRE.

Supplementary Material

vdaf134_suppl_Supplementary_Figures_S1-S3

vdaf134_suppl_supplementary_figures_s1-s3.docx^{(44.3KB, docx)}

Acknowledgments

The authors would like to acknowledge the DFCI Oncology Data Retrieval System (OncDRS) for the aggregation, management, and delivery of the clinical and operational research data used in this project. The content is solely the responsibility of the authors.

Contributor Information

Daniel J Zhou, Center for Neuroengineering and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, USA; Penn Epilepsy Center, Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Colin A Ellis, Center for Neuroengineering and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, USA; Penn Epilepsy Center, Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Kevin Xie, Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA; Center for Neuroengineering and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Nishant Sinha, Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA; Center for Neuroengineering and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Sharon X Xie, Department of Biostatistics, Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Kathryn A Davis, Center for Neuroengineering and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, USA; Penn Epilepsy Center, Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Joel M Stein, Division of Neuroradiology, Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA; Center for Neuroengineering and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Tara Jennings, Penn Epilepsy Center, Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Stephen J Bagley, Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Arati Desai, Center for Neuro-Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA; Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Patrick Y Wen, Center for Neuro-Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.

David A Reardon, Center for Neuro-Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.

Steven Tobochnik, Center for Neuro-Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.

Funding

DZ was supported by the American Epilepsy Society Research and Training Fellowship for Clinicians (1282834) and the National Institute of Neurologic Disorders and Stroke (5T32NS091008-07). CE was supported by the National Institute of Neurologic Disorders and Stroke (5K23NS121520-05) and the National Human Genome Research Institute. NS received funding from the National Institute of Neurological Disorders and Stroke (K99NS138680). SB received research support from Kite (a Gilead company), GSK, Novocure, Lilly, and Incyte. PW received research support from Astra Zeneca, Black Diamond, Bristol Meyers Squibb, Chimerix, Eli Lily, Erasca, Global Coalition For Adaptive Research, Kazia, MediciNova, Merck, Nerviano, Novartis, Quadriga, Servier.

Ethics Approval

The University of Pennsylvania Institutional Review Board approved this study with waiver of consent (835008). The Dana-Farber Institutional Review Board approved this study with waiver of consent (21-425).

Conflict of interest statement. CE received personal fees for consulting for Epiminder and advisory board for As2Bio. SB received personal fees for advisory boards from Modifi Bio, Servier, Telix, Kiyatec, Bayer, and Novocure. JS received personal fees for consulting for Epiminder. PW received personal fees for advisory boards or consulting for Astra Zeneca, Black Diamond, Celularity, Chimerix, Day One Bio, Fore Biotherapeutics, Genenta, Glaxo Smith Kline, Kintara, Merck, Mundipharma, Nerviano Medical Sciences, Novartis, Novocure, Rigel, Sapience, Servier, Tango, Telix, VBI Vaccines. DR received personal fees for consulting for Abbvie, Advantagene, Agenus, Agios, Amgen, AnHeart Therapeutics, Avita Biomedical, Inc., Bayer; Boston Biomedical, Boehringer Ingelheim, Bristol-Myers Squibb, Celldex, Deciphera, Del Mar Pharma, DNAtrix, Ellipses Pharma, EMD Serono, Genenta, Genentech/Roche, Hoffman-LaRoche, Ltd, Imvax, Inovio, Janssen Research & Development, LLC, Johnson & Johnson, Pharmac, Kintara, Kiyatec, Medicenna Biopharma, Inc., Merck, Merck KGaA, Monteris, Neuvogen, Novartis, Novocure, Oncorus, Oxigene, Regeneron, Stemline, Sumitono Dainippon Pharma, Pyramid, Taiho Oncology, Inc., Vivacitas Oncology, Inc., Y-mabs Therapeutics. ST received personal fees for consulting from Blackrock Neurotech. All other authors report no conflict of interest.

Authorship Statement

DZ: Study concept/design; analysis/interpretation of data; drafting/revising manuscript for content. CE: Major role in acquisition of data; analysis/interpretation of data; revising manuscript for content. KX: Major role in acquisition of data; analysis/interpretation of data; revising manuscript for content. NS: Analysis/interpretation of data; revising manuscript for content. SX: Analysis/interpretation of data; revising manuscript for content. KD: Interpretation of data; revising manuscript for content. JS: Interpretation of data; revising manuscript for content. TJ: Interpretation of data; revising manuscript for content. SB: Interpretation of data; revising manuscript for content. AD: Interpretation of data; revising manuscript for content. PW: Interpretation of data; revising manuscript for content. DR: Interpretation of data; revising manuscript for content. ST: Study design; analysis/interpretation of data; drafting/revising manuscript for content.

Data Availability

De-identified individual patient data are provided in the Supplementary Tables (S1–S3). The data analysis pipeline using the patient dataset can be found on GitHub: https://github.com/danzh07/pxa.git

References

1. Giannini C, Scheithauer BW, Burger PC, et al. Pleomorphic xanthoastrocytoma: what do we really know about it? Cancer. 1999;85(9):2033–2045. [PubMed] [Google Scholar]
2. Shaikh N, Brahmbhatt N, Kruser TJ, et al. Pleomorphic xanthoastrocytoma: a brief review. CNS Oncol 2019;8(3):CNS39. [DOI] [PMC free article] [PubMed] [Google Scholar]
3. Yan J, Cheng J, Liu F, Liu X.. Pleomorphic xanthoastrocytomas of adults: MRI features, molecular markers, and clinical outcomes. Sci Rep. 2018;8(1):14275. [DOI] [PMC free article] [PubMed] [Google Scholar]
4. Louis DN, Perry A, Wesseling P, et al. The 2021 WHO classification of tumors of the central nervous system: a summary. Neuro Oncol. 2021;23(8):1231–1251. [DOI] [PMC free article] [PubMed] [Google Scholar]
5. Lee C, Byeon Y, Kim GJ, et al. Exploring prognostic factors and treatment strategies for long-term survival in pleomorphic xanthoastrocytoma patients. Sci Rep. 2024;14(1):4615. [DOI] [PMC free article] [PubMed] [Google Scholar]
6. Dono A, Lopez-Rivera V, Chandra A, et al. Predictors of outcome in pleomorphic xanthoastrocytoma. Neurooncol. Pract.. 2020;8(2):222–229. [DOI] [PMC free article] [PubMed] [Google Scholar]
7. Vaubel R, Zschernack V, Tran QT, et al. Biology and grading of pleomorphic xanthoastrocytoma—what have we learned about it? Brain Pathol. 2020;31(1):20–32. [DOI] [PMC free article] [PubMed] [Google Scholar]
8. Mahajan S, Dandapath I, Garg A, et al. The evolution of pleomorphic xanthoastrocytoma: from genesis to molecular alterations and mimics. Laboratory Investigation; A Journal of Technical Methods and Pathology. 2022;102(7):670–681. [DOI] [PubMed] [Google Scholar]
9. Phillips JJ, Gong H, Chen K, et al. The genetic landscape of anaplastic pleomorphic xanthoastrocytoma. Brain Pathol. 2019;29(1):85–96. [DOI] [PMC free article] [PubMed] [Google Scholar]
10. Dias-Santagata D, Lam Q, Vernovsky K, et al. BRAF V600E mutations are common in pleomorphic xanthoastrocytoma: Diagnostic and therapeutic implications. PLoS One. 2011;6(3):e17948. [DOI] [PMC free article] [PubMed] [Google Scholar]
11. Gandham EJ, Goyal-Honavar A, Beno D, et al. Impact of grade on survival in pleomorphic xanthoastrocytoma and low prevalence of BRAF V600E mutation. World Neurosurg. 2022;164:e922–e928. [DOI] [PubMed] [Google Scholar]
12. Ida CM, Rodriguez FJ, Burger PC, et al. Pleomorphic xanthoastrocytoma: Natural history and long‐term follow‐up. Brain Pathol. 2014;25(5):575–586. [DOI] [PMC free article] [PubMed] [Google Scholar]
13. Ma C, Feng R, Chen H, et al. BRAF V600E, TERT, and IDH2 mutations in pleomorphic xanthoastrocytoma: Observations from a large case-series study. World Neurosurgery. 2018;120:e1225–e1233. [DOI] [PubMed] [Google Scholar]
14. Ebrahimi A, Korshunov A, Reifenberger G, et al. Pleomorphic xanthoastrocytoma is a heterogeneous entity with pTERT mutations prognosticating shorter survival. Acta Neuropathologica Communications. 2022;10(1):5. [DOI] [PMC free article] [PubMed] [Google Scholar]
15. Wu W, Zuo P, Li C, Gong J.. Clinical features and surgical results of pediatric pleomorphic xanthoastrocytoma: Analysis of 17 cases with a literature review. World Neurosurgery. 2021;151:e778–e785. [DOI] [PubMed] [Google Scholar]
16. Zuo P, Li T, Sun T, et al. Clinical features and surgical outcomes of high grade pleomorphic xanthoastrocytomas: a single-center experience with a systematic review. Front Oncol. 2023;13. [DOI] [PMC free article] [PubMed] [Google Scholar]
17. Vogt VL, Witt JA, Delev D, et al. Cognitive features and surgical outcome of patients with long-term epilepsy-associated tumors (LEATs) within the temporal lobe. Epilepsy & Behavior. 2018;88:25–32. [DOI] [PubMed] [Google Scholar]
18. He C, Hu L, Chen C, et al. Clinical characteristics of low-grade tumor-related epilepsy and its predictors for surgical outcome. Ann Clin Transl Neurol. 2021;8(7):1446–1455. [DOI] [PMC free article] [PubMed] [Google Scholar]
19. Wallace DJ, Byrne RW, Ruban D, et al. Temporal lobe pleomorphic xanthoastrocytoma and chronic epilepsy: Long-term surgical outcomes. Clin Neurol Neurosurg. 2011;113(10):918–922. [DOI] [PubMed] [Google Scholar]
20. Deng SL, Jin RH, Liu YM, Jing Y, Guan Y.. Cerebral pleomorphic xanthoastrocytoma mimicking inflammatory granuloma: Two case reports. Medicine (Baltim). 2020;99(41):e22478. [DOI] [PMC free article] [PubMed] [Google Scholar]
21. Kim B, Chung CK, Myung JK, Park SH.. Pleomorphic xanthoastrocytoma associated with long-standing Taylor-type IIB-focal cortical dysplasia in an adult. Pathol Res Pract. 2009;205(2):113–117. [DOI] [PubMed] [Google Scholar]
22. Ramelli GP, von der Weid N, Remonda L, Mariani L, Weis J.. Pleomorphic xanthoastrocytoma derived from glioneuronal malformation in a child with intractable epilepsy. J Child Neurol. 2000;15(4):270–272. [DOI] [PubMed] [Google Scholar]
23. Babini M, Giulioni M, Galassi E, et al. Seizure outcome of surgical treatment of focal epilepsy associated with low-grade tumors in children. J Neurosurg Pediatr. 2013;11(2):214–223. doi: https://doi.org/ 10.3171/2012.11.PEDS12137 [DOI] [PubMed] [Google Scholar]
24. Kim SK, Wang KC, Cho BK.. Intractable seizures associated with brain tumor in childhood: lesionectomy and seizure outcome. Child Nerv Syst. 1995;11(11):634–638. [DOI] [PubMed] [Google Scholar]
25. Delev D, Daka K, Heynckes S, et al. Long-term epilepsy-associated tumors: transcriptional signatures reflect clinical course. Sci Rep. 2020;10(1):96. [DOI] [PMC free article] [PubMed] [Google Scholar]
26. Rudà R, Bruno F, Pellerino A.. Epilepsy in gliomas: recent insights into risk factors and molecular pathways. Curr Opin Neurol. 2023;36(6):557–563. [DOI] [PubMed] [Google Scholar]
27. Wen PY, van den Bent M, Youssef G, et al. RANO 2.0: Update to the response assessment in neuro-oncology criteria for high- and low-grade gliomas in adults. J Clin Oncol. 2023;41(33):5187–5199. [DOI] [PMC free article] [PubMed] [Google Scholar]
28. Ellingson BM, Sanvito F, Cloughesy TF, et al. A neuroradiologist’s guide to operationalizing the response assessment in neuro-oncology (RANO) criteria Version 2.0 for gliomas in adults. AJNR Am J Neuroradiol. 2024;45(12):1846–1856. [DOI] [PMC free article] [PubMed] [Google Scholar]
29. Sholl LM, Do K, Shivdasani P, et al. Institutional implementation of clinical tumor profiling on an unselected cancer population. JCI Insight. 2016;1(19):e87062. [DOI] [PMC free article] [PubMed] [Google Scholar]
30. Garcia EP, Minkovsky A, Jia Y, et al. Validation of oncopanel: A targeted next-generation sequencing assay for the detection of somatic variants in cancer. Arch Pathol Lab Med. 2017;141(6):751–758. [DOI] [PubMed] [Google Scholar]
31. Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia. 2010;51(6):1069–1077. [DOI] [PubMed] [Google Scholar]
32. Wieser HG, Blume WT, Fish D, et al. ; Commission on Neurosurgery of the International League Against Epilepsy (ILAE). Proposal for a new classification of outcome with respect to epileptic seizures following epilepsy surgery. Epilepsia. 2001;42(2):282–286. [PubMed] [Google Scholar]
33. Englot DJ, Chang EF, Vecht CJ.. Epilepsy and brain tumors. Handb Clin Neurol. 2016;134:267–285. [DOI] [PMC free article] [PubMed] [Google Scholar]
34. Avila EK, Tobochnik S, Inati SK, et al. Brain tumor-related epilepsy management: A Society for Neuro-oncology (SNO) consensus review on current management. Neuro-Oncology. 2024;26(1):7–24. [DOI] [PMC free article] [PubMed] [Google Scholar]
35. Koh HY, Kim SH, Jang J, et al. BRAF somatic mutation contributes to intrinsic epileptogenicity in pediatric brain tumors. Nat Med. 2018;24(11):1662–1668. [DOI] [PubMed] [Google Scholar]
36. Xing H, Song Y, Zhang Z, Koch PD.. Clinical characteristics of BRAF V600E gene mutation in patients of epilepsy-associated brain tumor: a meta-analysis. J Mol Neurosci. 2021;71(9):1815–1824. [DOI] [PubMed] [Google Scholar]
37. Song L, Quan X, Chen C, Chen L, Zhou J.. Correlation between tumor molecular markers and perioperative epilepsy in patients with glioma: A systematic review and meta-analysis. Front Neurol. 2021;12:692751. [DOI] [PMC free article] [PubMed] [Google Scholar]
38. Drumm MR, Wang W, Sears TK, et al. Postoperative risk of IDH-mutant glioma–associated seizures and their potential management with IDH-mutant inhibitors. J Clin Invest. 2023;133(12):e168035. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

vdaf134_suppl_Supplementary_Figures_S1-S3

vdaf134_suppl_supplementary_figures_s1-s3.docx^{(44.3KB, docx)}

Data Availability Statement

[CIT0001] 1. Giannini C, Scheithauer BW, Burger PC, et al. Pleomorphic xanthoastrocytoma: what do we really know about it? Cancer. 1999;85(9):2033–2045. [PubMed] [Google Scholar]

[CIT0002] 2. Shaikh N, Brahmbhatt N, Kruser TJ, et al. Pleomorphic xanthoastrocytoma: a brief review. CNS Oncol 2019;8(3):CNS39. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0003] 3. Yan J, Cheng J, Liu F, Liu X.. Pleomorphic xanthoastrocytomas of adults: MRI features, molecular markers, and clinical outcomes. Sci Rep. 2018;8(1):14275. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0004] 4. Louis DN, Perry A, Wesseling P, et al. The 2021 WHO classification of tumors of the central nervous system: a summary. Neuro Oncol. 2021;23(8):1231–1251. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0005] 5. Lee C, Byeon Y, Kim GJ, et al. Exploring prognostic factors and treatment strategies for long-term survival in pleomorphic xanthoastrocytoma patients. Sci Rep. 2024;14(1):4615. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0006] 6. Dono A, Lopez-Rivera V, Chandra A, et al. Predictors of outcome in pleomorphic xanthoastrocytoma. Neurooncol. Pract.. 2020;8(2):222–229. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0007] 7. Vaubel R, Zschernack V, Tran QT, et al. Biology and grading of pleomorphic xanthoastrocytoma—what have we learned about it? Brain Pathol. 2020;31(1):20–32. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0008] 8. Mahajan S, Dandapath I, Garg A, et al. The evolution of pleomorphic xanthoastrocytoma: from genesis to molecular alterations and mimics. Laboratory Investigation; A Journal of Technical Methods and Pathology. 2022;102(7):670–681. [DOI] [PubMed] [Google Scholar]

[CIT0009] 9. Phillips JJ, Gong H, Chen K, et al. The genetic landscape of anaplastic pleomorphic xanthoastrocytoma. Brain Pathol. 2019;29(1):85–96. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0010] 10. Dias-Santagata D, Lam Q, Vernovsky K, et al. BRAF V600E mutations are common in pleomorphic xanthoastrocytoma: Diagnostic and therapeutic implications. PLoS One. 2011;6(3):e17948. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0011] 11. Gandham EJ, Goyal-Honavar A, Beno D, et al. Impact of grade on survival in pleomorphic xanthoastrocytoma and low prevalence of BRAF V600E mutation. World Neurosurg. 2022;164:e922–e928. [DOI] [PubMed] [Google Scholar]

[CIT0012] 12. Ida CM, Rodriguez FJ, Burger PC, et al. Pleomorphic xanthoastrocytoma: Natural history and long‐term follow‐up. Brain Pathol. 2014;25(5):575–586. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0013] 13. Ma C, Feng R, Chen H, et al. BRAF V600E, TERT, and IDH2 mutations in pleomorphic xanthoastrocytoma: Observations from a large case-series study. World Neurosurgery. 2018;120:e1225–e1233. [DOI] [PubMed] [Google Scholar]

[CIT0014] 14. Ebrahimi A, Korshunov A, Reifenberger G, et al. Pleomorphic xanthoastrocytoma is a heterogeneous entity with pTERT mutations prognosticating shorter survival. Acta Neuropathologica Communications. 2022;10(1):5. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0015] 15. Wu W, Zuo P, Li C, Gong J.. Clinical features and surgical results of pediatric pleomorphic xanthoastrocytoma: Analysis of 17 cases with a literature review. World Neurosurgery. 2021;151:e778–e785. [DOI] [PubMed] [Google Scholar]

[CIT0016] 16. Zuo P, Li T, Sun T, et al. Clinical features and surgical outcomes of high grade pleomorphic xanthoastrocytomas: a single-center experience with a systematic review. Front Oncol. 2023;13. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0017] 17. Vogt VL, Witt JA, Delev D, et al. Cognitive features and surgical outcome of patients with long-term epilepsy-associated tumors (LEATs) within the temporal lobe. Epilepsy & Behavior. 2018;88:25–32. [DOI] [PubMed] [Google Scholar]

[CIT0018] 18. He C, Hu L, Chen C, et al. Clinical characteristics of low-grade tumor-related epilepsy and its predictors for surgical outcome. Ann Clin Transl Neurol. 2021;8(7):1446–1455. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0019] 19. Wallace DJ, Byrne RW, Ruban D, et al. Temporal lobe pleomorphic xanthoastrocytoma and chronic epilepsy: Long-term surgical outcomes. Clin Neurol Neurosurg. 2011;113(10):918–922. [DOI] [PubMed] [Google Scholar]

[CIT0020] 20. Deng SL, Jin RH, Liu YM, Jing Y, Guan Y.. Cerebral pleomorphic xanthoastrocytoma mimicking inflammatory granuloma: Two case reports. Medicine (Baltim). 2020;99(41):e22478. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0021] 21. Kim B, Chung CK, Myung JK, Park SH.. Pleomorphic xanthoastrocytoma associated with long-standing Taylor-type IIB-focal cortical dysplasia in an adult. Pathol Res Pract. 2009;205(2):113–117. [DOI] [PubMed] [Google Scholar]

[CIT0022] 22. Ramelli GP, von der Weid N, Remonda L, Mariani L, Weis J.. Pleomorphic xanthoastrocytoma derived from glioneuronal malformation in a child with intractable epilepsy. J Child Neurol. 2000;15(4):270–272. [DOI] [PubMed] [Google Scholar]

[CIT0023] 23. Babini M, Giulioni M, Galassi E, et al. Seizure outcome of surgical treatment of focal epilepsy associated with low-grade tumors in children. J Neurosurg Pediatr. 2013;11(2):214–223. doi: https://doi.org/ 10.3171/2012.11.PEDS12137 [DOI] [PubMed] [Google Scholar]

[CIT0024] 24. Kim SK, Wang KC, Cho BK.. Intractable seizures associated with brain tumor in childhood: lesionectomy and seizure outcome. Child Nerv Syst. 1995;11(11):634–638. [DOI] [PubMed] [Google Scholar]

[CIT0025] 25. Delev D, Daka K, Heynckes S, et al. Long-term epilepsy-associated tumors: transcriptional signatures reflect clinical course. Sci Rep. 2020;10(1):96. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0026] 26. Rudà R, Bruno F, Pellerino A.. Epilepsy in gliomas: recent insights into risk factors and molecular pathways. Curr Opin Neurol. 2023;36(6):557–563. [DOI] [PubMed] [Google Scholar]

[CIT0027] 27. Wen PY, van den Bent M, Youssef G, et al. RANO 2.0: Update to the response assessment in neuro-oncology criteria for high- and low-grade gliomas in adults. J Clin Oncol. 2023;41(33):5187–5199. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0028] 28. Ellingson BM, Sanvito F, Cloughesy TF, et al. A neuroradiologist’s guide to operationalizing the response assessment in neuro-oncology (RANO) criteria Version 2.0 for gliomas in adults. AJNR Am J Neuroradiol. 2024;45(12):1846–1856. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0029] 29. Sholl LM, Do K, Shivdasani P, et al. Institutional implementation of clinical tumor profiling on an unselected cancer population. JCI Insight. 2016;1(19):e87062. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0030] 30. Garcia EP, Minkovsky A, Jia Y, et al. Validation of oncopanel: A targeted next-generation sequencing assay for the detection of somatic variants in cancer. Arch Pathol Lab Med. 2017;141(6):751–758. [DOI] [PubMed] [Google Scholar]

[CIT0031] 31. Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia. 2010;51(6):1069–1077. [DOI] [PubMed] [Google Scholar]

[CIT0032] 32. Wieser HG, Blume WT, Fish D, et al. ; Commission on Neurosurgery of the International League Against Epilepsy (ILAE). Proposal for a new classification of outcome with respect to epileptic seizures following epilepsy surgery. Epilepsia. 2001;42(2):282–286. [PubMed] [Google Scholar]

[CIT0033] 33. Englot DJ, Chang EF, Vecht CJ.. Epilepsy and brain tumors. Handb Clin Neurol. 2016;134:267–285. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0034] 34. Avila EK, Tobochnik S, Inati SK, et al. Brain tumor-related epilepsy management: A Society for Neuro-oncology (SNO) consensus review on current management. Neuro-Oncology. 2024;26(1):7–24. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0035] 35. Koh HY, Kim SH, Jang J, et al. BRAF somatic mutation contributes to intrinsic epileptogenicity in pediatric brain tumors. Nat Med. 2018;24(11):1662–1668. [DOI] [PubMed] [Google Scholar]

[CIT0036] 36. Xing H, Song Y, Zhang Z, Koch PD.. Clinical characteristics of BRAF V600E gene mutation in patients of epilepsy-associated brain tumor: a meta-analysis. J Mol Neurosci. 2021;71(9):1815–1824. [DOI] [PubMed] [Google Scholar]

[CIT0037] 37. Song L, Quan X, Chen C, Chen L, Zhou J.. Correlation between tumor molecular markers and perioperative epilepsy in patients with glioma: A systematic review and meta-analysis. Front Neurol. 2021;12:692751. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0038] 38. Drumm MR, Wang W, Sears TK, et al. Postoperative risk of IDH-mutant glioma–associated seizures and their potential management with IDH-mutant inhibitors. J Clin Invest. 2023;133(12):e168035. [DOI] [PMC free article] [PubMed] [Google Scholar]

PERMALINK

Seizure characteristics and outcomes in patients with pleomorphic xanthoastrocytoma

Daniel J Zhou

Colin A Ellis

Kevin Xie

Nishant Sinha

Sharon X Xie

Kathryn A Davis

Joel M Stein

Tara Jennings

Stephen J Bagley

Arati Desai

Patrick Y Wen

David A Reardon

Steven Tobochnik

Abstract

Background

Methods

Results

Conclusion

Key Points.

Importance of the Study.

Materials and Methods

Patient Selection

Variables

Statistical Analyses

Results

Population Characteristics

Factors Related to Presence of Tumor-Related Epilepsy

Table 1.

Factors Related to Seizure Freedom after Resection

Table 2.

Overall Survival Outcomes With and Without Tumor-Related Epilepsy

Figure 1.

Table 3.

Tumor-Directed Chemotherapy and Outcomes

Discussion

Supplementary Material

Acknowledgments

Contributor Information

Funding

Ethics Approval

Authorship Statement

Data Availability

References

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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