White matter integrity and its correlation to seizures in diffuse glioma.

Finding the anaplastic focus in diffuse gliomas: The value of Gd-DTPA enhanced MRI, FET-PET, and intraoperative, ALA-derived tissue fluorescence

Background Histone gene mutant malignant gliomas - H3K27-altered diffuse midline glioma (DMG) and diffuse hemispheric glioma (DHG) H3G34-mutant - occur in all age groups and can have significant variation in clinical outcomes. Here, we report comprehensive genomic profiling from one of the largest collections of H3F3A-mutant gliomas analyzed to date, identifying subsets defined by recurrently co-mutated genes. Material and Methods We identified 390 H3F3A-mutant diffuse gliomas WHO grade 4 (201 females and 189 males) that were profiled in the comprehensive genomic profiling program at Foundation Medicine between 2013-2020. Information from pathology reports, histopathology review, and patient clinical data was assessed Results Our cohort comprised 304 (77.9%) H3K27M-mutant DMG WHO grade 4 (156 females and 148 males) and 86 H3G34-mutant DHG (45 females and 41 males) with a median age of 20 years (1- 74 years). H3K27M-mutant DMG distributed equally between pediatric and adult patients, with 52% of the patients older than 20 years, 30% older than 30 years, and 18% older than 40 years at the time of first diagnosis. Clonal FGFR1 hotspot mutations were exclusively detected in K27M-mutant DMG (n = 64/304, 21%; p=0.0001), with a significant association with a higher age at first diagnosis (median 32.5 years), and with a wide tumor distribution across the diencephalon. Additional genes which were significantly more frequently altered in K27M-mutant compared to G34-mutant diffuse gliomas included NF1 (31% vs. 8.1%; p=0.0001) and PIK3CA/PIK3R1 (27.9% vs. 15.1%; p=0.016). Conversely, targetable alterations of the cell-cycle pathway (CDK4/6 amplifications and CDKN2A/B deletions) were enriched in H3G34-mutant DHG (26%) compared to H3K27M-mutant DMG (7%). Potentially targetable PDGFR alterations were present in 32.5% of H3G34-mutant DHG and in 18% of H3K27M-mutant DMG. Conclusion These data expand our understanding of the tumor-specific molecular features of pediatric-type high-grade gliomas, identifying cohort sub-structure by recurrent co-mutations, which can inform diagnosis and clinical trial design.

Until now, the Pignatti risk score has been used to guide treatment decisions after histological diagnosis of diffuse glioma WHO grade 2. However, its prognostic value was derived from a historic cohort that has been diagnosed by morphologic rather than molecular criteria. We re-challenged the Pignatti score in a contemporary, molecularly characterized cohort. From our institutional cohort of 422 diffuse gliomas WHO grade 2, 202 patients were identified for whom IDH mutation status was known and 1p/19q co-deletion or loss of ATRX expression unambiguously classified tumors into astrocytoma or oligodendroglioma. Patients with IDH wildtype astrocytoma (n=9), multifocal lesions or brainstem involvement were excluded. Potential prognostic factors including the individual items of the Pignatti score (astrocytoma; age ≥40 years; neurologic deficit; maximum tumor diameter ≥6cm; tumor crossing midline) were correlated with progression-free survival (PFS) by univariate log-rank und multivariate Cox regression analysis. 165 patients with astrocytoma or oligodendroglioma were analysed of whom 109 (66%) did not receive adjuvant radio- or chemotherapy. 94 untreated patients with a minimum follow-up of 24 months entered survival analysis. These patients were classified as “high-risk” (Pignatti 3-5) and “low-risk” (Pignatti 0-2) in 15% and 85% and did not differ with regard to potential prognostic factors (gender; resection vs. biopsy; tumor recurrence) other than the individual Pignatti score items. Diameter ≥6 cm (p=0.006; HR=2.18) and midline crossing (p=0.003; HR=3.54) were identified as independent prognostic factors of PFS. Noteworthy, prognostic factors coincided when all patients (n=144) with a minimum follow-up of 24 months, regardless of adjuvant treatment, were analysed. In IDH mutant, molecularly characterized diffuse gliomas WHO grade 2, the Pignatti risk score as a whole no longer seems to be of prognostic relevance. Instead, outcome seems to be determined by tumor burden.

OBJECTIVES: There has recently been increasing evidence that IDH-mutant diffuse gliomas WHO grades II and III – which are still graded based upon light microscopical criteria – share many clinical similarities. Here, we sought to determine whether IDH-mutant diffuse gliomas grades II/III have similar radiological presentations in magnetic resonance imaging (MRI). METHODS: Clinical and radiological data of 79 patients; 40 patients with an glioma WHO grade II and 39 patients with glioma WHO grade III were collected. Sequencing of IDH1 codon 132, IDH2 codon 172 as well as of the TERT-promoter (C146 and C160) was performed. Moreover, The 1p/19q-co deletion status was determined in gliomas harboring oligodendroglial components (n = 32). Using immunohistochemistry, the MIB-1 index and the p53 over-expression status were detected. All molecular data were correlated to the tumor features on MRI before treatment. RESULTS: IDH mutations were present in 63 patients (79.7%; in 34 patients with grade II and 29 patients with grade III gliomas, respectively). TERT mutations were detected in 36% and a co-deleted 1p/19q status in 31% of the entire group. Both groups of glioma grades with an IDH mutation depicted similar radiological features – in regard to tumor size, tumor localization, insular involvement, contrast enhancement, local and/or bilateral infiltration pattern, midline shifting and diffusion restriction – without any significant differences. IDH-mutant gliomas with TERT mutations and/or 1p/19q co-deletion were predominantly located in the frontal lobe and did not cross the midline nor involve insular structures, making a gross total resection more amenable. A high MIB-1-index and a p53 over-expression were associated with a bigger tumor size and bilateral infiltration of the hemispheres. CONCLUSIONS: Our analysis implicates that IDH-mutant gliomas WHO grades II and III are MR-radiologically indistinguishable. We further elucidate that the clinical behavior of diffuse gliomas more likely underlines molecular alterations than the pathological subclasses.

Venous thromboembolism (VTE) is a cause of increased morbidity and risk of death. Studies report VTE in up to 30% of glioma patients but the results vary. The VTE risk is relevant when evaluating prophylaxis to avoid unnecessary bleeding or overdiagnosis. This study examines the VTE incidence in patients with glioma WHO grade 2-4, and when VTE occurred, risk factors, and overall survival (OS) for patients with WHO grade 4. In total 3,630 patients with WHO grade 2 (n = 230), grade 3 (n = 317), and grade 4 (n = 3,083) gliomas from 2010 to 2018 were identified using the Danish Neuro-Oncology Registry. VTE diagnoses and time of death were obtained from Statistics Denmark. The VTE incidence was 5.2, 6.3, and 6.8% in patients with WHO grade 2, 3, and 4 gliomas, respectively. The VTE incidence rate was highest during the first 3 months after the diagnosis with 53 events. Increasing age (HR 1.03, 95%CI 1.01-1.04), male sex (HR 1.47, 95%CI 1.09-1.99), poor performance status (HR 1.57, 95%CI 1.10-2.25), and post-operative long-course radiochemotherapy (HR 2.10, 95%CI 1.19-3.72) were predictors of VTE in patients with glioma WHO grade 4. There was no difference in OS comparing patients having VTE to those without (p = 0.068). In conclusion, patients with glioma WHO grade 2-4 were at high risk of VTE, especially the first 3 months after diagnosis. Increasing age, male sex, poor performance status, and long-course radiochemotherapy were associated with increased risk of VTE in patients with glioma WHO grade 4.

<h3>Objective:</h3> To determine the factors which predict the occurrence of preoperative seizures (PRS) and post-operative seizures (POS) among patients with glioblastoma (GBM). <h3>Background:</h3> Seizures have been well described in patients with GBM, albeit at a lower frequency than low grade gliomas. Although recent studies suggest epileptogenesis has more to do with genetic molecular markers in low grade glioma-related seizure, information on factors that influence the development of of GBM-related PRS and POS is lacking. <h3>Design/Methods:</h3> We performed a single-center retrospective cohort study of patients with GBM evaluated at Mayo Clinic Florida, between 2018 and 2022. Clinical factors including, tumor molecular markers, neurophysiological and imaging findings were analyzed according to the status of PRS and POS. <h3>Results:</h3> One hundred thirty-two adult patients (median age=61.5 years), 79 (59.85%) females) were included. The most common locations were the temporal (n=50, 42.02%) and frontal (n=47, 39.50%) lobes. All patients underwent GBM resection, with 17.1% undergoing total resection (n=22). Sixty-two patients (46.27%) underwent intra-operative electrocorticography during GBM resection. Isocitrate dehydrogenase 1 (IDH1) wildtype was present in 121 patients (90.3%), 61 patients had O⁶-methylguanine-DNA methyltransferase (<i>MGMT</i>)-methylated GBM (46.21%). Forty patients (33.9%) had PRS, and 39 patients (38.24%) had POS (median follow-up=17.27 months; IQR=10.6–30.1). IDH1 wildtype and MGMT methylation status were not associated with PRS or POS. Patients with PRS were younger (59 years vs. 64 years, <b><i>p=0.021</i></b>) and experienced a longer survival time (16.1 months vs. 8.3 months, <b><i>p=0.044</i></b>) compared to patients without PRS. Occipital lobe GBM was associated with a lower likelihood of PRS (<b><i>p=0.043</i></b>) and POS (<b><i>p=0.001</i></b>). <h3>Conclusions:</h3> PRS is associated with younger age and longer survival time. PRS and POS are less likely to occur with occipital lobe tumors. Further studies are needed to confirm our findings and elucidate the influence of other tumor molecular markers in the development of PRS and POS in patients with GBM. <b>Disclosure:</b> Dr. Sánchez Boluarte has nothing to disclose. Dr. Garcia has nothing to disclose. Dr. Gunasekera has nothing to disclose. Dr. Tatum has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Bioserenity. Dr. Tatum has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier. Dr. Tatum has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Defense Law Firm on behalf of a patient with epilepsy with funds donated to the Epilepsy Foundation of America. The institution of Dr. Tatum has received research support from Esai. The institution of Dr. Tatum has received research support from Mayo Clinic. The institution of Dr. Tatum has received research support from Liva Nova. The institution of Dr. Tatum has received research support from Engage Pharmaceuticals. The institution of Dr. Tatum has received research support from Xenon. Dr. Tatum has received publishing royalties from a publication relating to health care. Dr. Tatum has received publishing royalties from a publication relating to health care. Dr. Sirven has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for UCB. Dr. Sirven has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Medtronic. Dr. Sirven has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Neurelis. Dr. Sirven has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Medtronic. Dr. Sirven has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for AAN. Dr. Sirven has stock in Doximity. Dr. Sirven has received publishing royalties from a publication relating to health care. Dr. Sirven has a non-compensated relationship as a Host with WJCT Public Media/ NPR that is relevant to AAN interests or activities. Dr. Freund has nothing to disclose. The institution of Dr. Ritaccio has received research support from NIH. Dr. Ritaccio has received intellectual property interests from a discovery or technology relating to health care. Kaisorn Chaichana has nothing to disclose. Alfredo Quiñones-Hinojosa has nothing to disclose. Dr. Feyissa has nothing to disclose.

OBJECTIVES Histone gene mutant malignant gliomas - H3K27-altered diffuse midline glioma (DMG) and diffuse hemispheric glioma (DHG) H3G34-mutant - occur in all age groups and can have significant variation in clinical outcomes. Here, we report comprehensive genomic profiling from one of the largest collections of H3F3A-mutant gliomas analyzed to date, identifying subsets defined by recurrently co-mutated genes. METHODS We identified 390 H3F3A-mutant diffuse gliomas WHO grade 4 (201 females and 189 males) that were profiled in the comprehensive genomic profiling program at Foundation Medicine between 2013-2020. Information from pathology reports, histopathology reviews, and clinical data was assessed. RESULTS Our cohort comprised 304 (77.9%) H3K27M-mutant DMG WHO grade 4 (156 females and 148 males) and 86 H3G34-mutant DHG (45 females and 41 males) with a median age of 20 years (1-74 years). H3K27M-mutant DMG distributed equally between pediatric and adult patients, with 52% of the patients older than 20 years, 30% older than 30 years, and 18% older than 40 years at the time of first diagnosis. Clonal FGFR1 hotspot mutations were exclusively detected in K27M-mutant DMG (n = 64/304, 21%; p=0.0001), with a significant association with a higher age at first diagnosis (median 32.5 years), and with a wide tumor distribution across the diencephalon. Additional genes which were significantly more frequently altered in K27M-mutant compared to G34-mutant diffuse gliomas included NF1 (31% vs. 8.1%; p=0.0001) and PIK3CA/PIK3R1 (27.9% vs. 15.1%; p=0.016). Conversely, targetable alterations of the cell-cycle pathway (CDK4/6 amplifications and CDKN2A/B deletions) were enriched in H3G34-mutant DHG (26%) compared to H3K27M-mutant DMG (7%). Potentially targetable PDGFR alterations were present in 32.5% of H3G34-mutant DHG and in 18% of H3K27M-mutant DMG. CONCLUSIONS These data expand our understanding of the tumor-specific molecular features of pediatric-type high-grade gliomas, identifying cohort sub-structure by recurrent co-mutations, which can inform diagnosis and clinical trial design.

Background:Contrast enhancement (CE) and anaplasia have been reported to indicate poor outcome in diffuse glioma. Recently, mutational status of the IDH1/2 gene and loss of heterozygosity on chromosome 1p/19q (LOH1p/19q) have gained relevance for the evaluation of clinical outcome. Currently, a three-way classification based on IDH1/2 mutation and LOH 1p/19q has gained further importance and will eventually supersede the current WHO grading system in terms of risk stratification and treatment planning. Thus, we aimed in the present study to re-evaluate CE and histopathological WHO grading as risk factors for survival within the framework of these molecular markers.Methods:332 patients with diffuse glioma WHO grade II (n=189) or grade III (n=143) were stratified into 3 groups: IDH1/2 wild type (n=118), IDH1/2 mutated with (n=123) and without (n=91) LOH1p/19q. Preoperative magnetic resonance (MR) imaging was reviewed for presence of CE. Univariate and multivariate analyses were conducted taking into account CE, WHO grading, molecular as well as age, Karnofsky performance status, surgical procedure and adjuvant therapy.Results:In multivariate analysis, CE was not associated with OS in IDH1/2 wild type tumors whereas histopathological WHO grading had a strong independent prognostic value on OS in (p=0.001). In gliomas with IDH1/2 mutation, CE independently predicts shorter survival (p=0.04) and this effect seems to be especially pronounced in the IDH1/2 mutated group without LOH 1p/19q.Conclusions:In patients with diffuse gliomas WHO grade II/III and IDH1/2 wildtype, CE is not associated with survival in contrast to WHO grading. In patients with an IDH1/2 mutation, presence of CE on initial MRI is linked to inferior survival while grading is not.

Risk factors for preoperative and postoperative seizures in patients with glioblastoma according to the 2021 World Health Organization classification

The aim of this study was to compare MR imaging characteristics with histopathological findings of intrinsic brainstem lesions and also to show the prognostic factors in patients with diffuse brainstem glioma. Between February 1988 and August 2007, 44 brainstem biopsies were performed at the Roger Salengro Hospital in Lille, France, in children with intrinsic brainstem lesions not amenable to excision. Twenty-six were female and 18 male, and the mean age was 6 years. Histological evaluation revealed diffuse brainstem glioma in all patients with diffuse nonenhancing brainstem lesions. Diffuse brainstem glioma was found in 18 patients (90%) with diffuse enhancing brainstem lesions. Pathological entities different from diffuse glioma were verified in 2 patients (10%)-1 with ependymoma and 1 with ganglioglioma. In 4 of 5 patients with a focal nonenhancing brainstem lesion, the histopathological diagnosis was diffuse low-grade glioma. In 6 of 10 patients with focal enhancing brainstem lesion, the diagnosis was diffuse brainstem glioma, and pathological entities different from diffuse brainstem glioma were verified in 2 (20%), both with pilocytic astrocytoma. The mean 1-year actuarial survival rates for patients classified with low-grade and high-grade glioma were 80.4% ± 0.08% and 48.6% ± 0.14%, respectively. The impact of stereotactic biopsy on intrinsic brainstem lesions was greater in patients with MR imaging-documented enhancing lesions in whom the diagnosis of diffuse glioma was less frequent. Patients with low-grade glioma seem to have longer survival than those with high-grade glioma.

White Matter Microstructural Integrity Is Associated with Executive Function and Processing Speed in Older Adults with Coronary Artery Disease.

The association of seizures with meningiomas is poorly understood. Moreover, any relationship between seizures and the underlying meningioma genomic subgroup has not been studied. Herein, the authors report on their experience with identifying clinical and genomic factors associated with preoperative and postoperative seizure presentation in meningioma patients. Clinical and genomic sequencing data on 394 patients surgically treated for meningioma at Yale New Haven Hospital were reviewed. Correlations between clinical, histological, or genomic variables and the occurrence of preoperative and postoperative seizures were analyzed. Logistic regression models were developed for assessing multiple risk factors for pre- and postoperative seizures. Mediation analyses were also conducted to investigate the causal pathways between genomic subgroups and seizures. Seventeen percent of the cohort had presented with preoperative seizures. In a univariate analysis, patients with preoperative seizures were more likely to have tumors with a somatic NF2 mutation (p = 0.020), WHO grade II or III tumor (p = 0.029), atypical histology (p = 0.004), edema (p < 0.001), brain invasion (p = 0.009), and worse progression-free survival (HR 2.68, 95% CI 1.30-5.50). In a multivariate analysis, edema (OR 3.11, 95% CI 1.46-6.65, p = 0.003) and atypical histology (OR 2.00, 95% CI 1.03-3.90, p = 0.041) were positive predictors of preoperative seizures, while genomic subgroup was not, such that the effect of an NF2 mutation was indirectly mediated through atypical histology and edema (p = 0.012). Seizure freedom was achieved in 83.3% of the cohort, and only 20.8% of the seizure-free patients, who were more likely to have undergone gross-total resection (p = 0.031), were able to discontinue antiepileptic drug use postoperatively. Preoperative seizures (OR 3.54, 95% CI 1.37-9.12, p = 0.009), recurrent tumors (OR 2.89, 95% CI 1.08-7.74, p = 0.035), and tumors requiring postoperative radiation (OR 2.82, 95% CI 1.09-7.33, p = 0.033) were significant predictors of postoperative seizures in a multivariate analysis. Seizures are relatively common at meningioma presentation. While NF2-mutated tumors are significantly associated with preoperative seizures, the association appears to be mediated through edema and atypical histology. Patients who undergo radiation and/or have a recurrence are at risk for postoperative seizures, regardless of the extent of resection. Preoperative seizures may indeed portend a more potentially aggressive molecular entity and challenging clinical course with a higher risk of recurrence.

BackgroundThe 2016 World Health Organization (WHO) classification of central nervous system (CNS) tumors has been modified to incorporate the IDH mutation and 1p/19q co-deletion in the diagnosis of diffuse gliomas. In this study, we aimed to evaluate the feasibility and prognostic significance of the revised 2016 WHO classification of CNS tumors in Mongolian patients with diffuse gliomas.MethodsA total of 124 cases of diffuse gliomas were collected, and tissue microarray blocks were made. IDH1 mutation was tested using immunohistochemistry, and 1p/19q co-deletion status was examined using fluorescence in situ hybridization analysis.ResultsAccording to the 2016 WHO classification, 124 cases of diffuse brain glioma were reclassified as follows: 10 oligodendroglioma, IDHmut and 1p/19q co-deleted; three anaplastic oligodendroglioma, IDHmut and 1p/19q co-deleted; 35 diffuse astrocytoma, IDHmut, 11 diffuse astrocytoma, IDHwt, not otherwise specified (NOS); 22 anaplastic astrocytoma, IDHmut, eight anaplastic astrocytoma, IDHwt, NOS; and 35 glioblastoma, IDHwt, NOS, respectively. The 2016 WHO classification presented better prognostic value for overall survival in patients with grade II tumors than traditional histological classification. Among patients with grade II tumors, those with oligodendroglioma IDHmut and 1p/19q co-deleted and diffuse astrocytoma IDHmut showed significantly higher survival than those with diffuse astrocytoma IDHwt, NOS (p<.01).ConclusionsMongolian diffuse gliomas could be reclassified according to the new 2016 WHO classification. Reclassification revealed substantial changes in diagnosis of both oligodendroglial and astrocytic entities. We have confirmed that the revised 2016 WHO CNS tumor classification has prognostic significance in Mongolian patients with diffuse gliomas, especially those with grade II tumors.

Plenary 7

Maximum safe resection of diffuse adult-type glioma WHO grade 4 (glioma °4) is a well-established procedure in order to prolong a patient’s lifetime. However, differentiation between glioma and healthy brain tissue remains a challenge in an intraoperative setting. As shown previously, the attenuation coefficient extracted from OCT images does not provide sufficient discrimination between healthy gray matter and tumor infiltrated tissue. On the other hand, the majority of published approaches based on structural information in OCT images uses sophisticated machine learning approaches as e.g. deep convolutional neural networks which bring the need for large data sets for reasonable modeling. In this work, we propose a method, which is based on comprehensible texture features and provides reasonable classification performance for healthy gray and white matter against glioma °4 samples, while requiring a relatively low number of samples for training. Our sample collective consists of 36 tissue samples from 27 different patients. Texture features based on the average contrast were optimized with respect to best discrimination of the tissue types of interest. Best discrimination could be obtained for the contrast of structure sizes of approximately 100μm. By using a linear discriminant analysis (LDA), we could achieve a sensitivity and specificity of 97.7% and 91.7%, respectively, when classifying white matter and samples with a mixture of white and gray matter against glioma °4 samples. For an extended data set, also including pure gray matter samples, we determined a sensitivity of 86.7% and a specificity of 86.3%.