Higher WHO Grade Research Articles

Analysis of Neuronal Excitability Profiles for Motor-Eloquent Brain Tumor Entities Using nTMS in 800 Patients.

Non-invasive motor mapping with navigated transcranial magnetic stimulation (nTMS) is an established diagnostic tool to identify spatial relationships between functional and tumor areas and to characterize motor excitability. Recently, nTMS has been used to analyze the impact of different brain tumor entities on motor excitability. However, entity-specific excitability patterns are not sufficiently validated yet. We retrospectively analyzed nTMS motor mapping data of 800 motor-eloquent brain tumor patients in this observational study. The motor excitability profile consisted of four nTMS parameters (resting motor threshold (RMT), cortical motor area, amplitude and latency) measured on both hemispheres. The relationship between motor excitability parameters and tumor entity, glioma subtype and motor status were assessed using multiple regressions analyses. Regression models included patient- and tumor-specific factors. Gliomas had more frequent pathologic RMT ratios (OR 1.76, 95%CI: 1.06-2.89, p = 0.030) compared to benign entities. In the subgroup of gliomas, pathologic RMT ratios were more associated with the isocitrate dehydrogenase (IDH)-wildtype status (OR 0.43, 95%CI: 0.23-0.79, p = 0.006) and less so with higher WHO grades (OR 1.61, 95%CI: 0.96-2.71, p = 0.074). This was true for both IDH-mutant astrocytomas (OR 0.43, 95%CI: 0.20-0.91, p = 0.027) and IDH-mutant oligodendrogliomas (OR 0.43, 95%CI: 0.20-0.93, p = 0.031). Motor area enlargement on the tumor hemisphere was more frequently observed in lower WHO-graded gliomas (OR 0.87, 95%CI: 0.78-0.97, p = 0.019). Interestingly, a larger cortical motor area was additionally found for oligodendrogliomas on the healthy hemisphere (OR 1.18, 95%CI: 1.01-1.39, p = 0.041). Motor deficits were related with higher RMT (OR 1.12, 95%CI: 1.05-1.21, p = 0.001), reduced amplitude (OR 0.78, 95%CI: 0.64-0.96, p = 0.019) and prolonged latency (OR 1.12, 95%CI: 1.02-1.24, p = 0.025) in the tumor hemisphere. Neuroplastic phenomena such as adjustment of the motor excitability level and an enlargement of the nTMS-positive motor area were more frequently observed in benign tumors and in IDH-mutated gliomas. Consequently, patients experienced motor deficits less often, suggesting a differentiated susceptibility to resection-related paresis. Future studies will analyze which stimulation paradigms are most effective in stimulating and optimizing neuroplasticity processes to improve the functional outcomes (and thus the quality of life) for patients.

Age at diagnosis of paediatric unilateral and bilateral permanent hearing loss in Eastern Switzerland: a retrospective cohort study

STUDY AIM: Undiagnosed and therefore untreated permanent paediatric hearing loss can have a detrimental impact on a child’s speech, language, social and educational development, and quality of life. Therefore, early diagnosis is required for successful treatment with hearing aids to minimise the negative impact of hearing loss. Newborn hearing screening programmes may have decreased the average age at diagnosis of hearing loss worldwide, but outcomes vary widely between countries. In this study, we therefore aimed to assess the median age of children at diagnosis of permanent unilateral and bilateral hearing loss in Eastern Switzerland. METHODS: In this retrospective cohort study, children born in Eastern Switzerland with permanent hearing loss diagnosed at the Division of Paediatric Audiology at the Cantonal Hospital of St Gallen (the tertiary referral centre for Eastern Switzerland) were included. The study period was from 1 January 2014 to 31 December 2019. The primary endpoint was age at diagnosis of permanent unilateral or bilateral hearing loss. Descriptive data collected were the type and WHO grade of hearing loss, the status of newborn hearing screening and other information such as path of referral and place of residence. RESULTS: In total, 107 children with permanent hearing loss were included in this study. Overall, the median age at diagnosis was 45.0 months (interquartile range [IQR] 5.7–74.8). The median age at diagnosis for children with bilateral hearing loss was 25.8 months (IQR 3.6–70.5), compared to 63.1 months (IQR 11.4–88.5) for children with unilateral hearing loss. For children with bilateral hearing loss, the median age at diagnosis was lower with higher WHO grades of hearing loss: 65.6 months (IQR 11.1–131.6) for grade I vs 4.5 months (IQR 2.2–6.0) for grade IV. Children with bilateral hearing loss and a documented failed newborn hearing screen were diagnosed early: median age at diagnosis 4.0 months (IQR 2.2–12.3). CONCLUSION: In conclusion, the age at diagnosis of paediatric permanent hearing loss in our study is variable and, in some cases, late. This applies particularly to bilateral hearing loss that should have been diagnosed by the newborn hearing screen in congenital cases and unilateral hearing loss.

Complications after resection of parasagittal and superior sagittal sinus meningiomas.

Parasagittal meningiomas (PSM) represent one of the most frequently encountered intracranial meningiomas and pose unique challenges given their intimate relationship with parasagittal bridging veins and superior sagittal sinus (SSS). Compromise of venous drainage during resection might be a source of significant postoperative complications including catastrophic intraparenchymal hemorrhage. Objective of this study was to identify postoperative complications and associated factors predisposing to their development. A retrospective review of histologically confirmed parasagittal meningiomas (Sindou grade 1-6) resected between 2011 and 2020 was performed. A total of 62 patients (35 females (56.45%); mean age 55.72) years were included. The mean follow-up was 40.84 months. Forty-two patients (67.74%) were treatment naïve. Complete SSS occlusion was noted in 23 (37.1%). WHO grade 1 tumor was diagnosed in 32 (51.61%), WHO 2 in 23 (37.1%) and WHO 3 in 7 cases (11.29%). The SSS was resected in 24 (38.71%) patients. Intraparenchymal hemorrhage (ICH) was noted after 8 (12.90%) surgeries. Prior surgery (p = 0.006, OR = 22.1; 95% CI = 2.48-196.5) and higher tumor grade (OR = 4.64, 95% CI = 1.45-14.79, p = 0.01) were independently associated with greater risk of ICH. Resection of the SSS was not associated with postoperative ICH (p = 0.1388). A procedure-related mortality was noted in 2 patients (3.2%). Long term postoperative headaches were reported in 14 (22.58%) patients, associated with the resection of the SSS (p = 0.0003). Four (6.56%) patients had a CSF diversion procedure noted at the last follow up, correlated with ICH (p = 0.0124). History of prior surgery and higher WHO grade seem to be correlated with a significantly elevated risk of hemorrhage. Increased intracranial pressure, requiring CSF diversion is relatively infrequent occurring only in 6% patients, however awareness is important as prevention of its sequela is straightforward, preventing debilitating morbidity.

Thioredoxin related transmembrane protein 1acts as a prognostic indictor and promotes proliferation and TMZ resistance of lower-grade glioma

Thioredoxin Related Transmembrane Protein 1 (TMX1) encodes a thiol-disulfide oxidoreductase and regulates cleavage, formation, or isomerization of disulfide bonds among cysteine residues in proteins. Using bioinformatic analysis, we firstly prove TMX1 is significantly upregulated in lower-grade gliomas (LGGs) and associated with poor prognosis of LGG patients. Besides, it’s also highly expressed in higher WHO grade, 1p/19q non-co-deleted and isocitrate dehydrogenase (IDH) wildtype LGGs, thus we established a TMX1-based nomogram model, which exhibits a strong and stable predictive ability in the prognosis of LGG patients. Then, we also noticed that TMX1 was significantly associated with the immune cell infiltrations in LGGs, especially in B cell, CD8+ T cell, CD4+T cell, dendritic cell, macrophage and neutrophil. Meanwhile, it was also highly correlated to the expressions of MKI67, PCNA, PROM1 and SOX2 in LGGs, and that higher TMX1 LGGs showed a stronger resistance to temozolomide (TMZ). Finally, in our in vitro and in vivo experiments, we verified that TMX1 is highly expressed in LGG patients clinically, and it not only regulates the proliferative ability of SW1088 and SW1783 cells both in vitro and in vivo, it can also be inhibited to increase the TMZ therapy sensitivity in vivo. These results revealed that TMX1 acts as a strong prognostic biomarker in LGGs, and targeting TMX1 can be an efficient way to increase the TMZ therapy in LGG patients.

Risk factors associated with higher WHO grade in meningiomas: a multicentric study of 552 skull base meningiomas

The histological grade is crucial for therapeutic management, and its reliable preoperative detection can significantly influence treatment approach. Lacking established risk factors, this study identifies preoperative predictors of high-grade skull base meningiomas and discusses the implications of non-invasive detection. A multicentric study was conducted on 552 patients with skull base meningiomas who underwent primary surgical resection between 2014 and 2019. Data were gathered from clinical, surgical and pathology records and radiological diagnostics. The predictive factors of higher WHO grade were analysed in univariate analysis and multivariate stepwise selection logistic regression analysis. Histological analysis revealed 511 grade 1 (92.6%) and 41 grade 2 (7.4%) meningiomas. A prognostic model predicting the probability of WHO grade 2 skull base meningioma (AUC 0.79; SE 0.04; 95% Wald Confidence Limits (0.71; 0.86)) based on meningioma diameter, presence of an arachnoid plane and cranial nerve palsy was built. Accurate preoperative detection of WHO grade in skull base meningiomas is essential for effective treatment planning. Our logistic regression model, based on diameter, cranial nerve palsy, and arachnoid plane, is tailored for detecting WHO grade 2 skull base meningiomas, even in outpatient settings.

Primary Extradural Meningioma: A Systematic Review of Diagnostic Features, Clinical Management, and Surgical Outcomes.

Objective: This systematic review consolidates the literature on primary extradural meningiomas (PEMs), a rare subset of meningiomas. We describe the clinical features, management strategies used, and treatment outcomes for published cases. Methods: A systematic review was conducted using PRISMA guidelines across multiple databases to 29 July 2024. Inclusion criteria were adult patients with primarily extradural meningioma and where individual patient clinical data were provided. Results: Of 216 studies that met the initial search criteria, 41 satisfied the final inclusion criteria. These 41 studies included 82 patients with 84 total PEMs. The cohort was balanced between sexes with a median age of 46 (range 18-82). Frequent symptoms at initial presentation included pain/headache (46%), weakness (44%), paresthesias (24%), and a palpable superficial mass (23%). The median duration of symptoms to diagnosis was 11 months (range 0.75-120). Surgical resection was the primary treatment approach, achieving a gross total resection in 67% of cases. The majority of lesions were classified as WHO grade 1 (87%). A recurrence was identified during the published follow-up in 11% of cases and a higher WHO grade was expectedly associated with a greater risk of recurrence. The described practice was to use adjuvant radiotherapy in recurrent and high-grade cases. Most cranial lesions were located in the frontal bone, while most spinal lesions affected the cervical spine. Post-treatment symptom improvement or resolution was described in almost all patients at the last follow-up. Conclusions: In comparison to intradural meningiomas, PEMs largely follow a more indolent course with a longer duration of symptoms prior to diagnosis, more benign symptoms, a higher proportion of grade 1 tumors, and favorable outcomes; however, there is a small subset of PEMs with extension outside the cranium and spine that require specific considerations for management.

PATH-28. KI-67 INDEX AS A PREDICTIVE MARKER OF MENINGIOMA RECURRENCE FOLLOWING SURGICAL RESECTION

Abstract BACKGROUND Meningiomas are the most common primary intracranial tumors in adults. Although benign in a majority of cases, they have a variable clinical course and may recur even after a thorough surgical resection. Ki-67, a nuclear protein involved in cell cycle regulation, has been widely studied as a marker of cellular proliferation in various cancers. Here, we investigate the Ki-67 index, as a predictive marker of meningioma recurrence following resection. METHODS The medical records of 451 patients with previously untreated cranial meningiomas who underwent resections from January 2011 to January 2021 at North Shore University Hospital (NSUH) were reviewed. Collected data included WHO grade, Ki-67 proliferative index, degree of resection - gross (GTR) vs subtotal (STR) - as judged by the surgeon, tumor location, and meningioma recurrence. This study was approved by the NSUH Institutional Review Board IRB 21-1107. RESULTS There were 290 patients with grade I, 154 with grade II, and 7 with grade III meningiomas. Higher WHO grades were associated with higher rates of recurrence, with rates of 11.4 %, 27.9 %, and 71.4 % for grades 1, 2, and 3, respectively, and subtotal resection corresponded to a higher rate of recurrence than total resection (34.3 % and 13.4 %, respectively). Higher WHO grades also correlated with higher Ki-67 scores (2.59, 10.01, and 20.71) for grades 1, 2, and 3, respectively. A multivariate logistic regression model identified Ki-67 and degree of resection as independent predictive variables for meningioma recurrence, with Ki-67 specifically predicting recurrence in the WHO grade II subset when analyzed separately for WHO grades I and II. CONCLUSION Our 10-year retrospective study suggests that the Ki-67 index is an important predictive marker for recurrence of intracranial meningiomas following surgical resection, particularly among patients with WHO grade II tumors. Our findings add to a growing body of data that support inclusion of Ki-67 index in the WHO grading criteria for patients with meningiomas.

NCOG-36. CLINICAL AND DEMOGRAPHIC CHARACTERISTICS PREDICT POSTOPERATIVE BEHAVIORAL DYSFUNCTION FOLLOWING HIGH-GRADE (WHO 2-4) GLIOMA RESECTION

Abstract BACKGROUND Gliomas have the highest incidence (85%) of cancer-related cognitive and behavioral impairments. Few studies have explored preoperative clinical and demographic drivers/predictors of postoperative behavioral impairment. METHODS We analyzed prospectively collected data from patients 1) who underwent glioma (WHO 2-4) resection and 2) who had postoperative Flanker testing, an assessment of inhibitory control and selective attention (NIH Toolbox Cognition Battery). Patients whose age-adjusted Flanker score (last follow-up) was less than the cohort mean were classified as having “poor” outcomes. Univariate analysis, multivariate logistic, and LASSO regressions were performed to identify drivers of poor outcomes. RESULTS In total, 43 patients (mean age at diagnosis 45.9 [range 18-77] years, 35% female) met inclusion criteria. The average age-adjusted Flanker score was 83.3±13.6; twenty (46.5%) patients had below-average scores. On univariate analysis, there were no significant differences in demographic factors (age, sex, education, employment) and tumor characteristics (grade, location). Multivariate logistic regression identified having high school versus higher degree (OR:1.6x10^4, p=0.017), WHO Grade 4 versus Grade 2 (OR:2.36, p=0.026), and parietal lesion (OR:1.6x10^3, p=0.034) as risk factors, while increased age (OR per 1-year increase:0.71, p=0.009) and dominant language hemisphere lesion (OR 0.002, p=0.048) were protective against poor behavioral outcome. LASSO regression (efficiently narrows down predictors) identified higher WHO grade (4 vs. 2), lower education (high school vs. higher), and insular and parietal lesions as predictive of poor outcomes. Increased age at diagnosis, frontal lobe lesions, and lesions on the dominant language hemisphere were protective. CONCLUSION Lower education status, higher WHO grade, and insular and parietal lesions are risk factors for poor behavioral outcomes postoperatively following glioma resection. In contrast, increased age, frontal lobe lesions, and dominant language hemisphere lesions were positive prognostic factors. Neuro-oncologists may use these findings to preoperatively counsel patients and tailor care plans with necessary postoperative support.

PATH-12. CLINICAL AND NEUROPATHOLOGICAL MARKERS FOR DISTINGUISHING BETWEEN IDH-MUTANT ASTROCYTOMAS OF WHO GRADE 2 AND 3

Abstract BACKGROUND The neuropathological criteria of anaplasia to distinguish between IDH-mutant astrocytomas of WHO grade 2 and 3 are ill-defined by the WHO 2021 classification. Following the positive phase III trial results and the expected approval of Vorasidenib for grade 2 astrocytomas, identifying prognostic markers distinguishing grade 2 and 3 tumors remains crucial. METHODS We retrospectively searched our institutional database for patients meeting the diagnostic criteria for IDH-mutant astrocytomas per the WHO 2021 classification. Clinical, neuropathological, and molecular data were collected, and outcomes compared using log-rank analysis. Centralized slide review is ongoing to exclude inter-rater variability due to the study’s retrospective nature. RESULTS We identified 99 patients with IDH-mutant astrocytomas in which detailed neuropathological and clinical information were available for review, including 63 tumors (63.6%) which were assigned to WHO grade 2 and 36 tumors (36.4%) assigned to WHO grade 3. At a median follow-up of 7.5 years, median progression-free survival was 5.7 years for WHO grade 2 tumors and 4.4 years for WHO grade 3 tumors. Median overall survival for WHO grade 2 and WHO grade 3 tumors was not reached. On univariate analysis, higher WHO grade, an increased number of mitoses, elevated Ki67 indices and the presence of contrast-enhancement on pre-operative imaging were associated with less favourable outcome. However, only the presence of contrast-enhancement retained its prognostic significance when forwarded into a multivariate model (p = 0.034 for overall survival, p = 0.012 for progression-free survival). The findings on the association between contrast-enhancement and outcome were confirmed in treatment-based subgroups, including individuals treated with a watch-and-scan approach (n = 30), radiotherapy (n = 25), or chemotherapy (n = 33). CONCLUSION While our findings await confirmation in larger prospective cohorts, neuropathological criteria for anaplasia might need to be accompanied by clinical information including contrast enhancement to prognostically distinguish grade 2 from grade 3 tumors particularly in patients undergoing biopsy given the risk for undersampling.

CTNI-71. RELA FUSION-POSITIVE EPENDYMOMA, DIFFUSE MIDLINE GLIOMA AND GRADE 4 IDH MUTANT ASTROCYTOMA TREATED WITH VAL-083 UNDER EXPANDED ACCESS: CASE REPORTS

Abstract RELA fusion-positive ependymoma is associated with supratentorial location, higher WHO grade and poor prognosis. Diffuse Midline Glioma (DMG) is a relatively rare CNS tumor, originating in the midline location of the brain. Surgical intervention is restricted to biopsy and radiation. Grade-4 astrocytoma, is highly aggressive with rapid progression. Standard treatment includes surgery and radiation therapy, with limited systemic options other than clinical trials for recurrent disease. VAL-083 is a DNA-targeting agent which rapidly induces inter-strand DNA cross-links at O6- and N7-guanine inducing double-strand breaks causing cell death and acts independent of MGMT DNA repair in high-grade gliomas. We report on 4 patients who had recent disease progression and unmethylated MGMT promoter status treated with VAL-083 under an expanded access program: Case #1: a 47-yo male diagnosed with IDHwt, RELA fusion-positive ependymoma. Case #2: an 18-yo male diagnosed with IDHwt, MAP2K1 and RELA fusion-positive ependymoma. Case #3: a 25-yo male diagnosed with IDHmut Grade 4 astrocytoma, with ATRX, INPP4A, RET and TP53 mutations. Case #4: a 21 yo male diagnosed with IDHwt DMG of the brain stem. All patients had multiple recurrences, received radiation and multiple systemic treatment regimens. They received VAL-083 (30 mg/m2 for 3 days every 21 days) under an expanded access program. Patients with ependymoma received 6 and 5 cycles of VAL-083, (case 1 and 2, respectively), while the patients with IDHmut Gr 4. astrocytoma and DMG received 5 and 18 cycles of VAL-083, respectively. No adverse events were reported and no dose reductions were required. These cases highlight that VAL-83 may be a treatment option for recurrent RELA fusion-positive ependymoma, Gr4. IDHmut astrocytoma, and DMG refractory to other treatment regimens. Additional outcomes related to these cases will be presented at the meeting. Clinicaltrials.gov Identifier: NCT03138629. The treatment plans for the EA patients were approved by MD Anderson Cancer Center IRB

NCMP-19. IMPACT OF SUBVENTRICULAR ZONE INVASION ON PREOPERATIVE COGNITIVE DECLINE IN DIFFUSE GLIOMA PATIENTS

Abstract PURPOSE To determine the impact of subventricular zone (SVZ) invasion on neurocognitive dysfunction in diffuse glioma patients. MATERIALS AND METHODS We collected neuropsychological assessments of treatment-naïve WHO grade 2-4 diffuse glioma patients between 2017 to 2023. The Chi-square test determined the odds ratio (OR), and multiple linear regression identified factors related to cognitive deficits using Python 3.11.4. RESULTS Of the 129 patients, 64 exhibited SVZ invasion (SVZ+) while 65 were SVZ-. Groups were matched for WHO grading. SVZ+ was associated with more defective domains than SVZ- in both lower grade (WHO grade 2,3, 3.2 ± 2.1 vs. 2.1 ± 1.9, p=0.019) and high grade (WHO grade 4, 4.9 ± 1.6 vs. 3.6 ± 2.2, p=0.019) tumors. In lower grade gliomas, SVZ+ increased risks of language (OR 7.500, p<0.001) and visual learning impairments (OR 4.375, p=0.014). In high grade gliomas, SVZ+ rendered greater language (OR 8.556, p=0.003) and auditory learning vulnerability (OR 3.850, p=0.039). In right hemispheric tumors, SVZ+ lesions conferred worse executive (OR 6.667, p=0.006) and language function (OR 9.063, p=0.017); in left hemispheric tumors, SVZ+ lesions increased language (OR 3.125, p=0.012) and auditory learning (OR 2.889, p=0.024) impairment. Frontal horn of SVZ+ was related to working memory decline, and body part of SVZ+ was related to emotional deficits. Age and WHO grade 4 were associate with more defective domains in the SVZ+ group. In the SVZ- group, parietal lobe tumor was associate with more defective domains, while high education, temporal lobe, and WHO grade 2 were associate with fewer defective domains. CONCLUSION SVZ invasion impacts pre-operative neurocognitive function regardless of lesion laterality and WHO grade. Distinct SVZ sub-regions are linked to specific cognitive impairments. These findings highlight the need for precise tumor mapping involving the SVZ to evaluate neurocognitive outcomes and consider preventive or rehabilitative interventions.

HOXD12 defines an age-related aggressive subtype of oligodendroglioma

Oligodendroglioma, IDH-mutant and 1p/19q-codeleted has highly variable outcomes that are strongly influenced by patient age. The distribution of oligodendroglioma age is non-Gaussian and reportedly bimodal, which motivated our investigation of age-associated molecular alterations that may drive poorer outcomes. We found that elevated HOXD12 expression was associated with both older patient age and shorter survival in the TCGA (FDR < 0.01, FDR = 1e−5) and the CGGA (p = 0.03, p < 1e−3). HOXD12 gene body hypermethylation was associated with older age, higher WHO grade, and shorter survival in the TCGA (p < 1e−6, p < 0.001, p < 1e−3) and with older age and higher WHO grade in Capper et al. (p < 0.002, p = 0.014). In the TCGA, HOXD12 gene body hypermethylation and elevated expression were independently prognostic of NOTCH1 and PIK3CA mutations, loss of 15q, MYC activation, and standard histopathological features. Single-nucleus RNA and ATAC sequencing data showed that HOXD12 activity was elevated in neoplastic tissue, particularly within cycling and OPC-like cells, and was associated with a stem-like phenotype. A pan-HOX DNA methylation analysis revealed an age and survival-associated HOX-high signature that was tightly associated with HOXD12 gene body methylation. Overall, HOXD12 expression and gene body hypermethylation were associated with an older, atypically aggressive subtype of oligodendroglioma.

Clinical and methylomic features of spinal meningiomas.

The objective of our study was to analyze methylomic and clinical features of a cohort of spinal meningiomas (SMs) resected at our institution. This is a retrospective study of patients undergoing SM resection at our institution between 2010 and 2023. Clinical and radiographic characteristics were reviewed and analyzed with standard statistical methods. A Partitioning Around Medoids approach was used to cluster SMs with methylation data in a combined cohort from our institution and a publicly available dataset by methylation profiles. Clinical variables and pathway analyses were compared for the resulting clusters. Sixty-five SMs were resected in 53 patients with median radiographic follow-up of 34 months. Forty-six (87%) patients were female. The median age at surgery was 65 years and median tumor diameter was 1.9cm. The five-year progression-free survival rate was 90%, with subtotal resection being associated with recurrence or progression (p = .017). SMs clustered into hypermethylation, intermediate methylation, and hypomethylation subgroups. Tumors in the hypermethylated subgroup were associated with higher WHO grade (p = .046) and higher risk histological subtypes (p <.001), while tumors in the hypomethylated subgroup were least likely to present with copy-number loss in chromosome 22q (p <.0001). SMs classified as immune-enriched under a previously developed intracranial meningioma classifier did not have increased leukocyte fractions or hypomethylation of genes typically hypomethylated in immune-enriched tumors. SMs are more benign than their intracranial counterparts, and gross-total resection results in long term PFS. Methylation profiling identifies subgroups with differences in clinical variables.

Combined NF2/PTEN mutations as predictors of meningioma aggressiveness.

e14044 Background: In meningiomas, loss of the NF2 tumor suppressor gene function leads to dysregulation of cell proliferation and tumor formation. PTEN, another tumor suppressor gene correlated with worse prognosis in tumors like gliomas, has also been reported in meningiomas, but the impact of its mutation alone or in conjunction with NF2 loss on outcomes in these tumors is unexplored. We aimed to evaluate whether dual NF2/PTEN mutations comprise a more aggressive meningioma phenotype compared to tumors with only NF2 mutations. Identifying this high-risk genetic profile could allow for preventative and individualized treatment of these aggressive meningiomas. Methods: We reviewed patients who underwent meningioma resection at our institution from January 2018 through October 2022. Demographic information, tumor characteristics, pre- and post-operative clinical characteristics, and outcomes were collected. Meningioma specimens were analyzed by immunohistochemistry for WHO grading and Ki67 proliferation index and by sequencing for genomic alterations. We performed multivariable logistic regression analyses to identify clinical outcomes associated with proliferation index and genetic mutations. Results: We identified NF2 mutations in 24 meningiomas and dual NF2/PTEN mutations in 7 meningiomas. Mutation rates did not significantly differ based on demographic factors including sex, age, race, socioeconomic status, or prior cranial radiation status (p&gt;0.05). The majority of tumors with these mutations (93%) were in non-skull base regions (i.e. convexity, parafalcine). Tumors with both NF2 and PTEN mutations were more likely to be WHO grade III tumors than those with the NF2 mutation alone (29% versus 9%). Tumors with dual mutations had higher likelihood of having Ki67 proliferation indices ≥ 10% (OR 5.98, p&lt;0.01). While higher Ki67 index was significantly associated with features of more aggressive tumors including higher WHO grade and recurrence rates, dual mutation in NF2 and PTEN is associated with higher rate of recurrence (OR 13.13, p&lt;0.001) and mortality (OR 5.14, p&lt;0.05) compared to NF2 irrespective of Ki67 index. Notably, patients with mutations in NF2 alone or both NF2/PTEN did not differ in preoperative Karnofsky performance score, Simpson resection grade, or presence of post operative residual tumor. Conclusions: Our results demonstrated that concomitant NF2 and PTEN mutations in meningiomas were associated with higher WHO grades, tumor proliferation indices, recurrence rates, and mortality rates. This finding suggests that NF2/PTEN mutated meningiomas represent a distinct subset of tumors that demonstrate a more aggressive clinical and histopathological phenotype that may require more aggressive treatment and closer surveillance. Further investigation is warranted to confirm the prognostic relevance of NF2/PTEN mutations in meningioma and elucidate their underlying molecular mechanisms.

F.3 Multicentre prospective validation of integrated molecular classification of meningiomas and prediction of recurrence risk using DNA methylation

Background: Meningiomas have significant heterogeneity between patients, making prognostication challenging. For this study, we prospectively validate the prognostic capabilities of a DNA methylation-based predictor and multiomic molecular groups (MG) of meningiomas. Methods: DNA methylation profiles were generated using the Illumina EPICarray. MG were assigned as previously published. Performance of our methylation-based predictor and MG were compared with WHO grade using generalized boosted regression modeling by generating time-dependent receiver operating characteristic (ROC) curves and computing area under the ROC curves (AUCs) along with their 95% confidence interval using bootstrap resampling. Results: 295 meningiomas treated from 2018-2021 were included. Methylation-defined high-risk meningiomas had significantly poorer PFS and OS compared to low-risk cases (p&lt;0.0001). Methylation risk increased with higher WHO grade and MG. Higher methylome risk (HR 4.89, 95%CI 2.02-11.82) and proliferative MG (HR 4.11, 95%CI 1.29-13.06) were associated with significantly worse PFS independent of WHO grade, extent of resection, and adjuvant RT. Both methylome-risk and MG classification predicted 3- and 5-year PFS and OS more accurately than WHO grade alone (ΔAUC=0.10-0.23). 42 cases were prescribed adjuvant RT prospectively although RT did not significantly improve PFS in high-risk cases (p=0.41). Conclusions: Molecular profiling outperforms conventional WHO grading for prognostication in an independent, prospectively collected cohort of meningiomas.

Clinical value of semi-quantitative parameters in 68Ga-DOTANOC PET/CT in treatment and diagnostics of cranial meningioma in a single-center retrospective analysis

BackgroundThe value of somatostatin-analogon PET tracers in theranostics in cranial meningioma has been demonstrated in several studies however, the value of semi-quantitative parameters for therapy and patient outcome is still unclear.MethodsA retrospective study was performed comparing measured semi-quantitative 68Ga-DOTANOC PET/CT parameters (maximum standardized uptake value = SUVmax, mean standardized uptake value = SUVmean, and metabolic tumor volume = MTV) and calculated ratios (SUVmax tumor/to pituitary gland, SUVmax tumor to superior sinus sagittalis), versus WHO grades and overall outcome. Patients with histological confirmed meningioma or high probability for meningioma in previous cranial MRI were eligible.ResultsThirty-two patients from January 2018 to February 2023 were retrospectively included. WHO grade I meningioma was confirmed in 17 patients, WHO grade II in five patients, WHO grade III in two patients, while in eight patients diagnosis was solely based on MRI and 68Ga-DOTANOC PET/CT findings. In 12 cases stable disease was present, in 15 cases radiation therapy was chosen, in three cases neurosurgery was preferred while in two cases palliative care was chosen. Median SUVmax values increased with WHO grade (15.84, 17.22, and 28.4, p = 0.134, Kruskal–Wallis-test) and no statistically significant difference was present for MTV, SUVmax, and calculated ratios, although the ratio for SUVmax tumor to superior sinus sagittalis had the lowest value of p = 0.067.ConclusionIncreased SUVmax values in the tumor in 68Ga-DOTANOC PET/CT are associated with higher WHO grade, although further studies including larger patient collectives are needed to solidify this hypothesis.

Clinical value of semi-quantitative parameters in 68Ga-DOTANOC PET/CT in treatment and diagnostics of cranial meningioma in a single-center retrospective analysis

BackgroundThe value of somatostatin-analogon PET tracers in theranostics in cranial meningioma has been demonstrated in several studies; however, the value of semi-quantitative parameters for therapy and patient outcome is still unclear.MethodsA retrospective study was performed comparing measured semi-quantitative 68Ga-DOTANOC PET/CT parameters (maximum standardized uptake value = SUVmax, mean standardized uptake value = SUVmean, and metabolic tumor volume = MTV) and calculated ratios (SUVmax tumor to pituitary gland and SUVmax tumor to superior sinus sagittalis), versus the WHO grades and overall outcome. Patients with histological confirmed meningioma or high probability for meningioma in the previous cranial MRI were eligible.ResultsThirty-two patients from January 2018 to February 2023 were retrospectively included. The WHO grade I meningioma was confirmed in 17 patients, the WHO grade II in five patients, and the WHO grade III in two patients, while in eight patients, diagnosis was solely based on MRI and 68Ga-DOTANOC PET/CT findings. In 12 cases, stable disease was present, in 15 cases, radiation therapy was chosen, in three cases, neurosurgery was preferred, while in two cases, palliative care was chosen. Median SUVmax values increased with the WHO grade (15.84, 17.22, and 28.4, p = 0.134, Kruskal–Wallis test), and no statistically significant difference was present for MTV, SUVmax, and calculated ratios.ConclusionIncreased SUVmax values in the tumor in 68Ga-DOTANOC PET/CT are associated with higher WHO grade, although further studies including larger patient collectives are needed to solidify this hypothesis.

Predicting histological grade in symptomatic meningioma by an objective estimation of the tumoral surface irregularity

Predicting histological grade in symptomatic meningioma by an objective estimation of the tumoral surface irregularity

Identification and Validation of TEAD Family’s Prognostic Effects and Immune Microenvironment Regulations in Glioma

Background. Gliomas are primary malignant tumors of the central nervous system. The TEA domain transcription factor (TEAD) family proteins are the ultimate effector molecules of the Hippo pathway. However, their expression and function in gliomas have not been further studied. Methods. This study employed R software as the primary analysis tool. Public databases were used to analyze the expression and prognostic significance of TEADs. Functional enrichment analyses were conducted to determine the functions of the TEADs. We then explored their interaction with tumor‐infiltrating immune cells and immune checkpoint proteins (ICPs). A Cox regression model was used to estimate the prognostic value of the TEADs. Finally, we conducted experiments to confirm TEAD3’s function in vitro. Results. TEAD expression was frequently increased in glioma and other malignant tumors. High TEAD expression was found to be substantially linked with isocitrate dehydrogenase (IDH) wild type, noncodeletion of 1p/19q, high WHO grade, and poor prognosis in glioma patients. Functional analyses revealed TEAD involvement in cancer cell transcription. The high expression of TEADs was greatly related to the myeloid‐derived suppressor cells (MDSCs) and regulatory T‐cells (Tregs) infiltration. TEADs also showed significant correlations with ICP expression in glioma tissues. The Cox regression model demonstrated significant diagnostic and prognostic efficacy in glioma patients. The reduction in TEAD3 affects tumor cell proliferation, migration, invasion, and immune regulation. RNA sequencing disclosed that TEAD3 regulates immune‐related pathways, including negative regulation of the CTLA4 inhibitory pathway. Higher TEAD3 expression portended shorter overall survival (OS) and disease‐free survival (DFS) in patients with gliomas based on clinical samples. Conclusions. TEADs are overexpressed in gliomas and are associated with a poor prognosis. Importantly, this study discovered that TEADs influence the immunological milieu of glioma by modulating genes associated with immune infiltration.

Circulating Regulatory T Cells: A Novel Marker Associated with Liver Metastasis and the Treatment Response of Transarterial Embolization in Gastroenteropancreatic Neuroendocrine Tumors

Introduction: The aim of this study was to investigate the role of circulating regulatory T cells (Tregs) as a novel marker associated with liver metastases and treatment response to transarterial embolization (TAE) in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Methods: Circulating Tregs, defined as the CD4+CD25+CD127low/− population, were examined by flow cytometry in peripheral blood mononuclear cells from patients with GEP-NETs. Clinicopathological parameters, radiologic response, and hepatic progression-free survival (hPFS) data were collected. Results: The association between circulating Tregs and clinicopathological parameters was analyzed in 139 GEP-NET patients. Higher Treg levels were significantly associated with more progressive clinical features, including a higher WHO grade, more advanced TNM stage, and the presence of liver metastases. A Treg level ≥8.015% distinguished between patients with and without liver metastases. Among a cohort of 51 GEP-NET patients who were subjected to TAE for reducing liver metastasis burden, patients with higher Treg levels depicted unfavorable responses and significantly reduced hPFS after TAE treatment. We also revealed that patients with Treghigh (≥8.975%) displayed significantly shorter median hPFS than patients with Treglow (<8.975%). Additionally, after adjusting for other confounding clinical parameters, the association between Tregs and treatment response as well as hPFS remained significant, suggesting that Tregs may have a strong and independent prognostic impact in GEP-NETs. Conclusion: Our data suggest that circulating Tregs are a novel immunological marker associated with liver metastases and treatment response to TAE in patients with GEP-NETs.