Atypical Meningioma Research Articles

Radiopathologic predictors of recurrence in patients with a gross totally resected atypical meningioma

ABSTRACT Background Atypical meningiomas (AM) comprise a heterogeneous conglomeration of meningiomas with higher local recurrence rates than their benign counterparts. Although adjuvant therapy following subtotal resection is the standard, the use of adjuvant therapy following gross total resection (GTR) remains controversial. This study seeks to add to the literature by identifying radiopathologic predictors of recurrence in patients with a GTR AM and better identify those patients who may benefit from adjuvant therapy. Methods A total of 103 consecutive patients who received gross total resection for AM at our center between Apr 2010 and Apr 2019 were evaluated retrospectively. Recurrence was defined as new enhancing masses on MRI without requiring biopsy confirmation. Cumulative incidence plots were used to estimate survival, and the log-rank test was used to assess differences between groups. Cox proportional hazards models were used to evaluate the effect of radiopathologic variables on the hazard of recurrence. Results Of the 103 patients included in this study, 68 (66.0%) were female, and the mean age was 51.1 ± 11.4. The median overall survival for patients following surgery was 71 months while the median progression-free survival was 64 months. Recurrence occurred in 36 (35.0%) patients. Factors correlated with AM recurrence following GTR included peritumoral edema (p = 0.005), necrosis (p < 0.001), mitotic rate greater than 7/10 high-power field (HPF) (p < 0.001), and Ki67 > 15% (p < 0.001). However, following Cox proportional hazards regression analysis, only mitotic rate greater than 7/10HPF (p = 0.018) and Ki67 > 15% (p = 0.035) were significantly associated with AM recurrence. Conclusions Our results showed high mitotic index (greater than 7/10 HPF) and Ki67 greater than 15% as independent predictors of recurrence in patients with a GTR AM. These findings could help stratify patients who may benefit from adjuvant therapy. Abbreviations: AM: Atypical meningiomas; GTR: gross total resection; HPF: high power field; STR: subtotal resection; RFS: recurrence-free survival

Long-Term Outcomes for Patients With Atypical or Malignant Meningiomas Treated With or Without Radiation Therapy: A 25-Year Retrospective Analysis of a Single-Institution Experience

PurposeAtypical (World Health Organization [WHO] grade 2) and malignant (WHO grade 3) meningiomas have high rates of local recurrence, and questions remain about the role of adjuvant radiation therapy (RT) for patients with WHO grade 2 disease. These patients frequently require salvage therapy, and optimal management is uncertain given limited prospective data. We report on the long-term outcomes for patients with atypical and malignant meningiomas treated with surgery and/or RT at our institution. Methods and MaterialsData were collected through a retrospective chart review for all patients with WHO grade 2 or 3 meningiomas treated with surgery and/or RT at our institution between January 1992 and March 2017. Progression-free survival (PFS) and overall survival (OS) were described using the KaplanMeier estimator. The outcomes in the subgroups were compared with a log-rank test. A Cox proportional hazards model was used for the univariable and multivariable analyses of predictors of PFS. ResultsA total of 66 patients were included in this analysis. The median follow-up was 12.4 years overall and 8.6 years among surviving patients. Fifty-two patients (78.8%) had WHO grade 2 meningiomas, and 14 patients (21.2%) had WHO grade 3 disease. Thirty-six patients (54.5%) were treated with surgery alone, 28 patients (42.4%) with surgery and adjuvant RT, and 2 patients (3%) with RT alone. Median PFS and OS were 3.2 years and 8.8 years, respectively. PFS was significantly improved with adjuvant RT compared with surgery alone (hazard ratio, 0.36; 95% confidence interval, 0.18-0.70). Patients with Ki-67 index >10% showed a trend toward worse PFS compared with patients with Ki-67 ≤10% (hazard ratio, 0.51; 95% confidence interval, 0.25-1.04). No significant differences in PFS or OS were observed with respect to Simpson or WHO grade. ConclusionsFor patients with atypical or malignant meningiomas, adjuvant RT was associated with significantly improved PFS, and Ki-67 index >10% was associated with a trend toward worse PFS. Given the long-term survival, high recurrence rates, and efficacy of salvage therapy, patients with atypical and malignant meningiomas should be monitored systematically long after initial treatment.

Imaging characteristics, histopathological features and surgical considerations regarding aggressive meningiomas

Meningiomas are tumours of the meninges that arise primarily from arachnoidal cap cells, but they can also occur rarely as primary tumours in other localizations, such as within the ventricles. They stand for 24-30% of primary intracranial tumours and affect mostly women in their middle age or later adult life [1, 2]. Meningiomas can be classified, according to the World Health Organization (WHO) classification of Central Nervous System (CNS) tumours, as benign (grade I, most frequently encountered type), atypical (grade II) or anaplastic (grade III), based mostly on histopathological criteria known to be associated with tumour progression, recurrence risk and survival. Since meningioma grading based on the WHO classification is the most important factor determining therapeutic management and tumour prognosis, there has been an increasing interest in adding new criteria for better characterization of these tumours. Thus, the 2016 edition of the WHO classification recognized brain invasion as an independent criterion for atypical (grade II) meningioma diagnosis [3]. However, meningiomas that display aggressive features such as rapid growth and higher recurrence rate, can also involve blood vessels and bone. Hence, the authors aim to describe a different entity, aggressive meningiomas, not previously listed as a tumour phenotype in the WHO classification of meningothelial-cell tumours, with regard to pre-, intra- and postoperative methods for diagnosis and explore the implications on surgical strategies and adjuvant therapy.

Clinicopathological features, imaging characteristics and surgical management in a novel tumour entity - aggressive meningiomas

Meningiomas are common neoplasms of the central nervous system, comprising between 24 and 30% of primary intracranial tumours, most commonly affecting females in their middle age or later adult life [1] [2].&#x0D; Meningiomas are classified as benign, atypical or anaplastic meningiomas depending mostly on histopathological criteria known to be associated with worse prognosis in terms of tumour progression, recurrence risk after surgery and overall survival. The 2016 edition of the World Health Organization (WHO) classification of Central Nervous System (CNS) tumours recognizes brain invasion as an independent criterion for diagnosing an atypical grade II meningioma [3]. Meningioma grading based on the WHO classification of CNS tumours thoroughly impacts therapeutic management and tumour prognosis.&#x0D; Aggressive meningiomas, a different phenotype of tumours, characterized by rapid growth and involvement of adjacent brain tissue, blood vessels and bone, was not previously listed as an independent entity in the WHO classification of meningothelial-cell tumours. &#x0D; Regarding the increasing importance of tumour grading in meningioma treatment strategies, the authors here provide an overview of clinicopathological and radiographic features, surgical management and long-term prognosis of this novel meningothelial tumour entity, the aggressive meningioma. In particular, we aimed to describe pre-, intra- and postoperative methods for recognizing aggressive meningiomas and explore the implications of this diagnosis on both surgical strategies and adjuvant therapy.

Differentiating atypical meningioma from anaplastic meningioma using diffusion weighted imaging

PurposeTo explore the value of MRI conventional features and apparent diffusion coefficient (ADC) on the differential diagnosis of atypical meningioma (AtM) and anaplastic meningioma (AnM). Materials and methodsThis retrospective study analyzed the preoperative clinical data, MRI conventional features, and DWI data of 55 AtM and 25 AnM confirmed by pathology in our hospital. The clinical features, MRI conventional features, ADCmean, ADCmin, and relative ADC (rADC) values were compared between the two tumors by Chi-square test or an independent sample t-test. Receiver operating characteristic curve (ROC) and binary logistic regression analysis were used to evaluate the diagnostic efficacy of each parameter to differentiate between these tumors. ResultsThe MRI conventional features had a certain ability to distinguish AnM and AtM, with an area under the curve value (AUC) of 0.824 (95% CI, 0.723–0.900). The ADCmean, ADCmin, and rADC values were significantly higher in AtM compared to AnM (all P < 0.05). ADCmean had the best identification effect with an AUC of 0.867 (95% CI, 0.772–0.933) among them, at an cut-off of 0.817 × 10−3 mm2/s, the sensitivity and specificity of distinguishing AtM from AnM were 78.18% and 88.00%, respectively. A combination of ADCmean and MRI conventional features showed the optimum discrimination ability for the two tumors, the AUC, sensitivity, specificity, and accuracy were 0.918 (95% CI, 0.835–0.967), 80.00%, 94.55%, and 90.00%, respectively. ConclusionMRI conventional features combined with ADCmean, as a non-invasive method, has potential clinical value in the preoperative diagnosis of AtM and AnM.

Clinical Implications of the Mitotic Index as a Predictive Factor for Malignant Transformation of Atypical Meningiomas.

ObjectiveIntracranial atypical meningiomas have a poor prognosis and high rates of recurrence. Moreover, up to one-third of the recurrences undergo high-grade transformation into malignant meningiomas. We aimed to investigate the clinical factors that can predict the propensity of malignant transformation from atypical to anaplastic meningiomas. MethodsBetween 2001 and 2018, all patients with atypical meningioma, in whom the tumors had undergone malignant transformation to anaplastic meningioma, were included. The patients’ medical records documenting the diagnosis of atypical meningioma prior to malignant transformation were reviewed to identify the predictors of transformation. The control group comprised 56 patients with atypical meningiomas who were first diagnosed between January 2017 and December 2018 and had no malignant transformation. ResultsNine patients in whom the atypical meningiomas underwent malignant transformation were included. The median time interval from diagnosis of atypical meningioma to malignant transformation was 19 months (range, 7–78). The study group showed a significant difference in heterogeneous enhancement (77.8% vs. 33.9%), bone invasion (55.6% vs. 12.5%), mitotic index (MI; 14.8±4.9 vs. 3.5±3.9), and Ki-67 index (20.7±13.9 vs. 9.5±7.1) compared with the control group. In multivariate analysis, increased MI (odds ratio, 1.436; 95% confidence interval, 1.127–1.900; p=0.004) was the only significant factor for predicting malignant transformation. ConclusionAn increased MI within atypical meningiomas might be used as a predictor of malignant transformation. Tumors at high risk for malignant transformation might require more attentive surveillance and management than other atypical meningiomas.

Progestin-related WHO grade II meningiomas behavior-a single-institution comparative case series.

WHO grade II progestin-related meningiomas have been reported in recent series but we found no previous study describing their long-term outcome. Our study aimed to evaluate patients operated on for high-grade intracranial meningioma and who underwent long-term exposure to high dose of cyproterone acetate, nomegestrol acetate, and chlormadinone acetate. Our study retrospectively included 9 patients with high-grade progestin-related intracranial meningioma between December 2006 and September 2021. In each patient, clinico-radiological follow-up was performed every 6months after diagnosis and treatment withdrawal recommendation. The mean progestative exposure was 11.4years. Edema existence or absence of cleft sign on MRI were the key factors for surgical indication. All patients underwent surgery. Adjuvant radiotherapy was indicated in 1 patient, and Gamma Knife radiosurgery was proposed in 2 other patients for a second location of meningioma. Six patients harbored a grade II chordoid meningioma subtype with 100% PR expression and 3 patients a grade II atypical meningioma subtype with lower PR expression. The mean follow-up was 8.1years and none of the 9 patients presented with a recurrence. Patients with grade II progestin-related meningiomas have less tumor recurrence after surgery than patients with sporadic grade II meningiomas, especially after progestin withdrawal. The presence/appearance of peri-meningioma edema and the absence of cleft sign before volumetric change should suggest the existence of an underlying WHO grade II meningiomas. In these cases, surgical resection may immediately be considered and adjuvant radiotherapy should be reserved for proven recurrence cases.

FDG avid cerebellar atypical meningioma masquerading as solitary brain metastases in a recently diagnosed breast malignancy: a toss between MR and CT

BackgroundSUV Max is a glycolytic index obtained from PET imaging, relates to tumour cell proliferation. FDG uptake (i.e. SUV max) is found to be high in aggressive tumours and is used to identify malignant from benign pathologies. Meningiomas are intracranial tumours which display varying grades of FDG avidity based on its biological aggressiveness. Benign grade I meningiomas are FDG non-avid, while the rest of the typical and atypical meningiomas show varying degrees of FDG avidity. Uptake of FDG can be high in certain infectious and inflammatory brain etiologies and pose a diagnostic challenge in differentiating benign brain lesions from neoplasms. MRI is the preferred modality for accurately identifying meningiomas, providing superior contrast differentiation and its ability to differentiate extra-axial from intra-axial brain lesions. CT is said to be superior in specific types of meningioma where there is calcification and adjacent changes in calvarium. Although typical meningiomas have characteristic MRI features, care must be taken to avoid misleading diagnosis between brain tumours and atypical meningiomas.Case presentationWe are presenting a recently diagnosed case of invasive breast carcinoma (Ca) referred for staging by PET/MR imaging. Based on atypical DWI and ADC map findings, MRI falsely reported an atypical meningioma as a brain metastasis. Abnormal intense FDG uptake was noted in a well-defined homogeneously enhancing mass lesion in posterior fossa in left paramedian aspect and broad base to left transverse sinus protruding into left cerebellar hemisphere. Atypical meningioma Grade III, i.e. papillary meningioma was later histologically proven.ConclusionsWe wish to highlight the inconsistency of DWI and ADC map MR findings in papillary meningioma masquerading as solitary brain metastases in a Ca breast patient on 18F FDG PET/MR imaging. From an imaging standpoint, it is important to recognize the variable and pleomorphic features exhibited by meningiomas in MR based on atypical location, histological subtypes, and biologic behaviours. Further FDG PET was incremental in displaying a high SUV max indicating biologic aggressiveness of lesion and correlating with the CT diagnosis of papillary meningioma.

Totally Endoscopic Resection of Recurrent Convexity Meningioma Following Multiple Surgeries: Oblique Trajectory to Avoid Manipulation of a Vascularized Free Flap: A Technical Note

Endoscopic surgery is widely used for intraventricular and skull base tumor resections; however, its utility is not limited to deep parts of the brain. A 73-year-old female presented with left-side hemiparesis and seizures due to a relapsed atypical meningioma of convexity. The tumor was located just under a synthetic bone substitute and was covered by a delicate myocutaneous free flap, preventing the usual skin incision route to approach the lesion. The tumor was successfully removed using an endoscope without damaging the flap. With the aid of an endoscope, a superficial meningioma could be removed with the affected dura through a small craniotomy.

Variations and natural history of primary intraparenchymal lesions associated with neurofibromatosis type 2.

The study aimed to investigate the clinical implications and natural history of primary intraparenchymal lesions in patients with neurofibromatosis type 2. Radiological findings of 15 neurofibromatosis type 2 cases were retrospectively collected. Twenty-seven primary intraparenchymal lesions were observed in 7 out of 15 patients (47%). Cortical/subcortical T2 hyperintense lesions and enlarged Virchow-Robin spaces were the most common findings in five and four patients, respectively. During the follow-up period (median 84months), one new primary intraparenchymal lesion was identified and increased lesions were observed in two cases on contrast-enhanced MRI. Surgical resection was performed in one case pathologically diagnosed with atypical meningioma. Twenty-five other lesions without contrast enhancement presented no apparent growth during follow-up. Although most primary intraparenchymal lesions are benign, a subset of cases would present newly developed or increased lesions on contrast-enhanced MRI. Careful monitoring is necessary for such cases, and pathological confirmation should be considered.

Stereotactic Radiosurgery for Atypical (World Health Organization II) and Anaplastic (World Health Organization III) Meningiomas: Results From a Multicenter, International Cohort Study

Shepard, Matthew J MD; Xu, Zhiyuan MD; Kearns, Kathryn BS; Li, Chelsea BS; Chatrath, Ajay BS; Sheehan, Kimball; Sheehan, Darrah; Faramand, Andrew MD, MSc; Niranjan, Ajay MD, MBA; Kano, Hideyuki MD, PhD; Gurewitz, Jason BA; Bernstein, Kenneth MS; Liscak, Roman MD; Guseynova, Khumar MD; Grills, Inga S MD; Parzen, Jacob S MD; Cifarelli, Christopher P MD, PhD; Rehman, Azeem A MD; Atik, Ahmet MD; Bakhsheshian, Joshua MD; Zada, Gabriel MD; Chang, Eric MD; Giannotta, Steven MD; Speckter, Herwin MSc; Wu, Hsiu-mei MD; Kondziolka, Douglas MD; Golfinos, John G MD; Mathieu, David MD; Lee, Cheng-chia MD PhD; Warnick, Ronald E MD; Lunsford, L Dade MD; Sheehan, Jason P MD PhD

RADT-31. TREATMENT TRENDS AND SURVIVAL OUTCOMES IN ATYPICAL MENINGIOMA

Abstract BACKGROUND WHO grade II (atypical) meningiomas are treated with surgical resection, often followed by adjuvant fractionated radiation therapy (FRT). The increased availability of frameless stereotactic radiosurgery (SRS) presents an opportunity to offer patients a high biological effective dose over fewer fractions. Here we study the patterns of care and outcomes of these two forms of adjuvant RT. METHODS Patients with atypical meningioma were abstracted from the National Cancer Database (NCDB). Descriptive statistics were reported, and differences between treatment groups were assessed using either a chi-square test or ANOVA. Patients were grouped by treatment type and Kaplan Meier (KM) analysis was performed to compare overall survival (OS) using a log rank test. Univariable (UVA) and multivariable (MVA) cox regression analyses were completed. RESULTS Of 10,015 cases diagnosed from 2004-2016, 7,153 received surgery alone, 2,059 received surgery and adjuvant FRT (S+RT), and 362 received adjuvant SRS (S+SRS). The use of adjuvant RT increased by 71.8% for S+RT and 97.8% for S+SRS. In 2004, 15.1% of 443 registered patients received S+RT and 2.26% received S+SRS, while in 2016 these figures were 26.0% and 4.47%, respectively, for the 1051 registered patients (p&amp;lt; 0.001 and 0.022, respectively). For the 8,636 patients with survival data there was no significant difference in median OS between S+RT and S+SRS (130 months vs. 125 months, log rank p=0.935). On UVA, S+RT conferred better survival compared to surgery alone (HR 0.81 [0.72-0.91], p&amp;lt; 0.001) while S+SRS trended towards better survival (HR 0.82 [0.64-1.06], p=0.124). On MVA, no significant OS benefit was seen with S+RT (HR 0.96 [0.85-1.08], p=0.491) or S+SRS (HR 0.90 [0.69-1.16], p=0.413) versus surgery alone. CONCLUSIONS While the use of adjuvant RT for atypical meningioma has increased substantially since 2004, OS is comparable between FRT and SRS. The data presented here support further prospective investigation of adjuvant SRS.

RADT-28. RECURRENT MENINGIOMA WITH 1p/22q SOMATIC MUTATION OF GNAS: A CASE REPORT

Abstract OBJECTIVE Refractory meningioma faces the problems of low total resection rate, high recurrence rate and high disability rate. Here we report a patient with recurrent refractory meningioma who was benefited from precision treatment plan based on molecular diagnosis. METHODS Molecular diagnosis by next generation sequencing (NGS) test was used to test the hybridized captured DNA in the tumor tissue of the patient. RESULTS The 53-year-old female diagnosed with meningioma was admitted to our hospital after tumor progression was observed for 3 weeks. She had received 4 operations for the tumor previously. The first three times of postoperative pathology indicated WHO Ⅰ grade meningioma. The fourth postoperative pathology showed excessive meningioma, with active growth of tumor cells in some areas and small focal necrosis, WHO Ⅰ- fair grade. Somatic mutation GNAS p.F309VFS *25 and deletion of the short arm of chromosome 1 / long arm of chromosome 22 were also found (1P / 22Q) by NGS test. The second recurrent foci showed partial amplification of 17q and 19, except for 1p/22q deletions, compared with the first. Meningiomas with 1p/22q deletion are type C meningiomas (more than half are grade WHO Ⅰ). Meningiomas have been shown to be highly vascularized neoplasms, with a 2-fold increase in VEGF expression in atypical meningiomas and a 10-fold increase in malignant meningiomas. According to the molecular diagnosis results, the precise treatment plan was determined: concurrent chemoradiotherapy, followed by anti-VEGF-targeted drugs combined with temozolomide for 2 months. The residual lesions were significantly reduced after treatment. CONCLUSION This case is the first to report a meningioma with pituitary tumor driver gene GNAS mutation, which is more prone to recurrence due to the combination of 1P / 22Q chromosome mutation. Molecular diagnosis can guide precise treatment to benefit patients.

TAMI-77. CHARACTERIZATION OF METABOLIC DIFFERENCES IN MENINGIOMAS USING TUMOR TISSUE AND PATIENT-DERIVED CELL LINES

Abstract As more information emerges on metabolic changes in brain pathologies, mass spectrometry methodologies are needed to investigate cellular changes in primary brain tumors. Many approaches use technologies that lack sensitivity and selectivity, which hinders discovering potential novel diagnostic and prognostic features. Fresh frozen tissue from 26 patients (57% women, 43% men, age 21-67) underwent surgical resection for newly diagnosed meningiomas. We used patient-derived cell lines and arachnoid cells to validate and compare metabolic differences in patient tumor tissue. Primary metabolism (GC-TOF), lipidomics, and biogenic amines (RPLC and HILIC-HRMS) were analyzed using 10 mg of tissue and 1x106 cells. RESULTS: Primary metabolism and lipidomics showed significant differences between Grade I and Grade II tumors. We identified over one thousand total metabolites through authentic standards and MS2 fragmentation patterns. Ascorbic Acid was enriched in Grade I tumors compared to Grade II and enriched in tumors compared to non-neoplastic dura tissue from the same patient. Lysosomal activation in atypical meningiomas is indicated by a 2-fold increase (compared to Grade I tumors) of Bis(monoacylglycero)phosphate metabolites. We grouped metabolites into fifteen classes based on chemical ontology and function. Statistically significant differences were observed in total amino acids (AA), basic AA, cyclic AA, sulfur-containing AA, branched-chain AA, dipeptides, histidine-containing dipeptides, vitamins and cofactors, glutathione metabolites, acylcarnitine’s, sphingomyelins, phosphatidylethanolamines, phosphatidylinositol’s, cardiolipins, and nucleic acids. Thymine-containing nucleic acids and biogenic monoamines were 2-fold higher in Grade I compared to Grade II tumors. Using novel untargeted metabolomics, we found multiple classes of metabolites that were enriched in Grade II meningiomas compared to Grade I. This points towards possible pathways that drive malignancy and biomarkers that could be useful for diagnosis, grading, and treatment selection.

CTIM-31. A PHASE II, OPEN-LABEL, SINGLE ARM TRIAL OF PEMBROLIZUMAB FOR REFRACTORY ATYPICAL AND ANAPLASTIC MENINGIOMA AND HEMANGIOPERICYTOMA

Abstract BACKGROUND Grade II and III meningiomas are invasive tumors which tend to recur following initial treatment and are associated with shorter survival (relative to grade I). Hemangiopericytoma (HPC) is a dural based tumor that originates in the pericytes. Treatment options for these tumors include surgical resection and radiation. There are no defined standard treatments after failure these modalities, and effective systemic treatments are lacking. This trial concept was developed following previous reports of high PD-L1 levels in anaplastic meningioma. We currently report our initial experience with pembrolizumab for refractory atypical/anaplastic meningioma (RAM) and HPC patients. METHODS This is a single arm, single institute, phase 2 trial. Inclusion criteria included patients with RAM or HPC whose all previous lines of treatment were exhausted. All patients were treated with pembrolizumab (200mg every 3 weeks) until disease progression. Primary endpoint was 6- and 12-months progression free survival (PFS). The study was planned for 25 patients and we report here preliminary results. RESULTS Through February 2021, 12 patients were enrolled to this study (two with HPC, 10 with RAM). After a median follow up of 18.5 months, the 6 and 12 months PFS were 25% and 16.7% respectively, with a median PFS of 2.75 months. Two patients had a partial response while all others progressed, making the overall response rate 16.7%. One of the responders had HPC and has been stable for 30 months, while the second had atypical meningioma and was stable for 13 months. Median survival has not been reached yet; 1 year survival rate was 82.5%. Grade 3 toxicities included hyperglycemia, elevated liver enzymes and fatigue, with no grade 4 or 5 toxicities. CONCLUSIONS Pembrolizumab induced a low response rate for RAM and HPC. However, a subset of patients might benefit from this treatment with a prolonged response period.

EXTH-72. TRANSLATIONAL INVESTIGATION OF TD139 FOR THE TREATMENT OF HIGH-GRADE MENINGIOMA

Abstract BACKGROUND High-Grade Meningioma (HGM), such as atypical and anaplastic meningiomas, represent a subgroup of meningiomas with histologic and clinical features suggesting aggressive behavior with a penchant for recurrence, even after surgical resection. Here, we postulate that high levels of Galectin-3 (Gal-3) affect the cellular composition and are at the root of the profoundly immunosuppressive tumor microenvironment of HGM. Our study aimed to validate the effect of the Gal-3 inhibitor (TD139) in in vivo. METHODS In vivo MGS2 murine models of HGM were utilized to assess efficacy of treatment with TD139 via intravenous injection. We used ELISA spot, RT-PCR and western blots techniques. MRI and immunohistochemistry -staining methods were used to detect tumor growth in in vivo following TD139 treatments. RESULTS Our results demonstrated a significantly elevated level of Gal-3 in both HGM tissue and serum when compared to non-tumor patients. Furthermore, Epithelial membrane antigen, Ki-67, and Transglutaminase 2 were highly expressed in HGM, whereas the number of observed cytotoxic T-cells in HGM was markedly decreased. When human PBMCs were activated with anti-CD3 (1µg/ml) and anti-CD28 (2µg/ml) antibodies and treated with recombinant Gal-3 protein (500ng/ml) for 96hr, we found reduced expression of T-Box Transcription Factor 21 and RAR Related Orphan Receptor C mRNA with concurrent upregulated expression of GATA Binding protein 3 and Forkhead box P3 mRNA. These findings support the concept that Gal-3 skews the differentiation of CD4+ T cells towards Th2 and Treg cells. In vivo treatment of TD139 (1mg/kg per day for 14 days) showed significant decrease (∼35%) in MGS2 tumor growth in orthotopic allograft model (at Day 41) and increased survival via multiple mechanism. Additionally, we observed an upregulation of CD38 (M1 macrophages) and CD8+ T cells in treated cells. CONCLUSIONS These findings suggest that TD139 may be an effective approach in the treatment of HGM patients.

CTIM-32. IMMUNE CHECKPOINT INHIBITOR NIVOLUMAB IN PEOPLE WITH RECURRENT SELECT RARE CNS CANCERS: RESULTS OF INTERIM ANALYSIS IN A HEAVILY PRETREATED COHORT

Abstract INTRODUCTION Standard and experimental therapies for patients with rare CNS tumors are scarce. Nivolumab (PD-1 inhibitor) is approved for several non-CNS cancers. This ongoing Phase II trial (NCT03173950) will determine the efficacy of nivolumab in adults with recurrence/progression of one of 11 selected rare primary CNS tumors. Efficacy is measured by Disease Control Rate (DCR; confirmed CR/PR or durable SD for ≥ 6 months) in 2 cohorts: heavily and non-heavily pretreated patients (heavily pretreated: ≥ 3 prior therapies; non-heavily pretreated: ≤ 2). We report efficacy and safety results of a preplanned interim analysis in the heavily pretreated cohort. METHODS Eligibility includes recurrence/progression of an eligible tumor; age ≥ 18 years; tumor tissue available for histopathology, molecular and immune profiling; KPS ≥ 70; and no steroids at study entry. A total of 150 evaluable patients will be enrolled (75 to each cohort). Prior therapies include radiation and/or standard or investigational drugs. Nivolumab treatment is 240 mg IV every 2 weeks (4 doses); then 480 mg every 4 weeks (14 additional doses). Interim analysis was planned when sample size reached 32 in each cohort. RESULTS As of March 10, 2021, DCR exceeded the minimum required for interim analysis in the heavily pretreated cohort. Among 30 patients, 4 achieved SD &amp;gt; 6 months (medulloblastoma, anaplastic ependymoma, myxopapillary ependymoma, metastatic atypical meningioma). Safety profile (related AEs): grade 3 = 7; grade 4 = 1. Most frequent grade 3-5 AEs regardless of attribution: tumor progression (6); anemia, hydrocephalus, lymphopenia (3 each); cerebral edema, headache (2 each). CONCLUSION DCR exceeded the “go” boundary (i.e., &amp;gt; 2) in the heavily pretreated cohort. Nivolumab showed safety profile consistent with other studies. This cohort will continue to stage 2 and complete total accrual of 75 patients. The trial is currently being expanded to 10 additional sites across the BTTC/NCI-CONNECT consortium.

Molecular profile to guide personalized medicine in adult patients with primary brain tumors: results from the ProfiLER trial.

Immunohistochemistry and recent molecular technologies progressively guided access to personalized anti-tumoral therapies. We explored the feasibility, efficacy, and the impact of molecular profiling in patients with advanced brain tumors. This multicentric prospective trial ProfiLER enrolled patients with primary brain tumors, who have been pre-treated with at least one line of anti-cancer treatment, and for whom molecular profiles had been achieved using next-generation sequencing and/or comparative genomic hybridization on fresh or archived samples from tumor, relapse, or biopsies. A molecular tumor board weekly analyzed results and proposed molecular-based recommended therapy (MBRT). From February 2013 to December 2015, we enrolled 141 patients with primary brain tumor and analyzed 105 patients for whom tumor genomic profiles had been achieved. Histology mainly identified glioblastoma (N = 46, 44%), low-grade glioma (N = 26, 25%), high-grade glioma (N = 12, 11%), and atypical and anaplastic meningioma (N = 8, 8%). Forty-three (41%) patients presented at least one actionable molecular alteration. Out of 61 alterations identified, the most frequent alterations occurred in CDKN2A (N = 18), EGFR (N = 12), PDGFRa (N = 8), PTEN (N = 8), CDK4 (N = 7), KIT (N = 6), PIK3CA (N = 5), and MDM2 (N = 3). Sixteen (15%) patients could not be proposed for a MBRT due to early death (N = 5), lack of available clinical trials (N = 9), or inappropriate results (N = 2). Only six (6%) of the 27 (26%) patients for whom a MBRT had been proposed finally initiated MBRT (everolimus (N = 3), erlotinib (N = 1), ruxolitinib (N = 1), and sorafenib (N = 1)), but discontinued treatment for toxicity (N = 4) or clinical progression (N = 2). High-throughput sequencing in patients with brain tumors may be routinely performed, especially when macroscopic surgery samples are available; nevertheless delays should be reduced. Criteria for clinical trial enrollment should be reconsidered in patients with brain tumors, and a panel of genes specifically dedicated to neurologic tumors should be developed to help decision-making in clinical practice.

Adjuvant radiotherapy in grossly total resected grade II atypical meningiomas: a protective effect on recurrence?

Management of grade II atypical meningiomas (AM) remains controversial. Conflicting evidence exist on the possible protective effect of adjuvant radiotherapy (ART) on recurrence in grossly resected AMs. The aim of this meta-analysis is to evaluate the role of ART in grossly resected (Simpson grades 1-3) AMs on the recurrence and survival. Literature review was performed by the study investigators who handily queried the MEDLINE database using keywords and MeSH terms in different combinations using the Boolean operators "AND" or "OR," and database-related filters to maximize the chance to identify articles focusing on role of radiotherapy in atypical (WHO grade II) meningiomas. Data were retrieved from comparative studies of AMs undergone surgical resection alone vs. surgery + ART. Only grossly total resected AMs (Simpson grades 1-3) were included. The individual and pooled odds ratio (OR) for the crude recurrence, progression free survival (PFS) at 1, 3 and 5-years, as well as for the overall survival (OS) at 5-years were calculated by using the Mantel-Haenszel model in surgery alone vs. surgery + ART. Eleven studies were considered eligible. 8 were included for the outcome "crude recurrence;" 6 for PFS at 1-3 years, 7 for PFS at 5-years; 6 for the OS at 5-years. Results suggest that surgery + ART might have a protective role on recurrence in gross-totally resected AMs (OR:1.66). Specifically, surgery + ART slightly improved PFS at 1-year (OR:0.92) and more consistently at 3- and 5-years (OR:0.31 and 0.35 respectively) hence favoring a combined approach. Current literature on the impact of ART after gross total resection of AM are still heterogeneous and not systematically reported. The present meta-analysis suggests a possible protective role of postoperative RT against long-term recurrence as compared to surgical resection alone.

Cordoid Meningioma A Case Report

Introduction: Meningiomas are tumors of the central nervous system derived from the arachnoid layer of cells, represent less than 3% of all primary intracranial tumors in children, are prevalent in adolescents, and are rare in younger ages. Pediatric cases represent approximately 1.5% of all intracranial meningiomas, and very few cases show aggressive histology. The WHO classification meningioma divided into three grades: Grade I benign; II, atypical; and III, anaplastic / malignant. Chordoid meningioma grade II / atypical meningioma is a rare subtype, which represents only 0.5% of all meningiomas, have high growth rates, higher recurrence and greater possibilities to invade the brain parenchyma compared with meningiomas benign. One possible explanation for the high recurrence rate may be related to the quality mucoid stroma, which facilitates extension of tumor and makes it difficult to achieve a complete resection, which leads to subsequent recurrence. Case Report: We report the case of male patient 4 years of age diagnosed with meningioma Grade II, with clinic 2 months of evolution who presented progressive neurological deterioration, tumoral exeresis was performed in 3 opportunities and placement system ventriculo peritoneal in the course of 1 month and radiotherapy. Comments: Accurate diagnosis, therefore, assumes importance because these tumors have an aggressive clinical course and high probability of recurrence so knowing the pathological Clinical Aspects of this rare neoplasm is essential for the Treatment and Comprehensive monitoring.