CNS WHO Research Articles

SYSTEMIC INFLAMMATORY INDICES IN PATIENTS WITH MALIGNANT GLIOMAS AND EFFECTS OF PLATELET SECRETOME IN VITRO.

To date, no significant clinical progress has been achieved in the treatment of brain malignant gliomas (MG), and the active search for non-invasive circulating biomarkers continues. The prognostic significance of the ratio of the main peripheral blood cell populations of patients with MG is evaluated. Considerable attention is paid to the secretome of platelets (Pt) of peripheral blood. To evaluate the indicators of the peripheral blood cell population ratios in patients with brain MG and to study the influence of the secretome of Pt (SPt) of the peripheral blood of patients with brain MG in cell cultures in vitro. We studied samples of peripheral blood from patients with glioma CNS WHO grade G2 (n = 5), G3 (n = 12), and G4 (n = 20). The peripheral blood cell counts were analyzed in the preoperative period on an automatic hematology analyzer. The in vitro study of SPt was performed on the U251 human glioblastoma cell line cultured with SPt from MG patients or SPt pre-incubated with anti-TGF-β1 antibody. Cell cultures were observed for 72 h, and mitotic index (MI) was calculated. In MG patients, the count of peripheral blood leukocytes and neutrophils increased (p < 0.05). The neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammation index (SII) increased by 2-3 times compared to control. Nevertheless, correlation analysis did not reveal significant relationships between quantitative indicators of peripheral blood cells and the tumor malignancy degree in MG patients. The MI in U251 cells increased under the influence of SPt from patients with MG (p < 0.021), correlated with the tumor degree of malignancy (r = 0.246, p = 0.014). Pre-incubation of SPt with anti-TGF-β1 antibody tends to neutralize this promitotic effect. In MG patients, the integral indicators of NLR and SII increased but no significant relationship with the degree of tumor malignancy was found. In U251 cells, promitotic effects of SPt of MG patients partially decreased by anti-TGF-β1 antibody.

The role of preoperative [11C]methionine PET in defining tumor-related epilepsy and predicting short-term postoperative seizure control in temporal lobe low-grade gliomas.

Surgery is the mainstay of treatment for low-grade glioma (LGG)-related epilepsy. However, the goal of achieving both oncological radical resection and seizure freedom can be challenging. PET with [11C]methionine (MET) has been recently introduced in clinical practice for the management of patients with LGGs, not only to monitor the response to treatments, but also as a preoperative tool to define the metabolic tumor extent and to predict tumor grading, type, and prognosis. Still, its role in defining tumor-related epilepsy and postoperative seizure outcomes is limited. The aim of this preliminary study was to investigate the role of MET PET in defining preoperative seizure characteristics and short-term postoperative seizure control in a cohort of patients with newly diagnosed temporal lobe low-grade gliomas (tLGGs). Patients with newly diagnosed and histologically proven temporal lobe grade 2/3 gliomas (2021 WHO CNS tumor classification) who underwent resection at the authors' institution between July 2011 and March 2021 were included in this retrospective study. MET PET images were acquired, fused with MRI scans, and qualitatively and semiquantitatively analyzed. Any eventual PET/MRI involvement of the temporomesial area, seizure characteristics, and 1-year seizure outcomes were reported. A total of 52 patients with tLGGs met the inclusion criteria. MET PET was positive in 41 (79%) patients, with a median metabolic tumor volume of 14.56 cm3 (interquartile range [IQR] 6.5-28.2 cm3). The median maximum and mean tumor-to-background ratio (TBRmax, TBRmean) were 2.24 (IQR 1.58-2.86) and 1.53 (IQR 1.37-1.70), respectively. The metabolic tumor volume was found to be related to the presence of seizures at disease onset, but only in noncodeleted tumors (p = 0.014). Regarding patients with uncontrolled seizures at surgery, only the temporomesial area PET involvement showed a statistical correlation both in the univariate (p = 0.058) and in the multivariate analysis (p = 0.030). At 1-year follow-up, seizure control was correlated with MET PET-derived semiquantitative data. Particularly, higher TBRmax (p = 0.0192) and TBRmean (p = 0.0128) values were statistically related to uncontrolled seizures 1 year after surgery. This preliminary study suggests that MET PET may be used as a preoperative tool to define seizure characteristics and outcomes in patients with tLGGs. These findings need to be further validated in larger series with longer epileptological follow-ups.

The Clinicopathological Profile and Recurrence of Meningioma at Department of Anatomical Pathology, Faculty of Medicine, Universitas Indonesia/Dr. Cipto Mangunkusumo Hospital

Background Meningioma represents the most frequent primary intracranial tumor, and some subtypes may demonstrate aggressive characteristics with a correspondingly elevated risk of recurrence. To predict the likelihood of recurrence, clinical and pathological parameters are essential. More aggressive treatment strategies and strict follow-up can be implemented using these parameters. Therefore, this study aims to determine clinicopathological characteristics of meningioma and its relationship with recurrence. Method This study adopted a retrospective cross-sectional approach using secondary data of meningioma cases from the archives of the Department of Anatomical Pathology, Faculty of Medicine, Universitas Indonesia/Dr. Cipto Mangunkusumo Hospital in 2019-2021. The clinical data were obtained through electronic medical records, and histopathological data assessment, including grade, mitosis, brain invasion, bone invasion, and dural invasion, was conducted through microscopic examination. Result The data indicate that a total of 219 cases of meningioma were reassessed. The mean age of patients was 45±11 years, and the majority (88.1%) were female. The mean tumor size was 5±1.8 cm, with the most common tumor location being the skull base (71%) and 38.6% of cases showed radiological evidence of bone invasion. Subtotal resection was the treatment of choice for most patients (67.8%). CNS WHO grade 1 was found in 91.8% of cases, while Mitotic index ≥4/10 HPF, microscopic evidence of bone invasion, brain invasion, and dural invasion were found in 5%, 33.6%, 3.2%, and 16.8%, respectively. A minimum follow-up of 6 months was fulfilled by 71 cases, and 28% experienced recurrence/progression. These findings showed a significant association between the extent of resection (p=0.007) and tumor size (p=0.02) with the incidence of recurrence. Conclusion Clinical parameters such as the extent of resection and tumor size play a role in predicting the likelihood of meningioma recurrence. The predictive factors knowledge for meningioma recurrence is important in determining treatment strategies and follow-up

Efficacy and safety of cysto-ventricular catheter implantation for space-occupying cysts arising from glioma and brain metastasis: a retrospective study

BackgroundCysto-ventricular catheters (CVC) have emerged as promising treatment option for cystic craniopharyngioma and arachnoid cysts, but their effectiveness in treating cysts originating from glioma or brain metastasis (BM) remains limited. This study aimed to analyze the efficacy of CVC in patients with glioma and BM as well as procedure-associated morbidity.MethodsThis single-center retrospective study included all patients treated with CVC placement for acquired space-occupying cysts deriving from previously treated glioma or BMs between 1/2010 and 12/2021.ResultsA total of 57 patients with a median age of 47 years (IQR 38–63) were identified. Focal neurological deficits were the predominant symptoms in 60% of patients (n = 34), followed by cephalgia in 14% (n = 8), and epileptic seizures in 21.1% (n = 12). Accurate CVC placement was achieved in all but one case requiring revision surgery due to malposition. Three months after CVC implantation, 70% of patients showed symptomatic improvement. Multivariate logistic regression analysis identified the development of space-occupying cysts later in the course of the disease (OR 1.014; p = 0.04) and a higher reduction of cyst-volume postoperatively (OR 1.055; p = 0.05) were significant predictors of postoperative symptomatic improvement following CVC placement. Local cyst recurrence was observed in three cases during follow-up MRI after an average time of 5 months (range 3–9 months). Further complications included secondary malresorptive hydrocephalus in three cases and meningeosis neoplastica in one patient.ConclusionsStereotactic implantation of CVC is an efficient treatment option for patients suffering from symptomatic space-occupying cysts from BMs or glioma, independently from their CNS WHO grade. However, a vigilant approach is crucial regarding potential complications and treatment failures.

Improved prognostic stratification of patients with isocitrate dehydrogenase-mutant astrocytoma

Prognostic factors and standards of care for astrocytoma, isocitrate dehydrogenase (IDH)-mutant, CNS WHO grade 4, remain poorly defined. Here we sought to explore disease characteristics, prognostic markers, and outcome in patients with this newly defined tumor type. We determined molecular biomarkers and assembled clinical and outcome data in patients with IDH-mutant astrocytomas confirmed by central pathology review. Patients were identified in the German Glioma Network cohort study; additional cohorts of patients with CNS WHO grade 4 tumors were identified retrospectively at two sites. In total, 258 patients with IDH-mutant astrocytomas (114 CNS WHO grade 2, 73 CNS WHO grade 3, 71 CNS WHO grade 4) were studied. The median age at diagnosis was similar for all grades. Karnofsky performance status at diagnosis inversely correlated with CNS WHO grade (p < 0.001). Despite more intensive treatment upfront with higher grade, CNS WHO grade was strongly prognostic: median overall survival was not reached for grade 2 (median follow-up 10.4 years), 8.1 years (95% CI 5.4–10.8) for grade 3, and 4.7 years (95% CI 3.4–6.0) for grade 4. Among patients with CNS WHO grade 4 astrocytoma, median overall survival was 5.5 years (95% CI 4.3–6.7) without (n = 58) versus 1.8 years (95% CI 0–4.1) with (n = 12) homozygous CDKN2A deletion. Lower levels of global DNA methylation as detected by LINE-1 methylation analysis were strongly associated with CNS WHO grade 4 (p < 0.001) and poor outcome. MGMT promoter methylation status was not prognostic for overall survival. Histomolecular stratification based on CNS WHO grade, LINE-1 methylation level, and CDKN2A status revealed four subgroups of patients with significantly different outcomes. In conclusion, CNS WHO grade, global DNA methylation status, and CDKN2A homozygous deletion are prognostic in patients with IDH-mutant astrocytoma. Combination of these parameters allows for improved prediction of outcome. These data aid in designing upcoming trials using IDH inhibitors.

Prediction of WHO grade and methylation class of aggressive meningiomas: Extraction of diagnostic information from infrared spectroscopic data.

Infrared (IR) spectroscopy allows intraoperative, optical brain tumor diagnosis. Here, we explored it as a translational technology for the identification of aggressive meningioma types according to both, the WHO CNS grading system and the methylation classes (MC). Frozen sections of 47 meningioma were examined by IR spectroscopic imaging and different classification approaches were compared to discern samples according to WHO grade or MC. IR spectroscopic differences were more pronounced between WHO grade 2 and 3 than between MC intermediate and MC malignant, although similar spectral ranges were affected. Aggressive types of meningioma exhibited reduced bands of carbohydrates (at 1024cm-1) and nucleic acids (at 1080cm-1), along with increased bands of phospholipids (at 1240 and 1450cm-1). While linear discriminant analysis was able to discern spectra of WHO grade 2 and 3 meningiomas (AUC 0.89), it failed for MC (AUC 0.66). However, neural network classifiers were effective for classification according to both WHO grade (AUC 0.91) and MC (AUC 0.83), resulting in the correct classification of 20/23 meningiomas of the test set. IR spectroscopy proved capable of extracting information about the malignancy of meningiomas, not only according to the WHO grade, but also for a diagnostic system based on molecular tumor characteristics. In future clinical use, physicians could assess the goodness of the classification by considering classification probabilities and cross-measurement validation. This might enhance the overall accuracy and clinical utility, reinforcing the potential of IR spectroscopy in advancing precision medicine for meningioma characterization.

Treatment Outcomes after Dose-Escalated Moderately Hypofractionated Radiotherapy for Frail Patients with High-Grade Glioma.

For high-grade glioma (HGG) patients with old age or poor performance status, hypofractionated radiotherapy (hypoRT) in 10-15 fractions is recommended. Also, limited data exist on the impact of salvage treatment after progression in frail patients. We retrospectively analyzed the outcomes of dose-escalated hypoRT in 40 frail HGG patients who were treated with hypoRT between 2013 and 2021. With a median biologically effective dose of 71.7 Gy, a total dose of 56 Gy in 20 fractions was the most frequently used regimen (53.7%). The median age and Karnofsky Performance Status of patients were 74 years and 70, respectively. Most patients (n = 31, 77.5%) were diagnosed with glioblastoma, IDH-wildtype, CNS WHO grade 4. Only 10 (25.0%) patients underwent surgical resection, and 28 (70.0%) patients received concurrent temozolomide during hypoRT. With a median follow-up of 9.7 months, the median overall survival (OS) was 12.2 months. Of the 30 (75.0%) patients with disease progression, only 12 patients received salvage treatment. The OS after progression differed significantly depending on salvage treatment (median OS, 9.6 vs. 4.6 months, p = 0.032). Dose-escalated hypoRT in 20 fractions produced survival outcomes outperforming historical data for frail patients.

10179-NI-8 CLINICORADIOLOGICAL CHARACTERISTICS OF H3 K27-ALTERED THALAMIC GLIOMAS

Abstract BACKGROUND Diffuse midline glioma (DMG), H3 K27-altered (CNS WHO grade 4, 2021), exhibits diverse imaging features, and its characteristics have not yet been established. METHODS We retrospectively analyzed the imaging features and progression patterns of cases with H3p.K27M mutation in the thalamus, as part of the Kansai Molecular Diagnosis Network for CNS Tumors. RESULTS Among the H3p.K27M mutation cases accumulated from May 2007 to July 2022 (total 109 cases), 47 cases were located in the thalamus. The main tumor location was as follows: right side 23 cases, left side 19 cases, bilateral 4 cases and unknown 1 case. The tumor border was well-defined in 18 cases (38.3%), indistinct in 26 cases (55.3%), and uncertain in 3 cases (6.4%). Contrast enhancement was observed in 36 cases (76.6%), necrosis in 29 cases (61.7%), cyst formation in 11 cases (23.4%), peritumoral brain edema in 15 cases (31.9%), ventricular enlargement in 28 cases (59.6%), and evidence of cerebrospinal fluid dissemination on imaging in 8 cases (17.0%). The degree of tumor progression from the main tumor to the surrounding area was scored from 1 to 5 (mean: 3.5, median: 4). SURVIVAL RESULTS Among 43 cases with confirmed overall survival (OS) and progression-free survival (PFS), the median OS was 19.2 months (95% CI: 13.2-25.2), and the median PFS was 9.8 months (95% CI: 5.4-14.2). In univariate analysis, favorable prognostic factors were preoperative KPS 80 over(p = 0.007), and tumor progression score of 2 or less (p = 0.01). However, in multivariate analysis, only a tumor progression score of 2 or less remained the sole independent factor (p = 0.03, HR: 3.89, 95% CI: 1.14-13.3). DISCUSSION AND CONCLUSION A large-scale prospective study is needed, but in H3 K27M-mutant thalamic gliomas, the extent of tumor progression before surgery may be a prognostic factor.

10184-BT-14 CLINICAL FEATURE OF HEMISPHERIC GLIOMA WITH H3F3A, PEDIATRIC-TYPE HIGH GRADE GLIOMA, H3 K27-ALTERED, NEC AND DIFFUSE HEMISPHERIC GLIOMA, H3 G34-MUTANT, CNS WHO GRADE 4

Abstract INTRODUCTION Diffuse midline glioma (DMG), H3K27-altered, is a CNS WHO grade 4 glioma that usually located mainly in the brainstem, thalamus and spinal cord. However, DMG located in non-midline lesions are now described as pediatric-type high grade glioma, H3K27-altered, NEC (NDMG). On the other hand, diffuse hemispheric glioma, H3G34-mutant (DHG) located in the cerebral hemispheres, and is classified under the WHO 2021 classification. It is unknown that the differences in clinical characteristics of these hemispheric tumors with H3F3A mutations. In the present study, we report a comparative study of the clinical characteristics of two groups of NDMG and DHG. METHODS Among 4128 brain tumor samples collected in the Kansai Network for Molecular Diagnosis of Central Nervous System Tumors, 16 NDMG and 9 DHG cases were examined for comparison of clinical characteristics. RESULTS There were no differences in gender, tumor location, or pathology between NDMG and DHG. The median age was 47.3 years in NDMG and 26.2 years in DHG, and NDMG was significantly older than DHG (p=0.003). There was no significant difference in MGMT promoter methylation between NDMG and DHG (p=0.087). The Kaplan-Meier survival curve showed no significant difference, with a median survival of 495 days for NDMG and 587 days for DHG (p=0.765). There was no significant different survival rate between WHO grade 3 (n=15) and grade 4 (n=9) for pathological diagnosis. DISCUSSION AND CONCLUSION We compared the clinical characteristics of NDMG and DHG. There are some reports that NDMG and DHG gliomas located in non-midline lesion. Removing much tumor volume may improve the prognosis of non-midline glioma. We discuss the gliomas with H3F3A mutations located in a hemispheric lesions by literature review.

ED-1 PITUITARY TUMORS IN 5TH WHO CLASSIFICATION 2022: WHAT DO YOU MEAN BY PITNET?

Abstract It has been well known that the terminology has been changed from pituitary adenoma(4th WHO) which means benign epithelial tumors to pituitary neuroendocrine tumor(5th WHO 2022). It is apparent that the anterior pituitary cells and derived tumors contain intracytoplasmic neurosecretory granules and belong to neuroendocrine cells, and naturally neuroendocrine tumors. The pancreatic and gastrointestinal neuroendocrine neoplasms(NEN) are composed of well differentiated neuroendocrine tumors(NET) and poorly differentiated neuroendocrine carcinoma(NEC). NETs are potentially malignant(metastatic) tumors and are further graded to G1,G2,G3 by proliferative activities(mitoses or Ki-67 indices) showing correlation with prognosis . PitNET which means pituitary NET is now classified by transcription factors(PIT1,TPIT,SF1) and some tumors show clinical symptoms,(hormone production) invasive growth and rarely metastasize indicating potential malignant behavior. From this broad biological spectrum of PitNET, ICD-O coding /3(primary malignancy) has been proposed(5th WHO CNS, Pediatrics and Endocrine volumes). It has been known that some histological patterns (Sparsely granulated somatotroph PitNET, Crooke cell PitNET and others) are related more aggressive growth of PitNETs, but metastatic behavior is very hard to predict histologically. So in WHO 4th edition, the term pituitary carcinoma was used only after confirming metastasis or remote spread. The metastatic tumors are now called metastatic PitNETs. Five tiered grading by proliferation and invasion has been also proposed(Trouillas). Now we need more updated genomic studies such as single cell RNA sequencing to clarify biologic behavior of the individual PitNET cells to further clarify the their nature. . In my talk, several points of interests regarding PitNETs will be discussed by demonstrating histology and biology of representative cases.

Venous thromboembolism and intracranial hemorrhage in patients undergoing glioblastoma surgery

In the perioperative management of patients with glioblastoma (GBM), physicians face the question of whether and when to administer prophylactic or therapeutic anticoagulation (AC). In this study, we investigate the effects of the timing of postoperative heparinization on thromboembolic events (TE) and postoperative hemorrhage (bleeding, PH) as well as the interactions between the two in the context of an underlying intracerebral malignancy. For this retrospective data analysis, 222 patients who underwent surgery for grade IV glioblastoma, IDH-wildtype (2016 CNS WHO) between 01/01/2014 and 31/12/2019 were included. We followed up for 12 months. We assessed various biographical and clinical data for risk factors and focused on the connection between timepoint of AC and adverse events. Subgroup analyses were performed for pulmonary artery embolism (PE), deep vein thrombosis, and postoperative intracranial hemorrhage (PH) that either required surgical intervention or was controlled radiologically only. Statistical analysis was performed using Mann–Whitney U-Test, Chi-square test, Fisher’s exact test and univariate binomial logistic regression. p values below 0.05 were considered statistically significant. There was no significant association between prophylactic AC within 24 h and more frequent major bleeding (p = 0.350). AC in patients who developed major bleeding was regularly postponed by the physician/surgeon upon detection of the re-bleeding; therefore, patients with PH were anticoagulated significantly later (p = 0.034). The timing of anticoagulant administration did not differ significantly between patients who experienced a thromboembolic event and those who did not (p = 0.634). There was considerable overlap between the groups. Three of the six patients (50%) with PE had to be lysed or therapeutically anticoagulated and thereafter developed major bleeding (p < 0.001). Patients who experienced TE were more likely to die during hospitalization than those with major bleeding (p = 0.022 vs. p = 1.00). Prophylactic AC within 24 h after surgery does not result in more frequent bleeding. Our data suggests that postoperative intracranial hemorrhage is not caused by prophylactic AC but rather is a surgical complication or the result of antithrombotic therapy. However, thromboembolic events worsen patient outcomes far more than postoperative bleeding. The fact that bleeding may occur as a complication of life-saving lysis therapy in the setting of a thromboembolic event should be included in this cost–benefit consideration.

Temozolomide, Procarbazine and Nitrosoureas in the Therapy of Malignant Gliomas: Update of Mechanisms, Drug Resistance and Therapeutic Implications

The genotoxic methylating agents temozolomide (TMZ) and procarbazine and the chloroethylating nitrosourea lomustine (CCNU) are part of the standard repertoire in the therapy of malignant gliomas (CNS WHO grade 3 and 4). This review describes the mechanisms of their cytotoxicity and cytostatic activity through apoptosis, necroptosis, drug-induced senescence, and autophagy, interaction of critical damage with radiation-induced lesions, mechanisms of glioblastoma resistance to alkylating agents, including the alkyltransferase MGMT, mismatch repair, DNA double-strand break repair and DNA damage responses, as well as IDH-1 and PARP-1. Cyclin-dependent kinase inhibitors such as regorafenib, synthetic lethality using PARP inhibitors, and alternative therapies including tumor-treating fields (TTF) and CUSP9v3 are discussed in the context of alkylating drug therapy and overcoming glioblastoma chemoresistance. Recent studies have revealed that senescence is the main trait induced by TMZ in glioblastoma cells, exhibiting hereupon the senescence-associated secretory phenotype (SASP). Strategies to eradicate therapy-induced senescence by means of senolytics as well as attenuating SASP by senomorphics are receiving increasing attention, with therapeutic implications to be discussed.

Application of WHO CNS Fifth Edition Criteria for Glioblastoma Multiforme Diagnosis: A single center study

Abstract Introduction/Objective The fifth edition of the WHO classification of the tumors of the central nervous system (WHO CNS 5) published in 2021 introduced major changes that incorporate molecular diagnostics in CNS tumor classification along with histology and immunohistochemistry. Glioblastomas (GBM) were diagnosed based on the histologic features of diffuse and astrocytic glioma in adults, if there is microvascular proliferation and /or necrosis. Isocitrate dehydrogenase 1 (IDH) R132 H immunohistochemical stain expression and /or mutation analysis results were used to further classify GBMs as IDH mutant or IDH wild type. In WHO CNS 5 all IDH mutant diffuse astrocytic tumors are considered a single type (Astrocytoma, IDH mutant) and graded 2, 3, or 4. Glioblastoma IDH wild type is diagnosed in the setting of an IDH wild type diffuse and astrocytic glioma with microvascular proliferation or necrosis or TERT promoter mutation or EGFR gene amplification or +7/-10 chromosome copy number changes. In this study, we analyze how the change in diagnostic criterion would affect the classification of GBMs diagnosed in our institution retrospectively. Methods/Case Report The pathology database was searched for all diffuse gliomas diagnosed as GBM between 01/2019 and 12/2021. Age of the patient, gender, location of tumor, histologic features, IDH status and molecular alterations ( Onkosight Advanced solid tumor panel, 50 genes) were reviewed. Results (if a Case Study enter NA) A total of 74 adult high grade glial neoplasms were identified out of which 25 were GBMs. The age of the patients ranged from 40 to 87 years. 14 were men and 11 were females. All tumors had histologic features of GBM such as necrosis and microvascular proliferation. 24 (96%) tumors were IDH negative by immunohistochemistry and mutation analysis, and 1 (4%) was IDH strongly positive by immunohistochemistry. Molecular studies were not performed on this tumor. Conclusion 96% of GBMS diagnosed during the time period conformed to the WHO CNS 5 diagnostic criteria. The one IDH positive tumor would be reclassified as diffuse astrocytoma, IDH mutant, Grade 4. Like previous WHO classifications, WHO CNS 5 is a work in progress attempting to introduce new knowledge into the classification hoping to provide practical guidance to pathologists and neuro-oncologists and to benefit the patients with CNS tumors.

The Mini-Teddi-R Treatment Demonstrated a High Rate of Remission in Patients with DLBCL Involving the CNS Who Had Previously Been Exposed to BTK Inhibitors

Background: Secondary CNS B-cell lymphomas (SCNSL) are aggressive lymphomas with a bleak prognosis. TEDDI-R has been successful in achieving lasting remission in relapsed/refractory primary DLBCL of the CNS (PCNSL), but the effectiveness of ibrutinib-responsive tumors in SCNSL remains unknown. This study presents initial findings from the use of mini-TEDDi-R in SCNSL. Methods: Efficacy and safety data of mini-TEDDi-R were retrospectively analyzed for patients with DLBCL involving the CNS. All patients experienced relapse in the CNS or/and peripheral region after initial therapy. Brain parenchyma involvement allowed for treatment with MTX, Ara-c, and/or BTK inhibitors. The dosage of the drugs used in the original regimen was reduced, leading to the adoption of the term “mini-TEDDi-R.” Each 21-day cycle involved the following treatments: intravenous rituximab at a dose of 375 mg/m 2/day on days 1-2, oral temozolomide at a dose of 150 mg/m 2/day on days 2-5, intravenous infusion of 30 mg/m 2/day etoposide on days 2-5, intravenous infusion of 25 mg/m 2 of pegylated liposomal doxorubicin on day 2, intravenous infusion of dexamethasone at a dose of 10 mg/m 2/BID on days 1-5, and oral zanubrutinib at a dose of 200mg/BID or oral orelabrutinib at a dose of 150mg/qd or oral ibrutinib at a dose of 560mg/qd from day 1 until neutrophil count &amp;lt;0.5*10^9/L or platelet count &amp;lt;30*10^9/L. Additionally, intrathecal administration of 70 mg of cytarabine occurred on days 1 and 5, All remissions observed on MRI were confirmed through FDG-PET and CSF analysis. Results: Between December 2019 and June 2023, 24 patients with a median age of 53 (range 28-69) received mini-TEDDi-R treatment. All patients had DLBCL, comprising 16 (66.7%) non-GCB, 6 (25%) GCB, and 2 (8.3%) transformed from FL. All patients experienced relapse in the CNS system after a median of 6 (range 1-17) prior therapies, and all (100%) patients received prior anthracycline treatment. A total of 21 patients (87.5%) had received multiple lines of therapy before mini-TEDDi-R. Among them, 19 patients (79.2%) had received HD-MTX based salvage therapy, 11 patients (45.8%) had received HD-Ara-c based salvage therapy, and 14 patients (58.3%) had been exposed to BTK inhibitors. Seven patients (29.2%) showed triple resistance to MTX, Ara-c, and BTK inhibitors. Six patients had previously undergone transplantation, and four patients had experienced failure of CD19 CART treatment. Thirteen patients (54.2%) had isolated CNS disease, while 11 patients (45.8%) had both CNS and peripheral disease. Thirteen patients (54.2%) underwent 1 cycle of mini-TEDDi-R, 8 patients (33.3%) completed 2 cycles, 2 patients (8.3%) finished 3 cycles, and 1 patient (4.2%) completed 4 cycles. The objective remission rate (ORR) was determined to be 70.8%, with a complete remission (CR) rate of 58.3%. Notably, patients (N=14) exposed to BTK inhibitors previously exhibited a similar CR rate compared to patients (N=10) who had not received prior BTK inhibitor treatment (50% vs. 70%, p = 0.348). Patients (N=19) who had undergone HD-MTX based salvage therapy achieved an ORR of 74% and a CR rate of 58%. No significant difference in response rate was observed between patients with peripheral and non-peripheral secondary CNS involvement. In patients who achieved complete remission, only one patient experienced a second CNS relapse. Four patients bridged to auto-HSCT, 2 patients bridged to CART treatment, and 4 patients underwent auto-HSCT combined with CART treatment for consolidation. The median overall survival and median PFS have not been reached within the 11.8-month follow-up period. Toxicity was evaluated over 39 cycles. Grade 3 and 4 neutropenia occurred in 51% and 16% of cycles, respectively, while febrile neutropenia was observed in 10% of cycles. The median duration of neutropenia was 6 days (range 4-10). Three cycles (8%) were complicated by infections graded as ≥G3, but no opportunistic infections (including Aspergillus) were observed. Grade 3 and 4 thrombocytopenia occurred in 26% and 14% of cycles, respectively. The median duration of neutropenia was 7 days (range 3-14). Conclusions: The mini-TEDDi-R regimen demonstrated a favorable remission rate in patients with DLBCL involving the CNS. The treatment was well-tolerated, and patients with tumors that were previously exposed to BTK inhibitors and HD-MTX treatment also showed positive responses to mini-TEDDi-R.

Genetic alterations that deregulate RB and PDGFRA signaling pathways drive tumor progression in IDH2-mutant astrocytoma

In IDH-mutant astrocytoma, IDH2 mutation is quite rare and biological mechanisms underlying tumor progression in IDH2-mutant astrocytoma remain elusive. Here, we report a unique case of IDH2 mutant astrocytoma, CNS WHO grade 3 that developed tumor progression. We performed a comprehensive genomic and epigenomic analysis for primary and recurrent tumors and found that both tumors harbored recurrent IDH2R172K and TP53R248W mutation with CDKN2A/B hemizygous deletion. We also found amplifications of CDK4 and MDM2 with PDGFRA gain in the recurrent tumor and upregulated protein expressions of these genes. We further developed, for the first time, a xenograft mouse model of IDH2R172K and TP53R248W mutant astrocytoma from the recurrent tumor, but not from the primary tumor. Consistent with parent recurrent tumor cells, amplifications of CDK4 and MDM2 and PDGFRA gain were found, while CDKN2A/B was identified as homozygous deletion in the xenografts, qualifying for integrated diagnosis of astrocytoma, IDH2-mutant, CNS WHO grade 4. Cell viability assay found that CDK4/6 inhibitor and PDGFR inhibitor potently decreased cell viability in recurrent tumor cells, as compared to primary tumor cells. These findings suggest that gene alterations that activate retinoblastoma (RB) signaling pathways and PDGFR may drive tumor progression and xenograft formation in IDH2-mutant astrocytoma, which is equivalent to progressive IDH1-mutant astrocytoma. Also, our findings suggest that these genomic alterations may represent therapeutic targets in IDH2-mutant astrocytoma.

PATH-19. PROGNOSTIC FACTORS, RESPONSE TO TREATMENT, AND OUTCOME OF PATIENTS WITH ISOCITRATE DEHYDROGENASE (IDH)-MUTANT ASTROCYTOMA, CNS WHO GRADE 4

Abstract PURPOSE To study disease characteristics, prognostic markers and outcome in patients with isocitrate dehydrogenase (IDH)-mutant astrocytoma by CNS WHO grade. EXPERIMENTAL DESIGN We determined molecular biomarkers and assembled clinical and outcome data in a cohort of 258 patients with IDH-mutant astrocytomas (114 CNS WHO grade 2, 73 CNS WHO grade 3, 71 CNS WHO grade 4) confirmed by central pathology review. RESULTS The median age for astrocytoma, IDH mutant, CNS WHO grade 4, was 37 (range: 23-79 years) and similar to patients with CNS WHO grade 2 or 3 tumors. Karnofsky performance status at diagnosis inversely correlated with CNS WHO grade (p&amp;lt; 0.001). Despite more intensive treatment upfront with higher grade, CNS WHO grade was strongly prognostic: median overall survival was 22.2 years (95% n.a.) for grade 2, 8.1 years (95% 5.4-10.8) for grade 3 and 4.7 years (95% 3.4-6.0) for grade 4. Among patients with CNS WHO grade 4 astrocytoma, median overall survival was 5.5 years (95% 4.3-6.7) without (n=58) versus 1.8 years (95% 0-4.1) with (n=12) homozygous CDKN2A homozygous deletion. Reduced global DNA methylation as indicated by LINE-1 methylation levels was strongly associated with CNS WHO grade 4 (p&amp;lt; 0.001) and poor outcome among IDH-mutant astrocytoma patients. MGMT promoter methylation status was not prognostic for overall survival. CONCLUSIONS The CNS WHO grade is prognostic in patients with IDH-mutant astrocytoma. CDKN2A homozygous deletion and reduced LINE-1 methylation levels are linked to CNS WHO grade 4 and associate with shorter survival. These data serve to inform on clinical trial designs, e.g., using IDH inhibitors, in this patient population.

BIOM-38. MET FUSIONS AND SPLICING VARIANTS IS A STRONG ADVERSE PROGNOSTIC FACTOR IN ASTROCYTOMA, IDH-MUTANT

Abstract BACKGROUND Astrocytoma, IDH-mutant is currently characterized by both histological and molecular features according to the WHO CNS5 classification. However, there were still patients with IDH-mutant lower-grade astrocytomas (LGAs, CNS WHO grade 2 and 3) who suffered poor survival. Our previous research demonstrated the enrichment and predictive role of MET fusions and/or splicing variations (MET F/SVs) in previously classified secondary IDH-mutant glioblastoma, which could be a potential complement to the existing grading system. MATERIALS We herein presented descriptive, Kaplan-Meier, multivariable Cox regression outcome analyses, and DNA methylation profiling cluster analysis in a large cohort of astrocytomas, IDH-mutant. RESULTS A total of 427 astrocytomas, IDH-mutant were included. 28/427 (6.56%) patients were defined as carrying MET F/SVs, including 9/261 (3.45%) LGAs and 19/166 (11.45%) IDH-mutant high-grade astrocytomas (HGAs, CNS WHO grade 4). The distribution of MET F/SVs was significantly different between LGAs and HGAs (p = 0.0011). Kaplan-Meier analysis of PFS and OS confirmed MET F/SVs was significantly associated with inferior survival irrespective of CNS WHO grade. Multivariable Cox regression analysis with PFS and OS as the endpoint showed MET F/SVs were independently associated with worse survival (p = 0.006 for PFS and p &amp;lt; 0.0001 for OS). Moreover, we collected 159 astrocytomas, IDH-mutant with DNA methylation profiles for further analysis. The included patients were classified into the methylation class MC astrocytoma, IDH-mutant in version 12.5 of the Heidelberg brain tumor classifier. On the t-distributed stochastic neighbor embedding (t-SNE) projection, the IDH-mutant astrocytoma with MET F/SVs was more clustered in high-grade astrocytoma (p = 0.017). CONCLUSION Collectively, we demonstrated the utmost relevance of MET F/SVs as an adverse prognostic factor in IDH-mutant astrocytoma independent of the current WHO CNS grading system. We proposed that the LGAs with MET F/SVs should be designated into CNS WHO grade 4.

BIOM-54. VALIDATING MCM2 IMMUNOHISTOCHEMISTRY AS A SURROGATE MARKER FOR AGGRESSIVE MENINGIOMA

Abstract Increasing efforts have focused to improve meningioma classification through various multi-omic analyses. One such recent study (Nassiri, et al, Nature, 2021) proposed an integrative molecular classification for meningiomas that included 4 molecular subtypes (MG1-4), with possible immunohistochemical surrogates for each subtype including S100B, ACADL, SCGN, and MCM2, respectively. While these immunohistochemical surrogates have been proposed for meningioma risk-stratification, their clinical utility has not been thoroughly tested. In this study, we sought to evaluate the utility of these immunohistochemical markers for risk-stratification in an independent cohort of meningioma. Tissue microarrays containing meningioma tissues were constructed, immunohistochemically stained, and blindly scored. Our cohort included n = 142 tumors (CNS WHO: 1=93, 2=45, 3=4). Median age was 49 years (range 14-80 years) with 89 female and 53 male patients. We found that MCM2 immunopositivity was a univariate marker of poor prognosis (median progression-free survival 1.2 years) when compared to negative tumors (median progression-free survival 13.0 years). The other three markers (S100B, ACADL, SCGN) were not associated with survival. MCM2 staining held up as a significantly independent (p = 0.03) poor prognostic marker on multivariate Cox proportional hazard modeling including other histopathological features: CNS WHO grade, brain invasion, mitotic index, and tumor size. Although MCM2 staining was independent of CNS WHO grade, all 4 of the CNS WHO 3 meningiomas were positive for MCM2. MCM2-positive tumors had a higher average mitotic count (6.1 mitoses/10hpf) compared to MCM2-negative tumors (1.8 mitoses/10hpf) (p = 0.0002, two-tailed t test). There was no difference between MCM2-positive and MCM2-negative meningiomas in relation to maximum tumor size (4.9cm and 4.2cm, respectively) and mean age (51.71 years and 50.34 years, respectively). In summary, in our cohort we found MCM2 immunopositive staining (surrogate marker for high-risk molecular subtype M4) to be an independently poor prognostic biomarker in meningioma when accounting for other well-established histopathological characteristics.

NCOG-13. OUTCOMES OF CNS WHO GRADE 2 OLIGODENDROGLIOMA IN ADULT PATIENTS ; IMPACT OF ADJUVANT TREATMENT ON OVERALL RESULTS

Abstract OBJECTIVE Patients with oligodendroglioma (ODG), isocitrate dehydrogenase (IDH)-mutant, 1p19q codeleted, CNS WHO grade 2 have a median overall survival of longer than 10 years. Patients with ODG who are high-risk by RTOG criteria are offered radiation in combination with procarbazine, lomustine, and vincristine (PCV). The study aims to analyze the patient’s outcomes and assess the efficacy of postoperative treatment. METHODS A total of 138 adult patients who underwent resection for newly diagnosed grade 2 ODG between 1994 and 2021 were enrolled. Sixty-three (45.7%) were observed after gross total resection (GTR) or near total resection (NTR), 5 (0.4%) received adjuvant treatment after GTR or NTR, 37 (26.8%) were observed after subtotal resection (STR) or biopsy, and 33 (24.0%) received adjuvant treatment after STR or biopsy. The study analyzed progression-free survival (PFS), overall survival (OS), and risk variables. RESULTS Out of the 138 patients, 38 (27%) patients received adjuvant treatment, with 30 of them (78.9%) underwent radiotherapy only, 6 (15.8%) underwent radiochemotherapy, and 2 (5.3%) received chemotherapy alone. The median PFS was 6.8 years. Multivariate analysis revealed STR or biopsy (p=0.04), initial MR imaging enhancement (p=0.002), and postoperative observation(p=0.006) were associated with poorer PFS outcomes. The 5-year overall survival rate was 95.5% and the 10-year overall survival was 76.1%. Poor OS prognosis was associated with STR or biopsy (p=0.03), preoperative seizure (p=0.002), and initial MR imaging enhancement (p&amp;lt; 0.001). CONCLUSIONS : GTR and NTR is essential for achieving prolonged PFS and OS in ODG patients. Postoperative treatment is associated with favorable PFS outcomes but does not significantly affect OS. For an accurate diagnosis and appropriate treatment, the utmost care should be taken to avoid underestimating the results of the biopsy.

TMIC-83. THE MOLECULAR AND SPATIAL ARCHITECTURE OF AN IMMUNE-RICH GLIOMA SUBTYPE

Abstract Diffuse glioma exhibit an immunosuppressive microenvironment, yet glioma subsets driven by RAF-alterations exhibit an increased immune signature. In pleomorphic xanthoastrocytoma (PXA), we identified CXCL14 as an important factor promoting a cytotoxic T cell response. The molecular and spatial relationships within this tumor type, however, are unknown. To address this, we use single nucleus RNA sequencing (snRNAseq), spatial transcriptomics, and spatial molecular imaging to construct a high-resolution molecular landscape of PXA. SnRNAseq was performed on 36,781 cells from 10 tumors, including initial and recurrent pairs, spatial transcriptomes were performed on a total of 91 FOVs comprised of 17 PXAs, and spatial molecular imaging (SMI) of 1,000 RNA probes at subcellular resolution was performed on 48,518 cells from 6 tumors, including two PXA, two pilocytic astrocytoma, and two ganglioglioma. For snRNAseq, neoplastic cells were separated from non-malignant cells based on analysis of inferred copy number alterations. CellChat was used to infer cell-cell communication. For spatial transcriptomics, data from 200-300µm FOVs were normalized and divided into CD3-high versus CD3-low groups. For SMI, cells with fewer than 20 transcripts were eliminated, data were normalized using simple total counts, cells were segmented using the Nanostring pipeline, and semi-supervised clustering was performed. Dual CXCL14 RNAscope and Iba1/CD3 immunostaining confirmed spatial relationships within the tumor. In PXA with high-CD3, differential gene expression analysis demonstrated broad immune-enrichment and identified upregulation of several ligand-receptor pairs. Integrating these data with snRNAseq and cell-cell communication analysis inferred paracrine interactions between tumor cells and T cells. One such factor, CXCL14, was expressed widely by tumor cells but spatial analysis revealed cohesive clusters of CXCL14-high expressing tumor cells. In anaplastic (CNS WHO grade 3) tumors, however, both CXCL14 expression and microglia decreased. These high-resolution molecular analyses of PXA identify dynamic tumor-immune crosstalk regulating the immune microenvironment.