bluuebunny/crossref_metadata_2025 huggingface dataset:
P11.04.B ASSESSMENT OF TUMOR ELOQUENCE IN GLIOMA RESECTIONS: A SYSTEMATIC REVIEW
Authors: Rammeloo E , Schouten J W , Krikour K , Bos E M , Berger M S , Gerritsen J K W , Vincent A J P E
Published: September 2023

BACKGROUND

Tumor location and eloquence are two crucial factors when deciding on the optimal surgical strategy in glioma management. Consensus is currently lacking on the assessment and definition of eloquent areas. This systematic review aims to evaluate the existing definitions and assessment methods of eloquent areas used in current clinical practice.

MATERIAL AND METHODS

A computer-aided search of Embase, Medline (OvidSP), and Google Scholar was performed to identify relevant studies. This review includes articles describing preoperative definitions of eloquence in the study’s Methods section. These definitions were compared and categorized by anatomical structure. Additionally, various techniques to preoperatively assess tumor eloquence were extracted, along with their benefits, drawbacks and ease of use.

RESULTS

This review covers 98 articles including 12,714 participants. Evaluation of these studies indicated considerable variability in defining eloquence. Categorization of these definitions yielded a list of 32 brain regions that were considered eloquent. The most commonly used methods to preoperatively determine tumor eloquence were anatomical classification systems and structural MRI, followed by DTI-FT, functional MRI and nTMS.

CONCLUSION

None of the definitions or techniques to define eloquence described in the articles are entirely satisfactory as an objective, quantifiable, preoperative factor in glioma treatment and surgical decision-making. Therefore, we propose the development of a new, easily applicable and interpretable anatomical preoperative grading system to assess tumor eloquence. This may aid neurosurgeons in their perioperative decision-making to improve surgical outcomes on an individual patient level and to facilitate the execution and interpretation of multicenter studies.
P11.11.A VOLUMETRIC AND SPATIAL ANALYSES OF TREATMENT-RELATED INJURY IN GLIOMA
Authors: van der Boog A T J , David S , Vreeman M , Steennis A A M , Cialdella F , Dankbaar J , Snijders T J , Verhoeff J J C , Robe P A
Published: September 2023

BACKGROUND

As diffuse glioma cannot yet be cured, benefits of therapeutic strategies should be carefully balanced against their burden. Postoperative ischemia is a relatively common adverse event of surgery, which can lead to serious neurological deficits. Radiation therapy (RT) can cause post-RT lesions, which may cause clinical symptoms and can create a therapeutic impasse since they mimic tumor progression. We aimed to explore the spatial and volumetric tumor and treatment characteristics in relation to development of treatment-related effects in glioma. Materials and

METHODS

We retrospectively included 144 WHO grade II-IV supratentorial glioma cases, which were resected from 2012 till 2014 and had early postoperative MRI with diffusion-weighted imaging (DWI). Tumors were delineated on preoperative contrast-enhanced T1 MRI for high grade gliomas and FLAIR for low grade gliomas. Postoperative ischemia was defined as new, confluent diffusion restriction on postoperative DWI. Post-RT injury was investigated in patients who received RT after first surgery and had at least 6 months of follow-up (FU), and was defined as new or increasing contrast-enhancement that subsequently stabilized or decreased during FU. After manual delineation and non-linear registration to MNI stereotaxic space, all lesions were investigated with regard to size and location of pre-operative tumor, resection cavity, residual tumor and extent of resection (EOR). Voxel-based analysis (VBA) was performed with family-wise error correction for multiple comparisons.

RESULTS

Postoperative ischemia occurred in 93 of 144 cases and was associated with a larger EOR (P=0.02). Ischemic volume was correlated with a larger preoperative tumor volume (P=0.009) and resection volume (P=0.001). Post-RT injury was found in 25 of 67 analyzed cases and was associated with a larger residual tumor volume (P=0.021) and a smaller EOR (P=0.005). VBA showed an association of the occurrence of post-RT lesions with a cluster of preoperative tumor voxels in the left temporal lobe and clusters of residual tumor voxels in the left temporal and right frontal region. No association in volume or location was found between postoperative ischemia and post-RT lesions.

CONCLUSION

Adverse events of glioma treatment may be influenced by tumor and treatment volumes. In our population, a larger EOR was associated with the occurrence of postoperative ischemia, and larger tumor and resection volumes were correlated with the volume of ischemia. Additionally, the occurrence of post-RT injury was associated with a larger residual tumor and a smaller EOR, as well as a left temporal preoperative tumor location and a right frontal or left temporal residual tumor location. A thorough examination of spatial and volumetric characteristics of the tumor, treatment and subsequent complications can help elucidate the etiology and guide treatment decisions.
P11.21.A LONG-TERM SURVIVAL WITH IDH WILDTYPE GLIOBLASTOMA: FIRST RESULTS FROM THE ETERNITY BRAIN TUMOR FUNDERS’ COLLABORATIVE CONSORTIUM (EORTC 1419)
Authors: Weller M , Felsberg J , Gramatzki D , Le Rhun E , Clarke J , Soffietti R , Wick W , Chinot O , Ducray F , Roth P , McDonald K , Hau P , Hottinger A F , Reijneveld J , Schnell O , Marosi C , Glantz M , Darlix A , Lombardi G , Krex D , Glas M , Reardon D A , van den Bent M J , Lefranc F , Herrlinger U , Razis E , Carpentier A F , Phillips S , Rudà R , Wick A , Tabouret E , Meyronet D , Maurage C , Rushing E , Rapkins R
Published: September 2023

BACKGROUND

Median survival with glioblastoma remains in the range of 12 months on population levels. Only few patients survive for more than 5 years. Patient and disease features associated with long-term survival remain poorly defined.

METHODS

European Organization for Research and Treatment of Cancer (EORTC) 1419 (ETERNITY) is a registry study supported by the Brain Tumor Funders Collaborative in the US and by the EORTC Brain Tumor Group. Patients with glioblastoma surviving at least 5 years from diagnosis were identified at 24 sites in Europe, US, and Australia. In patients with isocitrate dehydrogenase (IDH) wildtype tumors, prognostic factors were analyzed using the Kaplan-Meier method and the Cox proportional hazards model. A population-based reference cohort was obtained from the Cantonal cancer registry Zurich.

RESULTS

At the database lock of July 2020, 280 patients with histologically centrally confirmed glioblastoma (189 IDH wildtype, 80 IDH mutant, 11 incompletely characterized) had been registered. In the IDH wildtype population, median age was 56 years (range 24-78 years), 96 patients (50.8%) were female, 139 patients (74.3%) had tumors with O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. Median overall survival was 9.9 years (95% CI 7.9-11.9). Patients without recurrence experienced longer median survival (not reached) than patients with one or more recurrences (8.92 years) (p<0.001) and had a high rate (48.8%) of MGMT promoter unmethylated tumors.

CONCLUSION

s Freedom from progression is a powerful predictor of overall survival in long-term survivors with glioblastoma. Patients without relapse often have MGMT promoter-unmethylated glioblastoma and may represent a distinct subtype of glioblastoma.
P11.34.A MULTIFACTORIAL ANALYSIS OF SURGICAL TREATMENT OF INTRACRANIAL METASTASES IN ELDERLY PATIENTS
Authors: Gubian A , Sulejmani A , Ruder A M , Giordano F , Rinkel G , Etminan N , Brehmer S
Published: September 2023

BACKGROUND

Due to increasing age of the population, the number of elderly patients with brain metastasis accessible for surgery is increasing. The higher risk of peri-procedural complications and a reduced ability to tolerate aggressive treatment are often thought to limit intracranial surgery in older patients. However, little data are available on results of surgical brain metastasis treatment in elderly. In a subset of older patients who underwent surgical removal of brain metastases, we assessed the influence of age on survival and postoperative dependency.

MATERIAL AND METHODS

This is a retrospective observational study of patients over 65 years of age who underwent surgery for intracranial metastases between 2015 and 2022 at the Department of Neurosurgery, University Hospital Mannheim (Germany). The population was divided into group A (65-74 years old) and group B (75 years or older). The Eastern Cooperative Oncology Group (ECOG) score was used to assess functional status and independence. The primary endpoints were overall survival and the likelihood of remaining independent (ECOG <3) at 6 weeks. A wide range of clinical and radiological baseline factors were analysed.

RESULTS

80 patients were included in the analysis. The mean age in the overall cohort was 73.2 years, and 74% of patients had a preoperative ECOG score of 2 or less. 48 patients were included in group A and 32 in group B. The 1-, 2- and 3-year probabilities of overall survival were 31%, 23% and 16% in group A and 38%, 23% and 23% in group B (p-value=0.61). Functional status in the overall cohort remained stable after surgery for most patients (70%), while 17% experienced a decline and 13% an improvement. 42 (88%) and 43 (90%) patients in group A were independent before and after surgery, respectively. 27 (84%) and 26 (81%) patients in group B were independent before and after surgery, respectively. 33 (69%) patients in group A and 19 (59%) patients in group B were independent at follow-up (p=0.65). No significant difference was found between the two groups for independence status preoperatively, postoperatively as well as at follow-up (p-values 0.69, 0.29 and 0.32, respectively).

CONCLUSION

In our analysis, neither survival nor outcome after surgery for brain metastases showed a correlation with age. Age alone should not be a barrier to intracranial surgery in carefully selected elderly patients with intracranial metastases.
P11.37.B RADIOSURGERY-ASSOCIATED NEW-ONSET FACIAL SPASM AFTER THE TREATMENT OF VESTIBULAR SCHWANNOMA IS ASSOCIATED WITH INCIDENCE OF RECURRENCE
Authors: Wang S , Naros G , van Eck A , Horstmann G , Tatagiba M
Published: September 2023

BACKGROUND

Facial function preservation in the care of vestibular schwannoma (VS) is pre-dominantly measured in motoric function (e.g. House-Brackman (HB)). Facial spasm (FS) has been reported to be a possible side-effect in the radiosurgical treatment of VS. However, the exact incidence of FS is still unclear.

MATERIAL AND METHODS

This study aims to study the incidence of FS in the treatment of VS. Patient medical records of patients treated by treatment of VS between 2004 and 2020 ere analyzed retrospectively. Patient and tumor characteristics were analyzed (i.e., sex, age, tumor extension and size, intracanalicular extension).

RESULTS

N=104/1’998 (5%) of all patients treated by SRS presented with new-onset FS postinterventionally. FS was unrelated to tumor size. The incidence of new-onset FS was significantly higher in women (6%) compared to men (4%) (p=0.032). From all patients with FS, N=24/104 (23%) of new onset FS appeared after Re-SRS (second SRS treatment). In primary SRS therapy, facial spasm was associated with a higher recurrence rate of N=20/80 (25%) vs N=252/1"894 (13%) in nonFS patients (p=0.007). N=65/104 (62%) were permanent FS, whereas N=41/104 (39%) recovered spontaneously between 4 and 34 months, postinterventionally. The proportion (76%) of FS patients had tumors with extensive intra-canalicular extension (OHATA A-B) was higher in compared to a nonFS control group (64%) (p=0.015).

CONCLUSION

FS is a SRS therapy-related side effect with an overall incidence of 5%. Women were more commonly affected by new-onset SRS. Second-line SRS has the highest risk for new-onset FS. FS was associated with a higher incidence of recurrence compared to non-FS VS patients. Patients" consultation should address the relevant side effect.
P11.46.A ACTION: A RANDOMIZED PHASE 3 STUDY OF DORDAVIPRONE (ONC201) IN PATIENTS WITH NEWLY DIAGNOSED H3 K27M-MUTANT DIFFUSE GLIOMA
Authors: Arrillaga-Romany I , Lassman A , McGovern S L , Mueller S , Nabors L B , van den Bent M , Vogelbaum M , Allen J E , Melemed A S , Tarapore R , Wen P Y , Cloughsey T
Published: September 2023

BACKGROUND

H3 K27M-mutant diffuse midline glioma is a universally fatal malignancy primarily affecting children and young adults. While radiotherapy (RT) provides transient benefit, no effective systemic therapy is currently available and current standard of care is RT followed by monitoring. Dordaviprone (ONC201), a first-in-class imipridone, is an oral, blood-brain barrier penetrating, selective small molecule antagonist of dopamine receptor D2/3 (DRD2) and agonist of the mitochondrial protease ClpP. An integrated pooled analysis of five open-label trials previously demonstrated efficacy in dordaviprone-treated patients with recurrent disease. This phase 3 trial will be the first randomized, controlled study evaluating ONC201 in patients with H3 K27M-mutant disease.

MATERIAL AND METHODS

ACTION (NCT05580562) is a randomized, double-blind, placebo-controlled, parallel-group, international Phase 3 study of ONC201 in patients with newly diagnosed H3 K27M-mutant diffuse glioma. Patients who have completed standard frontline radiotherapy will be randomized 1:1:1 to receive placebo, once-weekly dordaviprone, or twice-weekly dordaviprone on two consecutive days. Primary efficacy endpoints are overall survival (OS) and progression-free survival (PFS) in all participants; PFS will be assessed by response assessment in neuro-oncology-high grade glioma by blind independent central review. Other objectives include assessments of safety, additional efficacy endpoints, clinical benefit, quality of life, pharmacokinetics, biomarkers, and healthcare resource utilization. Eligible patients will have histologically confirmed H3 K27M-mutant diffuse glioma, a Karnofsky/Lansky performance status ≥70, and completed first-line radiotherapy. Eligibility will not be restricted based on age; however, patients must be ≥10 kg at time of randomization. Patients with a primary spinal tumor, diffuse intrinsic pontine glioma, leptomeningeal disease, or cerebrospinal fluid dissemination are not eligible. ACTION is currently enrolling in the United States, with additional sites to be open internationally in 2023.
P11.49.B STEREOTACTIC RADIOSURGERY FOR CRANIAL AND SPINAL HEMANGIOBLASTOMAS: A SINGLE-INSTITUTION SERIES
Authors: Yoo K H , Park D J , Marianayagam N J , Gu X , Pollom E L , Soltys S G , Chang S D , Meola A
Published: September 2023

BACKGROUND

Stereotactic radiosurgery (SRS) has been an attractive treatment modality for both cranial and spinal hemangioblastomas, especially for multiple lesions commonly associated with von Hippel-Lindau (VHL) disease. This study aims to provide the largest long-term analysis of treatment efficacy and adverse effects of SRS for cranial and spinal hemangioblastomas at a single institution.

MATERIAL AND METHODS

We evaluated the clinical and radiological outcomes of patients with hemangioblastomas treated with CyberKnife SRS at our institute from 1998 to 2022. The follow-up data were available for 135 hemangioblastomas in 35 patients. Twenty-eight patients had 123 hemangioblastomas associated with VHL and 7 had 12 sporadic hemangioblastomas. The median age was 36 years and the median tumor volume accounted for 0.4 cc. The SRS was administered with the median single-fraction equivalent dose (SFED) of 18 Gy to the 77% median isodose line.

RESULTS

At a median follow-up of 57 months (range: 3-260), only 20 (16.2%) of the VHL-associated and 1 (8.3%) sporadic hemangioblastomas progressed. The 5-year local tumor control (LTC) rate was 91.3% for all hemangioblastomas, 91.7% among the sporadic lesions, and 92.9% in VHL patients. SRS improved tumor-associated symptoms of 98 (74.8%) of 131 symptomatic hemangioblastomas, including headache, neck pain, dizziness, visual disturbances, dysesthesia, ataxia, motor impairment, seizures, and dysphagia. Two patients developed radiation necrosis (5.7%) and 1 of them required surgical resection.

CONCLUSION

SRS is a safe and effective treatment option for patients with hemangioblastomas in critical locations such as the brainstem, cervicomedullary junction, and spinal cord, and in patients with multiple hemangioblastomas associated with VHL disease.
P11.64.A TREATMENT STRATEGIES BEFORE THE DIAGNOSIS OF BRAIN METASTASIS IN PATIENTS WITH RENAL CELL CANCER (RCC)
Authors: Derks S H A E , van der Meer E L , Joosse A , de Jonge M , Slagter C , Schouten J W , Oomen-de Hoop E , Smits M , van den Bent M J , Jongen J L M , van der Veldt A A M
Published: September 2023

BACKGROUND

Metastatic renal cell cancer (mRCC) is known for its variable disease course and can be categorized according to the International Metastatic RCC Database Consortium (IMDC) criteria. As patients with mRCC who have a favorable IMDC score and/or a low tumor burden usually have an indolent disease course, watchful waiting is often considered in daily clinical practice. However, it is unknown whether watchful waiting impacts the development of brain metastasis (BM). Therefore, we investigated variables that may affect the interval between first diagnosis of mRCC and BM (BM-free interval) in patients with RCC and BM.

MATERIAL AND METHODS

A single-center, retrospective cohort study was performed at the Erasmus MC Cancer Institute (Rotterdam, the Netherlands). All consecutive patients with a diagnosis of RCC and BM between 01-01-2011 and 31-07-2022 were included. The primary outcome was the BM-free interval. Secondary outcomes were intracranial progression-free survival (iPFS), progression-free survival (PFS) and overall survival (OS), since diagnosis of BM. Subgroups included patients with and without systemic treatment prior to the diagnosis of BM. Kaplan-Meier (Logrank test) and Cox Proportional Hazards Model (Likelihood ratio test) analyses were performed with significance considered at p-values <0.05.

RESULTS

A total of 46 patients with RCC and BM were included; 80% was male and 89.1% had a clear cell RCC subtype. In 84.8% of patients, BMs were diagnosed metachronous (>1 month) after the diagnosis of extracranial metastasis (ECM) and 80.4% of patients had symptomatic BM at BM diagnosis. After the diagnosis of BM, the median iPFS was 7.6 (IQR 3.5-12.2) months, the median PFS was 3.7 (IQR 2.3-8.7) months and the median OS was 10.1 (IQR 5.1-22.8) months. Prior to the diagnosis of BM, 25 (54.3%) patients had received systemic therapy, whereas 21 (45.7%) patients were treatment naïve. The median BM-free interval was 22.3 (IQR 5.7-46.7) months. The median BM-free interval was significantly shorter for treatment naïve patients (6.8 [IQR 1.0-7.0] months) as compared to patients who received previous systemic therapy (29.0 [IQR 12.6-57.0]; p=0.02). In multivariate analysis, a longer BM-free interval was significantly associated with nephrectomy (HR 0.10 [95%CI 0.03-0.31]) and systemic treatment prior to BM diagnosis (HR 0.10 [95%CI 0.03-0.30]).

CONCLUSION

In this cohort of patients with RCC BM, patients who had not received systemic treatment for ECM were earlier diagnosed with BM than patients who had received prior systemic treatment. Although the retrospective nature of this small selective cohort is a limitation, these results indicate that watchful waiting should be carefully considered for patients with mRCC.
P11.82.A TARGETING THE GLIOBLASTOMA MASTER REGULATOR C/EBPß: A PHARMACOKINETIC AND PHARMACODYNAMIC NEOADJUVANT STUDY OF ST101
Authors: Iwamoto F , Al Dalahmah O , Manjrekar K , Levrero C , Michel R , Bargo A , Kaesshaefer S , Butowski N , Peters K , Buerki R , Bexon A , Vainstein-Haras A
Published: September 2023

BACKGROUND

The vast amounts of genomics, epigenomics and transcriptomics data in glioblastoma (GBM) have yet to translate into better outcomes to most patients. One of the main challenges is to how to best integrate these diverse layers of omics to personalize and improve the treatment of glioblastomas. Cancer master regulators are often transcription factors (TFs), which control the expression of many genes and considered promising antitumor targets. CCAAT/enhancer-binding protein β (C/EBPβ) is an abundantly-expressed transcription factor (Zahnow 2009). C/EBPβ was previously described as a master regulator in GBM (Carro 2010). ST101 is a first-in-class cell-penetrating peptide antagonist of C/EBPβ with known ability to cross the blood-brain barrier. We have demonstrated potent anti-tumor activity with ST101 in multiple in vivo models including glioblastoma. Based on early efficacy data on the initial clinical study including objective responses in GBM, we designed this surgical study to further understand the antitumor mechanisms of ST101.

METHODS

we will recruit total of 12 newly diagnosed GBM and 6 recurrent patients. Recurrent GBM patients who are deemed surgical candidates will be treated with ST101 at the RP2D of 500 mg IV weekly for 2 to 4 weeks and then undergo standard of care surgical resection. After recovery from surgery, patients will continue ST101 until there is significant toxicity or tumor progression. 12 patients with newly diagnosed GBM who had undergone a prior biopsy or partial resection, and that upon further neurosurgical evaluation have an indication for additional debulking surgery will be eligible for this study. Patients will be treated with ST101 at the recommended phase 2 dose for 2 weeks and then undergo standard of care surgical resection. Patients will undergo standard of care treatment with radiation and temozolomide and continue ST101 after recovery from surgery. ST101 plasma concentration will be correlated with ST101 drug levels in enhancing and non-enhancing tumor tissue of recurrent and newly diagnosed patients. We will compare the molecular abnormalities in the post-treatment tissue through deep bulk whole-exome sequencing and mRNAseq against the intra-patient baseline tissue. Pharmacodynamics evaluation will focus on the expression of genes regulated by the transcription factor CEBPβ, such as BCL2, cyclins and cyclin-dependent kinases and inhibition of differentiation genes. Due to the diversity of cell types in the tumor microenvironment and the early data that ST101 can also reprogram M2 macrophages to M1 in addition to its direct antitumor effects, we will perform single nucleus RNAseq on these surgical specimens. Enrollment has started in January 2023 and 6 recurrent and 2 newly diagnosed patients have been accrued.
P11.85.B LONG-TERM OUTCOME AFTER INCOMPLETE RESECTION OF INTRAMEDULLARY GRADE II EPENDYMOMAS WITHOUT ADJUVANT RADIOTHERAPY
Authors: Chaskis E
Published: September 2023

BACKGROUND

Ependymomas are the most frequent intramedullary tumors in adults. While gross total resection is the aim of surgery, tumor infiltration might limit resection. In case of subtotal removal, the adjuvant management remains unclear. The aim of our study was to assess the need for adjuvant radiotherapy after incomplete resection of grade II intramedullary ependymomas (IME-II).

MATERIAL AND METHODS

We retrospectively reviewed all cases of IME-II operated in a single tertiary neurosurgical center from 2009 to 2018. Patients with anaplastic or myxopapillary ependymomas, and patients with a follow-up of less than 3 years were excluded.

RESULTS

We included 46 patients: 19 (41.3%) had gross total resection, 21 (45.7%) had subtotal resection and 6 (13%) had partial resection. None of the patients underwent adjuvant radiotherapy. Over a median follow-up of 79 months (range = 36-186), 7 patients presented a radiological tumor progression with a mean delay of 50.9 months (range =18-85), of which 2 were symptomatic (4.3%). Progression-free survival (PFS) was 90.1% at 5 years and 76.8% at 10 years. Extent of resection was the only significant risk factor for secondary tumor progression (p=0.012). 4 of the 7 patients with recurring IME-II were treated: 3 patients had a second surgery, leading to 2 GTR and 1STR, followed by radiotherapy in one case, and 1 patient underwent radiotherapy alone.

CONCLUSION

In this study, the rate of symptomatic progression and retreatment after incomplete resection of IME-II without adjuvant radiotherapy was low, supporting a conservative approach in such cases.
P12.01.A TUMOR CELL SENESCENCE AND IMMUNE MICROENVIRONMENT IN GLIOBLASTOMAS
Authors: Kim S , Roh T , Park T , Kim J
Published: September 2023

BACKGROUND

Cellular senescence (CS) is a state of irreversible cell cycle arrest, and the expression of p16INK4a in cells is one of the reliable markers for CS. However, senescent cells are metabolically active with the senescence-associated secretory phenotype (SASP), which can influence the tissue microenvironment by paracrine signaling to the adjacent tumor, non-tumor, and immune cells.

MATERIAL AND METHODS

In the present study, we evaluated p16INK4a expression in glioblastoma and investigated its association with CS and SASPs. We analyzed the expression of p16INK4a in 73 glioblastomas by immunostaining. To examine the association of p16INK4a expression and CS, we performed senescence-associated β-galactosidase (SA-β-Gal) staining, a standard marker of CS, using glioblastoma cell lines and fresh frozen tumor tissues. For SASPs analysis, RNA sequencing with Gene Set Enrichment Analysis (GSEA) was performed.

RESULTS

Among 73 glioblastomas, twenty-eight cases (38.4%) revealed diffuse strong p16INK4a expression in tumor cells. The glioblastoma with diffuse p16INK4a expression (GMDP) patients were younger (52.4 vs. 59.2 years) and showed prolonged overall survival (median: 25.5 vs. 12.3 months) compared to those harboring negative expression. In vitro analysis, p16INK4a over-expressed glioblastoma cell line showed increased expression of SA-β-Gal which indicates CS. In addition, fresh frozen tissues from GMDP also revealed SA-β-Gal positivity. RNA sequencing analysis revealed that splicing or protein biosynthetic genes were enriched in GMDP, and GSEA showed significant enrichment of SASP genes (false discovery rate <0.05), especially chemokines associated with monocytes and macrophages.

CONCLUSION

Our data suggest that increased expression of p16INK4a in glioblastoma is associated with tumor cell senescence, and SASPs from senescent tumor cells could be one of the crucial modulators in the tumor immune microenvironment.
P12.09.B SMAC MIMETICS REPROGRAMS GLIOBLASTOMA IMMUNE LANDSCAPE AND POLARIZES MICROGLIA TOWARD A PRO-INFLAMMATORY ANTI-TUMORAL PHENOTYPE
Authors: Snacel-Fazy E , Soubéran A , Colin C , Pagano A , Brustlein S , Grange M , Luche H , Siret C , Van De Pavert S , Debarbieux F , Rougon G , Figarella-Branger D , Tabouret E , Tchoghandjian A
Published: September 2023

BACKGROUND

Glioblastomas are the most aggressive brain tumors in adult characterized by an immunosuppressive microenvironment. They are invaded by tumor-associated macrophages (TAMs) supporting tumor growth and treatment escape. One current therapeutic challenge is to restore an immunocompetent environment to improve treatment efficiency. A better knowledge of spatial distribution and function of TAMs is needed to design new promising therapeutic strategies.

MATERIAL AND METHODS

We used small molecules SMAC mimetics (SM) which are inhibitor of apoptosis (IAP) antagonists to decipher spatial distribution and function of TAMs. By using a syngeneic glioblastoma mouse model, we performed whole mount stainings and brain clearing to investigate immune cells quantity, and spatial organization within tumors and related to tumor vessels. We then performed molecular mass cytometry (CYTOF) to accurately phenotype the immune cells involved in SM response and gain functional data. We finally used human derived glioblastoma models (explants, immune cells sorting and tumoroids) to investigate the clinical relevance of our results.

RESULTS

Results showed that SM promoted immune cells CD45+ quantity and penetration within tumors including microglia. The treatment increased monocyte-derived dendritic cells, CD8EM T cells, reactive microglia while decreasing anti-inflammatory macrophages and basal microglia. Furthermore, SM treatment decreased contacts between microglia and CD8 T cells, and microglia PDL1+. Thanks to the use of human derived model, we found that CD14 is decreased upon SM treatment. By using TCGA databases, we found that low level of CD14 expression was correlated with a better prognosis.

CONCLUSION

SM reprogram glioblastoma immune landscape and modulate immune cell infiltration and organization within tumors. Furthermore, microglia is a key mediator in SM response. The targeting of CD14, IAP and microglia would be a promising therapeutic strategy.
P14.05.B 2-HYDROXYGLUTARATE IN CEREBROSPINAL FLUID AS A MONITORING BIOMARKER FOR IDH-MUTANT GLIOMAS
Authors: Riviere-Cazaux C , Lacey J , Carlstrom L , Laxen W , Munoz-Casabella A , Hoplin M , Ikram S , bin Zubair A , Andersen K , Warrington A , Decker P , Kaufmann T , Campian J , Eckel-Passow J , Kizilbash S , Tortorelli S , Burns T
Published: September 2023

BACKGROUND

D-2-hydroxyglutarate (D-2-HG) is a well-established oncometabolite of isocitrate dehydrogenase (IDH) mutant gliomas. While prior studies have demonstrated that D-2-HG is elevated in the cerebrospinal fluid (CSF) of patients with IDH-mutant gliomas, no study has evaluated the ability of CSF D-2-HG to quantitatively monitor tumor burden and therapeutic response. Toward this goal, we are routinely obtaining CSF samples from patients prior to, during, and after treatment via intra-operative collection and CSF-access devices.

MATERIAL AND METHODS

Patients were enrolled into our Ommaya reservoir study (NCT04692337), which enables longitudinal access to CSF. The catheter for the implanted reservoir was placed within the surgical resection cavity following a standard-of-care resection. Intra-operatively collected CSF samples were also biobanked through Mayo Clinic’s Neuro-Oncology biorepository. CSF samples were also acquired via clinically indicated ventriculoperitoneal shunts (VP shunts) or external ventricular drains via our ongoing CSF biomarkers study (NCT04692324). D-and-L-2-HG were assayed from each CSF sample via gas chromatography-mass spectrometry (GC-MS) at Mayo Clinic’s Biochemical Genetics Laboratory.

RESULTS

CSF was collected prior to and after resection in patients via Ommaya reservoirs or VP shunts, all of whom underwent near gross total resections (>95% of tumor volume). D-2-HG and the D/L ratio fell on average by 57.9% (range: 15.1%-98.6%) and 68.8% (range: 49.3%-98.9%), respectively, following resection. In one patient with a largely intraventricular grade 4 IDH-mutant astrocytoma, D-and-L-2-HG fell by 99.1% and 99.3% by post-operative day 2, consistent with the impact of ventricular contact on baseline CSF D-2-HG levels. In patients for whom CSF was collected throughout chemoradiation, with or without immunotherapy, D-2-HG and the D/L ratio continued to decrease over time, despite concern for pseudoprogression versus progression on imaging.

CONCLUSION

Our early experience with this strategy demonstrates the potential for intracranial CSF D-2-HG as a monitoring biomarker for IDH-mutant gliomas. Work is ongoing to evaluate the reproducibility of these findings in a larger cohort of patients with low or high-grade gliomas, in addition to the impact of tumor recurrence on 2-HG. Future studies will evaluate the impact of IDH inhibitors and other experimental therapies on CSF 2-HG levels for pharmacodynamic monitoring of treatment response.
P15.09.B ALONG-TRACT ANALYSIS OF DTI PARAMETERS TO DETECT EXTENSION AND DIRECTION OF WHITE MATTER ABNORMALITIES IN PATIENTS WITH DIFFUSE LOW GRADE DIFFUSE GLIOMAS
Authors: Fahlström M , Mirza S , Latini F
Published: September 2023

BACKGROUND

Diffuse Low-grade gliomas (DLGG) show extensive infiltration through white matter (WM) tracts. Diffusion tensor tractography with along-tract analysis (ATA) has been used to non-invasively assess the microstructural integrity of WM pathways. The possibility to detect the extension and direction of WM infiltration using local DTI-based parameters in DLGG has been investigated with different techniques but displayed inconsistent results. The aim of this study was to use ATA analysis to compare DTI parameters in white matter pathways invaded/spared by DLGGs.

MATERIAL AND METHODS

Fourteen patients with a diagnosis of DLGG were included. DLGGs were manually segmented based on 3D-FLAIR images spatially normalised to MNI space. DTI was acquired for all the subjects using a single-shot echo-planar sequence on a 3T with 48 sampling directions. DTI data was reconstructed within MNI space using q-space diffeomorphic reconstruction (QSDR) in DSI studio. Five bilateral sets of WM pathways were reconstructed based on the HCP-1021 template. ATA was performed for FA, AD and RD for all five bilateral WM pathways. In short, all WH pathways were stretched to the same length of 100 indices, FA, RD and AD were sampled for each index. An overlay of tumour 3D reconstruction was used to detect contact with WM pathways . Not affected WM pathways were considered normal and included as normal data. All WM pathways were compared individually and per index to the normal data using a z-test.

RESULTS

Eight patients had an IDH-mutated grade 2 astrocytoma, 6 had a 1p19q co-deleted grade 2 Oligodendroglioma. ATA analysis displayed a clear difference between invaded and non-invaded WM pathways in all the DTI parameters. In infiltrated pathways, the z-test displayed: 1) significant lower FA only within a limited tumoral area but not along the all infiltrated segment; 2) RD was significantly higher compared with normal data in a larger area even beyond the tumour borders; 3) AD was significant lower in the infiltrated WM pathways beyond the tumour borders.

CONCLUSION

s: ATA analysis is a sensitive and reliable method to detect the extension and the direction of diffusion abnormalities within and beyond the DLGG extension. Our results support other studies suggesting that FA is not an enough sensitive index to detect gliomas related WM abnormalities. A wider use of this method may be valuable to better plan the surgical resection of patients with DLGG or to tailor radiotherapy planning according to WM invasion.
P16.02.B DIAGNOSTIC ACCURACY OF CSF LIQUID BIOPSY AND MRI FOR LEPTOMENINGEAL METASTASES IN SOLID CANCERS: A META-ANALYSIS
Authors: Nakasu Y , Deguchi S , Nakasu S , Yamazaki M , Notsu A , Mitsuya K , Hayashi N
Published: September 2023

BACKGROUND

Leptomeningeal metastasis (LM) is a life-threatening and quickly advancing complication in patients with solid cancer. Reliable diagnosis is challenging. CSF cytology remains the standard diagnostic test for LM, though the sensitivity has been reportedly at un-satisfactory levels ranging 40 to 60% in the literature. We evaluated the diagnostic accuracy of CSF liquid biopsy and advanced magnetic resonance imaging (MRI) for detecting LM in patients with solid cancers.

MATERIAL AND METHODS

A systematic search was conducted to identify all published diagnostic accuracy studies on CSF liquid biopsies and MRI on electronic databases with registration for PROSPERO. Articles were selected based on pre-defined criteria following the PRISMA 2020 statement. Assessment of Risk of Bias (ROB) was based on QUADAS 2.

RESULTS

The search yielded 3790 citations to screen between January 2000 to March 2022. Ten studies with 668 patients were included in the final analysis: seven studies of circulating tumor cells (CTC), five studies of MRI, and two studies of cell-free tumor DNA (ctDNA). The pooled prevalence of LM was 50.9% (340/668). The sensitivity was calculated presenting synthetic results as follows: CTC, 87.0% [95% CI: 77.9-92.6]; ctDNA, 97.9% [19.3-100]; MRI 59.4% [60.7-76.9]; cytology, 71.9% [54.7-82.9].The synthesized specificity was as follows: CTC, 93.8% [86.9-97.2]; ctDNA, 89.0% [25.3-99.5]; MRI 97.6% [77.3-99.8]. The diagnostic odds ratio was 100.6 (29.38-344.09) for CTC and 93.3 (88.42-1034.05) for MRI. ROB assessment showed high risk sources in domains of patient selection and index test.

CONCLUSION

his study showed a better sensitivity of CSF cytology than the reports in the literature. Novel CSF liquid biopsies had sufficient sensitivities, and advanced MRI had a high specificity. Cytology and the new diagnostic methods are complementary and may offer early diagnosis and improved diagnostic accuracy for LM in patients with solid cancers. Further research is required to specify the threshold values and to construct standards of biomarker-driven and less invasive approach for individual cancers, and they would facilitate clinical trials for LM in the era of targeted therapy.
P16.08.A SINGLE-CELL MAPPING OF LEPTOMENINGEAL DISEASE IN GLIOBLASTOMAS
Authors: Sankowski R , Dalmau Gasull A , Khavaran A , Cahueau J , Prinz M
Published: September 2023

BACKGROUND

The leading edge of glioblastomas is characterized by the crowding of neoplastic cells around neurons and inside the perivascular space, a phenomenon known as satellitosis. Recent research has focused on the interaction between glioblastoma cells and neuronal networks, but the specific cells contributing to perivascular satellitosis have not been comprehensively studied.

MATERIAL AND METHODS

To address this gap, we conducted single-nucleus RNA sequencing on glioblastoma samples, dissecting the leptomeninges and tumor core from freshly resected tissue. As the brain parenchyma and perivascular space cannot be easily separated, we sampled tumor cells from the leptomeninges, the outer limit of the perivascular space. This approach harnesses the fact that the subarachnoid and perivascular spaces are directly connected. Thus, we could isolate perivascularly located tumor cells.

RESULTS

Our analyses revealed distinct transcriptional signatures between tumor cells from the leptomeninges and those from the tumor core. Tumor core-associated cells showed transcriptional programs related to hypoxia and collagen expression, while leptomeningeal tumor cells displayed programs related to axonal guidance, synaptic function, and extracellular matrix expression. Interestingly, there was significant overlap with previously published gene expression programs found in tumor cells integrating into neuronal circuits. Cell-cell interaction analysis identified interaction between tumor cells and the resident cell types of the perivascular space, including fibroblasts, perivascular macrophages and lymphocytes.

CONCLUSION

Our study provides a robust methodology for high-dimensional analysis of glioblastoma cells spreading through the perivascular space in human patients. Using this methodology we shed light on the biological processes of perivascular satellitosis and the spread of glioblastoma cells via pre-existing anatomical niches. Due to the distinct cellular composition of the perivascular space, the biology of satellitosis is distinct from the processes in the parenchyma. These findings have important implications for the development of targeted molecular therapies for glioblastomas.
P17.09.B REIRRADIATION AS A SALVAGE THERAPY FOR LOCAL GLIOBLASTOMA RECURRENCE
Authors: Lucas Calduch A , Macià Garau M , Villà Freixa S , Plans Ahicart G , Mesía Barroso C , Majós Torró C , Pons Escoda A , García Expósito N , Vilariño Quintela N , Mosteiro Lamas M , Velasco Fargas R , Simó Parra M , Cuadros Margarit R , Esteve Gómez A , Bruna Escuer J
Published: September 2023

BACKGROUND

There is a lack of successful strategies to treat glioblastoma (GB) recurrences. Reirradiation is one of them, but it only can be considered in a few patients with localized relapses. This review aims to analyse the role of reirradiation in this setting and the management difficulties associated with this strategy.

MATERIAL AND METHODS

We have retrospectively reviewed the outcome of GB patients treated with surgery and the standard Stupp regimen, that have received stereotactic radiotherapy (RT) at the time of a local in-field relapse in our centre, during the period from 2005 to 2022.

RESULTS

44 patients have been identified. The recurrence occurred at a median time of 9.7 months (m) after the end of the first RT. It was the first relapse in 89% of patients, and RT was given exclusively in 47.7% of cases. In the remaining patients, RT was combined with other treatments. The median maximum diameter of the relapse was 13.5 mm. Treatment schemes were mainly two: 35 Gy in 3.5 Gy daily fractions (52%) and 20 Gy in 5 Gy daily fractions (39%). Acute toxicity was mild, with worsening of previous neurological symptoms in only 15% of patients. After a median follow-up of 15 m, radiological responses were observed in 40% of patients, with a remarkable number of distant progressions in less than 6m (32.5%). The median time to progression was 4.8 m, being longer for patients treated at first relapse, females and with a Karnofsky index (KI) >70. The diameter of the relapse showed a tendency to impact in time to progression, but no differences for RT dose, RT scheme or type of strategy (exclusive RT vs combined) have been detected. The median overall survival after reirradiation was 14.9 m. Related prognostic factors were KI >70, size of the relapse (maximum diameter <25 mm) and reirradiation given at first relapse. Radiological changes after reirradiation were commonly observed (47% of patients); differentiating them from true local progression was often difficult.

CONCLUSION

Reirradiation is a feasible and safe therapeutic option to treat localized GB relapses, able to control the disease for a few months in selected patients, especially those with first recurrences and small lesions. Further studies must be performed to improve the radiological evaluation in these patients and to determine the optimal combination with other treatment modalities.
P18.02.B RELATIONSHIP BETWEEN PROGESTERONE RECEPTOR EXPRESSION WITH HISTOPATHOLOGICAL GRADING IN MENINGIOMA
Authors: Rahmawati D , Retnani D , Holipah H , Damayanti Y
Published: September 2023

BACKGROUND

Meningioma is a group of mostly benign, slow-growing neoplasms that most likely derive from meningothelial cells of the arachnoid layer of the brain and spinal medulla. Meningiomas are found in one-third of all tumors in the central nervous system. Meningioma is three times more prevalent in women than in males, it is frequently related to hormones in women, particularly progesterone, which is considered to have the utmost impact on meningioma. Objective: this study aims at discovering the relationship between progesterone receptor expression and meningioma histopathological grading in Indonesia, especially at Saiful Anwar Hospital Malang. Method: This study employed a cross-sectional analytical observational research design. The study sample was a paraffin block of meningioma cases at The Anatomical Pathology laboratory of Saiful Anwar Hospital and The Medical Faculty of Brawijaya University, obtained from 2017 to 2020. The data were collected through histopathological preparations, immunohistochemical preparations, and immunohistochemical evaluation. The data analysis was performed by using SPSS version 20.

RESULTS

Most meningioma cases at Dr. Saiful Anwar Malang Hospital are women between 41 and 50 years. Then, it is located in the frontal part and acquired a grade of histopathology I and has a progesterone receptor expression score of 4. The chi-square test showed no significant association between progesterone receptor expression and histopathological grading of meningioma. At the same time, partial logistic regression tests showed no significant association between sex, age, and location with meningioma histopathological grading. In addition, multinomial logistic regression tests showed that the sex, age, and location did not significantly increase or decrease the risk (odds ratio) to the grade of meningioma histopathology.

CONCLUSION

This study showed no significant association between progesterone receptor expression and meningioma histopathological grading and no association between the sex, age, and location of lesions with meningioma histopathological grading and no significant increased risk of histopathological grading due to gender, age, or lesion location.
P18.03.A HYPOFRACTIONATION WITH OPTIMIZED STEREOTACTIC RADIOSURGERY PLANNING FOR SKULL BASE PERIOPTIC MENINGIOMAS
Authors: Cho Y , Yoon K , Lee D , Song S , Kim Y , Hong C , Kim J
Published: September 2023

BACKGROUND

Skull base perioptic meningiomas are challenging for stereotactic radiosurgery (SRS). The therapeutic window between tumor control and normal tissue complication is extremely narrow in these tumors, especially of large volume and/or in close proximity to the optic apparatus (OA). To minimize the risk of radiation toxicity, we optimized our SRS plans in terms of both steeper dose fall-off and dose-volume constraints for OA and delivered hypofractionation treatment.

MATERIAL AND METHODS

Thirty-one patients had been treated with hypofractionated SRS using the CyberKnife for perioptic meningiomas > 10 cm3 in volume (median 18.9 cm3). Tumor locations were cavernous sinus (n=7), petroclival (n=6), and tentorial edge (n=6). Optimization in SRS planning was carried in two aspects: 1) for steeper dose fall-off, multiple virtual shells outside the target were introduced and appropriate dose limits (formulated from our own Gamma Knife data) were applied; and 2) to minimize the risk of optic neuropathy, dose-volume constraints for OA (from AAPM TG101) were applied. SRS was delivered in five daily fractions with a median cumulative dose 27.8 Gy.

RESULTS

With a median follow-up of 33 months, tumor control was achieved in 28 of 31 patients (90.3%). Treatment response on MRI included partial response (volume decrease > 20%) in 17 patients, stable in 11, and progression (volume increase > 20%) in 3. Neurological symptoms improved in 10 patients, unchanged in 20, and worsened in 1.

CONCLUSION

Our current results show a promising role of hypofractionated SRS with optimization in steeper dose fall-off and dose-volume constraints for OA for large-sized skull base perioptic megningiomas in terms of both tumor control and neurological outcomes.
P19.08.B INCREASED CORTICAL EXCITABILITY TO TRANSCRANIAL MAGNETIC STIMULATION CONTRIBUTE TO EPILEPTOGENESIS IN IDH1-MUTANT GLIOMAS
Authors: Naros G , Gorbachuk M , Machetanz K , Leao M T , Wang S , Honegger J , Tatagiba M
Published: September 2023

BACKGROUND

In-vitro studies indicate that gliomas with a mutation of the isocitrate dehydrogenase (IDH) increase neuronal excitability of the peritumoral cortex contributing to epileptogenesis in these patients. However, in-vivo evidence is missing. This study evaluates the electric characteristics of the brain-tumor-interface (BTI) relative to the IDH mutation status.

MATERIAL AND METHODS

To investigate peritumoral cortical excitability (CE), we applied 5258 pulses of transcranial magnetic stimulation (TMS) at the BTI of IDH-mutant (IDH-mt) and IDH-wildtype (IDH-wt) glial tumors in 39 patients. CE was assessed by the resting motor threshold (RMT) and the synchronized electromyographic (EMG) activity (i.e., event-related spectral perturbation, ERSP) after TMS. ERSP values were related to the IDH status, tumor grading, antiepileptic drug intake (AED) and the spatial relationship to the tumor borders.

RESULTS

There was not significant group difference in RMT. TMS to the BTI triggered an EMG synchronization decreasing linearly with the distance to the functional hotspot. In contrast, IDH-mt gliomas demonstrated an increased cortical output of the peritumoral brain tissue compared to IDH-wt gliomas. This effect was not attributable to AED intake or other histological and molecular characteristics. Notably, cortical hyperexcitability was detectable well beyond the tumor border.

CONCLUSION

s: This study provides in-vivo evidence of cortical hyperexcitability at the BTI of IDH-mt gliomas which could contribute to the epileptogenesis in these patients.