bluuebunny/crossref_metadata_2025 huggingface dataset:
P10.10.A Tumor Treating Fields (TTFields), temozolomide and lomustine co-application is efficacious in glioblastoma cancer cell lines
Authors: Fishman H , Monin R , Dor-On E , Wolfbauer C , Haber A , Giladi M , Weinberg U , Palti Y
Published: September 2022

Background

Temozolomide (TMZ) is the standard of care chemotherapy for newly diagnosed glioblastoma (ndGBM), the most common primary malignant brain tumor in adults. However, 50% of patients do not respond to TMZ due to expression of O6-methylguanine-DNA methyltransferase (MGMT), the enzyme involved in repair of TMZ-induced damage. Tumor Treating Fields (TTFields) are alternating electric fields that display anti-mitotic effects on cancerous cells, and have been shown to induce a state of BRCAness in various cancer types. Concurrent treatment with TMZ and TTFields demonstrated a major advance in treatment of patients with ndGBM, and was approved by the FDA in 2014. Recently, the addition of lomustine (CCNU) to TMZ demonstrated clinical benefit in ndGBM patients, with improved overall and progression free survival. The aim of the current study was to examine in GBM cells the effect of TTFields in conjunction with TMZ and CCNU.

Materials and Methods

U-87 MG, LN229, U118 and LN18 human GBM cell lines were tested for their MGMT expression levels, and treated with TTFields (200 kHz, of 0.83 V/cm RMS) for 72 h using the inovitro system. Efficacy of concomitant application of TTFields with TMZ and/or CCNU was tested by measuring cell count, colony formation, and apoptosis levels.

Results

U-87 MG and LN229 displayed no expression of MGMT, while U118 and LN18 expressed low and high levels of MGMT, respectively. Application of TMZ and TTFields resulted in increased cytotoxicity compared with each treatment alone, with an additive interaction seen in all examined cell lines. The cytotoxic effect resulting from co-application of CCNU with TTFields suggested a synergistic interaction between the two modalities for U-87 MG, LN229, and U118, an additivity for LN18. Concurrent TTFields/TMZ/CCNU was more efficacious than TTFields or TMZ/CCNU separately in all cell lines.

Conclusions

Application of TTFields with TMZ was additive, irrespective of MGMT expression levels, while TTFields with CCNU was additive when MGMT was plentiful, but displayed tendency to synergism when MGMT was absent or limited. These outcomes are in line with the BRCAness state induced by TTFields, as in the absence of MGMT, DNA damage induced by CCNU requires the BRCA pathway for repair. Application of TTFields together with TMZ and CCNU demonstrated increased efficacy, suggesting potential benefit of such therapy for ndGBM treatment.
P10.17.B Androgen receptor signalling has independent prognostic value and is associated with resistance to temozolomide and tumour growth in glioblastoma
Authors: Birzu C , Boussier J , Belin L , Da Costa Pereira T , Quissac E , Zerara M , Lemaire N , Mokhtari K , Verreault M , Idbaih A
Published: September 2022

Background

The spectrum of sex differences in glioblastoma (GBM) is a rising topic. GBM is more frequent (sex ratio M:F=1.6) and seem to have worse prognosis in males (M) compared to females. Androgen receptor (AR) is expressed in GBM but its role in GBM biology and clinics is not yet fully understood.

Material and Methods

We have selected from our tumour tissue bank: (i) GBM samples with clinical, pathological and molecular annotations and (ii) GBM-patient derived cell lines -GBM-PDCL- with transcriptomic profiling and available tissue from parental tumours.AR expression was investigated using multiplex IHC Opal stained-FFPE sections. Sensitivity of PDCL to hormonotherapy (dihydrotestosterone or enzalutamide EZT) alone or combined with temozolomide (TMZ) was tested using WST1 viability assay. Response to drugs were correlated to AR expression (high: log2 [FPKM] >2 or low: log2 [FPKM] <2). PDCLs dihydrotestosterone secretion was examined by ELISA in both supernatants and cell lysates.

Results

In our cohort of 1188 IDH muted GBM patients, the median follow-up was 27.7 (25.8-31.3). The sex ratio M:F was 1.68 and the median age at diagnosis was 57 years [18-69]. Compared to males, females have better prognosis with a median overall survival of 26.1 months vs 20.8 months (p<0.0001). In multivariate analysis, male gender was an independent prognostic factor with a HR of 1.43 CI95%(1.21-1.69) (p<0.0001) adjusted on age, MGMT status and Karnofsky indice . Although interaction between age and sex was not significant (p = 0.854), HR of gender varied through age category 1.53 CI95%( 1.01-2.33 ), 1.51 CI95%( 0.888-2.55 ) and 1.38 CI95%( 0.857-2.21) for males <45 years, between 46-55 years and > 55 years respectively. In GBM tumours, AR staining was positive in 5- 30% tumour cells. After 72h exposure to 10nM dihydrotestosterone, ARhigh GBM-PDCLs exhibit AR nuclear translocation and c-myc expression upregulation, suggesting functional activation of the receptor. AR pharmacological blockade increased temozolomide sensitivity in ARhigh GBM-PDCLs regardless of the patient’s sex. Moreover, ARhigh PDCLs secreted DHT, suggesting autocrine and paracrine AR stimulation in tumour microenvironment.

Conclusion

Our study highlights the independent prognostic significance of sex in GBM patients, where males exhibit a worse prognosis. In GBM-PDCL, we show that androgen receptor is (i) functional in vitro and (ii) associated with resistance to temozolomide. Further studies are needed to investigate the role of AR in tumour tissue microenvironment.
P10.21.B Pharmacogenomics profiling of gliomas for precision medicine
Authors: Lipsa A , Hau A , Ermini L , Toth R , Oudin A , Klink B , Hertel F , Mittelbronn M , Golebiewska A , Niclou S
Published: September 2022

Background

Molecular characterization based on genomic, transcriptomic and epigenetic profiling has led to a better delineation of various glioma subtypes and highlighted the individual paths of glioma evolution upon treatment and recurrence. However, due to cellular and molecular diversity of these tumors, the pharmacological treatment of gliomas, in particular of its most malignant subtype Glioblastoma (GBM), remains a major challenge. To address this challenge, we here apply a pharmacogenomics approach, modelling the disease in matched patient-derived preclinical models and profiling the differential drug response among individual patients and glioma subtypes

Material and Methods

We generated a cohort of 45 Patient-Derived Orthotopic Xenografts (PDOX) from a collection of over 400 glioma patients. We used a multi-parametric approach based on genetic, transcriptomic and longitudinal profiling of patients and their matched xenografts for a comprehensive subgrouping of our glioma cohort. Based on PDOX-derived 3D tumor organoids we carried out a targeted drug screen focused on epigenetic regulators. A high throughput drug screening using an unbiased large chemical library containing a unique collection of FDA approved compounds with high pharmacological diversity is currently ongoing.

Results

Our glioma cohort with matched PDOX and 3D tumor organoids represents diverse subgroups of glioma patients, including a unique collection of primary and relapsed tumors from the same patient. Our preliminary drug screen analysis on 3D organoids highlights selective susceptibility to certain epigenetic inhibitors in primary disease but not in the same patient’s relapse. Results of matching genomics and functional data will be presented.

Conclusion

An integrated personalized approach to profile gliomas at multiple genomic and functional levels allows for pharmacogenomic subgrouping of patients for personalized treatment strategies. This analysis will allow to link genotypes to functional phenotypes and hopefully identify therapeutic options for selected glioma sub-populations.
P10.22.A Prognostic role ofTCF7L2 in glioblastoma
Authors: Radu R , Petrescu G E D , Ionita R , Gafencu A , Brehar F , Gorgan R M
Published: September 2022

Background

Glioblastoma is the most common and devastating brain cancer and despite maximal surgical resection, chemotherapy and radiotherapy, the five-year survival rate is less than 7%. The TCF7L2 gene encodes transcription factor 7-like 2, a main effector of Wnt/β-Catenin signaling pathway involved in cancer development and progression. Aberrant activation of the TCF7L2 gene is one of the primary events in tumorigenesis by maintaining stem-cell characteristics, however its role in glioblastoma is poorly studied.

Material and Methods

The expression of TCF7L2 was analyzed by qRT-PCR in a series of consecutive glioblastoma samples from patients that underwent surgical resection. Secondary or recurrent glioblastomas were excluded from the analysis. All patients underwent radio- and chemotherapy according to the protocol. Housekeeping gene RPL13 was used as reference gene. The 2-ΔCT method was used to calculate the relative expression of TCF7L2 to the reference gene.

Results

A total of 49 glioblastoma samples were included in the study. The mean survival period was 58.2 weeks. The median value of TCF7L2 expression was used as a cut-off point for the survival analysis. There were no statistically significant differences regarding the clinical and histopathological factors between the groups with low and high expression of TCF7L2. By using the Kaplan-Meier analysis, we observed that patients with overexpression of TCF7L2 had a decreased survival rate compared to patients with low levels of TCF7L2 (38.8 weeks vs. 77.34 weeks, p = 0.001).

Conclusion

These results demonstrate that glioblastoma patients with high levels of TCF7L2 have a poorer survival rate and TCF7L2 might be a useful prognostic factor for these patients. However, further studies are needed to elucidate the mechanisms through which TCF7L2 affects the prognosis and its implication as a possible therapeutic target.

This work was supported by an ERA PerMed grant - ERAPERMED2018-270 (PerProGlio).
P10.23.B Polycystin-1 induces mechanotransduction pathways in gioblastoma cells under hydrostatic pressure
Authors: Zoi I , Gargalionis A , Papavassiliou K , Nasiri-Ansari N , Piperi C , Basdra E , Papavassiliou A
Published: September 2022

Background

Increased mechanical load and stiffness of the tumor microenvironment are key features during progression of gliomas. Polycystin-1 (PC1) is a mechanosensitive protein which perceives extracellular mechanical cues. The aim of the study was to investigate PC1 participation in mechanisms of glioblastoma (GBM) progression under a mechanically-induced microenvironment.

Material and Methods

We generated monolayer cell cultures and tumor spheroids of the T98G glioblastoma cell line. Cells were subjected to continuous hydrostatic pressure (HP), inhibition of PC1 mechanical perception through functional blockage of its extracellular domain, and silencing of PKD1 expression. The level of activation of PC1 mechano-induced downstream kinases (mTOR, ERK, FAK) and transcription factors (YAP, TAZ) was evaluated via Western blot at specific time-points. Functional assays were performed to assess cell proliferation, clone formation, and cell migration. qPCR was employed to quantify the mRNA expression of markers regarding certain traits of cancer cells.

Results

In monolayer cell cultures, PC1 functional inhibition under HP is associated with mTOR and ERK activation and elevated expression of TAZ. On the other hand, PKD1 knockdown under HP is associated with activation of FAK, but not mTOR or ERK. In tumor spheroids, PC1 inhibition acts in synergy with HP to activate FAK and upregulate YAP, but not ERK or mTOR. PC1 inhibition under HP is associated with compact 3-dimensional spheroid structures. PC1 inhibition acts in synergy with HP to suppress cell proliferation, clone formation, and cell migration in GBM cells. The same synergistic effect is observed on the expression of respective markers of apoptosis, angiogenesis, proliferation, and epithelial-to-mesenchymal transition of GBM cells.

Conclusion

PC1 seems to be able to sense applied mechanical forces in GBM cells by regulating the activity of downstream molecules and enhance certain traits of tumor promotion. This work was co-financed by Operational Programme “Human Resources Development, Education and Lifelong Learning”, National Strategic Reference Framework (NSRF) 2014-2020, Ministry of Economy and Development, Greece & European Union (European Social Fund (ESF), in the context of the project “Investigation of the role of polycystin proteins in glioma neoplastic cells”; Grant/Award Number: MIS 5047967
P10.24.A A personalized BRAF mutant glioblastoma with Human2Humanex-vivo cortical cultures
Authors: Zhang J , Joseph K , Beck J , Schnell O , Ravi V M , Heiland D H
Published: September 2022

Background

Glioblastoma is among the most common primary malignancy with a poor medium survival post-diagnosis. The incredible heterogeneity of glioblastoma highlights its incurable nature. Methods to overcome difficulties leaded by glioblastoma heterogeneity remain to be explored. Here we present our Human2Human personalized autografted BRAF(V600E) mutant glioblastoma model, focusing on the idea of precision. This model, with an inoculation of self-derived glioblastoma cells, can imitate the tumor growth, invasion, metabolism and microenvironmental crosstalk within its “native” microenvironment and allows us to investigate the influence of different chemotherapies on the immunosuppressive tumor microenvironment from each specific individual glioblastoma patient.

Material and Methods

Non-neoplastic cortical tissue was obtained from a BRAF(V600E) mutant glioblastoma patient during surgical operation. Tissue was sectioned and inoculated with autografted glioblastoma cells in order to establish the ex-vivo Human2Human personalized brain slice model. Slice viability and tumor growth were monitored throughout the culture period, with and without day-wise refreshed treatments of clinically proved BRAF/MEK inhibitors. Sections were fixed and stained post cultivation. Pathway proteins p-ERK, p-Akt based on BRAF signaling along with markers (TMEM119, Iba-1, CD3, CD68, GFAP and NeuN) for major cell types in the environment were stained. Single Nuclei RNA Sequencing and Spatially Resolved Transcriptomics were applied.

Results

Tumor growth quantification over the culture period revealed different tumor reaction and tolerance towards various chemotherapies. The combination of Vemurafenib + Trametinib exhibited more efficient therapy response in comparison with either Dabrafenib + Trametinib or Encorafenib + Trametinib. Immunofluorescence and immunohistochemistry based quantification referring to neurons (NeuN), astrocytes (GFAP) and microglia/macrophage cells (Iba-1) suggested no toxic effects of the drug combinations on the tumor microenvironment. BRAF pathway proteins and immune cells showed various activation patterns upon different treatment combinations on an immunofluorescence base. Single Nuclei RNA Sequencing revealed the mesenchymal differentiation of BRAF mutant glioblastoma cells. Spatially Resolved Transcriptomics characterized tumor recurrence and suggested the therapy response accurately and visually.

Conclusion

The combination of Vemurafenib + Trametinib shows strategy to this specific BRAF mutant glioblastoma patient. And therefore, this Human2Human personalized model has a potential to provide in-depth information of the spatio-temporal tumor differentiation ex-vivo, correct inter-patient bias, and model therapy response in a very short time frame to provide drug testing results for clinical decision making.
P11.10.A An assessment of predictive factors for overall survival in glioblastoma - MGMT methylation is solely important for younger patients
Authors: Krigers A , Cosar T , Kerschbaumer J , Demetz M , Pinggera D , Thomé C , Freyschlag C F
Published: September 2022

Background

Diverse groups of factors - neuropathological characters, tumor position and epidemiological data - have been proposed for outcome evaluation of glioblastoma (GBM). We compared clinical signs, neuropathological features and the locus of the tumor with the follow-up data.

Material and Methods

All adult patients with firstly diagnosed and histologically proven GBM (according to WHO 2016), which were operated in our center between January 2010 and June 2021 were retrospectively assessed. Epidemiological, clinical and neuro-pathological characteristics were acquired from our institutional neuro-oncological database.

Results

A total of 399 patients could be evaluated. The mean follow-up was 13.9 months (CI95 12.2-15.6), within 266 (67%) patients were deceased. Estimated mean OS for entire cohort was 24.2 months (CI95 19.8-28.7). Age, MGMT promoter methylation, brainstem localization or if a patient received biopsy only showed significant impact on OS. Each year of life accounted for 3.4% additional hazard to decease (HR=1.034, CI95 1.020-1.048, p<0.001). If patients were younger than 65 years, mean OS was 34 months (CI95 26.5-41.8) compared to older than 65 years patients with a mean OS of 14.3 months (CI95 10.5-18.1, p<0.001). Generally, an unmethylated MGMT promoter status was linked to 75% higher hazards to decease (HR 1.75, CI95 1.27-2.40, p=0.027). If MGMT promoter status was methylated, mean OS was 25.7 months (CI95 19.9-31.5) or more compared to unmethylated with 14.5 months (CI95 12.0-16.9, p=0.01). Presence of MGMT promoter methylation showed influence on OS only in the younger cohort (<65y, mean OS 38.7 months [CI95 28.9-48.6]; HR 2.60 [CI95 1.55-4.37], p<0.001) as opposed to unmethylated MGMT (mean OS 17.7 months [CI95 14.1-21.2], p<0.001). In the older cohort (>65y) presence of methylated MGMT promoter showed no significant difference (p=0.364). For patients who received only biopsy, 2.4 times more hazards for worse OS were revealed (HR 3.36, CI95% 2.30-4.90, p<0.001). In these cases, mean OS was 7.1 months (CI95 5.3-8.8). Other factors, including gender or preoperative seizures, as well as EGFR, p53, IDH1, ATRX and TERT status did not show impact on OS in our series.

Conclusion

In our cohort, MGMT promoter methylation showed an impact on OS only in younger patients <65 years of age. Biopsy of GBM should only be considered very selected patients when resection is not possible.
P11.15.B First multicentric real-life experience with the combination of lomustine and temozolomide in newly diagnosedMGMT promoter methylatedIDH wildtype glioblastoma
Authors: Lazaridis L , Schmidt T , Agkatsev S , Blau T , Spille D , Heider S , Schulz T , Bumes E , Oster C , Feldheim J , Stummer W , Kessler A , Seidel C , Hau P , Sure U , Keyvani K , Herrlinger U , Kleinschnitz C , Stuschke M , Herrmann K , Deuschl C , Hattingen E , Scheffler B , Kebir S , Glas M
Published: September 2022

Background

The CeTeG/NOA-09 trial assessed in a randomized phase 3 setting, whether combined treatment of lomustine together with temozolomide was superior to temozolomide treatment alone in newly diagnosed MGMT (O(6)-methylguanine-DNA-methyltransferase) promoter methylated glioblastoma patients. Survival was significantly improved from 31.4 months with temozolomide alone to 48.1 months with the combination of lomustine plus temozolomide. In view of this encouraging data - suggesting this combination could have a significant impact on the survival of newly diagnosed glioblastoma patients - we were curious to assess safety and efficacy of this regimen under real-life conditions.

Material and Methods

We collected clinical and radiographic data from adult newly diagnosed MGMT promoter methylated IDH (isocitrate dehydrogenase) wildtype glioblastoma patients treated at five neuro-oncology centers in Germany. As a requirement for inclusion, first-line treatment with lomustine plus temozolomide had to be performed for at least six weeks (one course). The available radiographic data was independently reviewed by an experienced board-certified neuro-radiologist.

Results

In total, 70 patients were included. Median progression-free survival of the full cohort was 14.4 months and median overall survival was 36.0 months. Patients who received TTFields (Tumor Treating Fields) treatment for eight weeks or longer together with the combination of lomustine plus temozolomide (n=22, 31%) had a prolonged progression-free survival compared to those patients who received TTFields treatment less than eight weeks or did not receive treatment with TTFields (n=48, 69%) (21.5 months versus 11.2 months; HR: 2.118, 95% CI: 1.245-3.605; p=0.0105). In a multivariable Cox regression analysis the use of TTFields for eight weeks or longer together with the combination of lomustine plus temozolomide as well as the application of at least five courses of CeTeG therapy emerged as independent prognostic factors for progression-free survival and overall survival. Pseudoprogression occurred in n=16 (33%) of the patients. We observed no treatment related deaths and high-grade hematotoxicity in n=31 (44%) of the patients.

Conclusion

The results from this multicentric trial that investigated newly diagnosed MGMT promoter methylated IDH wildtype glioblastoma under real-life conditions indicate toxicity and survival estimates comparable to the CeTeG/NOA-09 trial. The use of TTFields for at least eight weeks in combination with this regimen was independently associated with extended progression-free and overall survival.
P11.16.A Questioning convention - is intrathecal chemotherapy (ITC) necessary for patients with newly diagnosed primary central nervous system lymphoma (PCNSL): combined results from three independent cohorts
Authors: Tuohy K , Aregawi D , Seidel S , Rieger L , Klapschus O , Zacharia B , Korfel A , Schlegel U , Glantz M
Published: September 2022

Background

Despite beguiling responses to initial therapy in many patients, PCNSL remains a therapeutic challenge. Relapse is common, cures are elusive for most patients, and overall response are disappointing compared to other diffuse large B-cell lymphomas. High-dose methotrexate-based therapies have become the standard of care, with many variations, but there is no consensus, and very little data regarding the role of ITC in the initial treatment of patients with PCNSL.

Material and Methods

We collected study-level and where possible, patient-level data from three independent clinical trials comparing adults with newly diagnosed PCNSL treated with regimens that differed based on the use of ITC. Patient characteristics, overall (OS) and progression-free survival (PFS), and characteristics of relapse were examined. The frequency of lymphomatous meningitis at diagnosis based on the location of CSF sampling - ventricular vs. lumbar - was also investigated. Complete data retrieval for this updated analysis has allowed us to combine data from the three studies and calculate summary statistics using a random effects model and inverse variance technique. In addition, predictors of OS and PFS were modeled using a Cox proportional hazards technique.

Results

The three cohorts were treated with: HD MTX/rituximab/ifosfamide followed by either HD MTX/cytarabine/ifosfamide (group Ia), or cytarabine/thiotepa and autologous stem cell transplant (group Ib) (n=80); HDMTX/vinca alkaloids/ifosfamide/cytarabine (group II) (n=83); or HD MTX/rituximab (group III) (n=49). ITC consisted of MTX/cytarabine/prednisolone (group Ia only, n=43); MTX/cytarabine/prednisolone (group II, n=65); or liposomal cytarabine (group III, n=21). One- and two-year OS was better in the ITC chemotherapy compared to the no-ITC group (RR 1.25 [1.16-1.34] and 1.20 [1.14-1.26] respectively, p< 0.001 for both comparisons). One-year PFS was also improved in the ITC group (RR 1.12 [1.01-1.25], p=0.031). Two-year PFS was not statistically different between groups (RR 1.20 [0.90-1.59], p=0.220). Relapse involving the CSF was more frequent in the non-IT chemotherapy group (RR 2.31 [2.03-2.62], p< 0.001). CSF cytology was positive in 81% of ventricular specimens vs 14.3% of lumbar specimens (p< 0.001).

Conclusion

This analysis of three independent cohorts of adults with newly diagnosed PCNSL suggests (when ventricular rather than lumbar CSF is sampled) that lymphomatous meningitis is dramatically more frequent, and perhaps universal. Including ITC as part of the initial treatment regimen increased both OS and PFS substantially. A randomized controlled trial is urgently required.
P11.18.A Localizing value of EEG recordings in patients with glioblastoma
Authors: Silvaieh S , Marko M , Trimmel K , Zulehner G , Berghoff A , Preusser M , Schmook M , Ulbrich L , Hainfellner J A , Widhalm G , Rössler K , Berger T , Pataraia E , Grisold A
Published: September 2022

Background

Glioblastoma is associated with a high risk of epileptic seizures ranging from 40% to 60%. Before the advent of modern imaging techniques, electroencephalography (EEG) was a critical component in evaluating patients with space-occupying lesions. In this retrospective single-center study, we aimed (1) to characterize a cohort of patients with glioblastoma with regards to EEG monitoring, seizure frequency and the frequency of prescribed anti-seizure medications (ASM) and (2) to assess the value of EEG as a localizing technique in patients with glioblastoma.

Material and Methods

We reviewed the charts of 179 patients with glioblastomas between January 1st, 2020 and January 1st, 2022, treated at the Medical University of Vienna. The diagnosis was based on MRI and/or confirmed by biopsy according to the 2016 World Health Organization Classification of Tumors of the Central Nervous System. Patients who received an in-house EEG as part of their diagnostic work-up were included if an MRI/CT scan was available (within an average time of +/-60 days). For localization, focal slowing (theta/delta activity) and/or epileptiform discharges were considered. EEG rating was performed by a board-certified electrophysiologist blinded for the diagnosis and MRI/biopsy findings.

Results

We included 52 patients (29.05% of screened cohort) with at least one EEG and MRI or CT scan performed before or after EEG, following inclusion criteria (median: 2 days; mean: 6 days; range: -29 to 52), in the final analysis. Clinical seizure activity and/or epileptiform discharges on EEG were detected in 46 patients (88.46%), and 48 patients (92.31%) were on ASM.

An IDH-wildtype glioblastoma was diagnosed in 45 patients (86.54%), 4 had an IDH-mutant glioblastoma (7.69%), and in 3 patients, IDH-status was unknown (5.77%). In 22 patients (42.31%), biopsy revealed a positive MGMT promoter methylation status, while 28 were unmethylated (53.84%), and two patients had an unknown MGMT promoter methylation status (3.85%). Intermittent and/or continuous focal slow-wave activity was registered in 45 patients (86.54%). In comparison, epileptiform discharges could only be found in 13 patients (25%). When compared to MRI/CT scans, the hemispheric tumor localization could be determined in 42 cases (80.77%). Moreover, the affected brain lobe was accurately predicted in 35 patients (67.31%). Three patients had diffuse EEG changes (5.77%), and EEG was unremarkable in 7 patients (13.46%).

Conclusion

Overall, our presented data indicate that the hemispheric localization of glioblastoma can be reliably predicted by EEG recordings, while a precise (brain lobe-specific) localization was only possible in around two-thirds of cases.
P11.19.B Bevacizumab in recurrent WHO grade 2-3 gliomas
Authors: Annakib S , Rigau V , Darlix A , Gozé C , Duffau H , Bauchet L , Mollevi C , Fabbro M
Published: September 2022

Background

Medical management of recurrent WHO grade 2-3 (rGII/III) gliomas is not well established. Bevacizumab (BEV) is an option at malignant recurrence. Yet, very few data are available in this indication. The aim of this study is to describe clinical outcomes in patients treated with BEV.

Material and Methods

A retrospective study was conducted including patients treated by BEV for a rGII/III glioma at our institution (2011 - 2019). Data were collected from medical records. Tumor samples were reviewed according to the WHO 2016 classification. Efficacy was assessed according RANO criteria. Progression Free Survival (PFS) and Overall Survival (OS) from BEV initiation were estimated using the Kaplan-Meier method. A Cox proportional hazards model was performed to estimate Hazard Ratios with 95% Confident Intervals (CI).

Results

A total of 81 patients was included (sex ratio: 1.6 M/W, median age at diagnosis: 38). Among them, 46 patients (56.8%) had a grade 2 and 35 (43.2%) a grade 3 glioma. The histological forms were astrocytoma (grade 2 -3) IDH mutated in 27 patients (33.3%), IDHwt in 15 patients (18.5%) and oligodendroglioma (grade 2 - 3) in 13 patients (16%). Twenty-six patients were not reclassified. Previous treatment included tumor resection for all patients (second intervention in 22.2%). First-line medical treatment consisted of chemotherapy in 60.5% patients before any radiotherapy. Chemotherapy was rechallenged in 52 patients (64.2%). All patients but one received radiation therapy and 19 patients (23.5%) received a reirradiation. BEV was administered at 10 or 15mg/kilogram every 2 or 3 weeks. All patients had a contrast enhancement on MRI at baseline. Median number of BEV cycles was 7 [1-79], in association with chemotherapy in 45.7%. Partial response, stable disease and progressive disease was observed in 27.2%, 22.2% and 50.6% respectively. Median OS from BEV introduction was 7.6 months (95% CI [5.5;9.9]). Median PFS was 4.9 months (95% CI [3.7;6.1]). In univariate analysis, grade 2 (Odd Ratio (OR)=0.41, 95% CI [0.17;1.02], p=0.054), Ki67<7% (OR=0.41, 95% CI [0.15;1.21], p=0.079) and initial total surgical resection (OR=2.75, 95% CI [0.68;11.11], p=0.097) showed a trend for delayed progression. BEV was stopped for progression in 70.4%, for toxicity in 8.6% and for others reasons in 21% patients. Twenty-four patients (29.6%) discontinued BEV without progression (medical decision, BEV toxicity or patient decision). Presence of 1p19q codeletion (OR=0.24, 95% CI [0.07;0.84], p=0.023) and age ≥ 38 (OR=0.36, 95% CI [0.13;0.99], p=0.042) at diagnosis were more frequent in this sub-population. Out these of 24 patients, 8 showed survival from 3 months to 5 years without any other treatment.

Conclusion

BEV can be a good option for patients with rGII/III glioma. One third of them stopped treatment without progression, reaching a survival of several years for some of them.
P11.23.B Neurological symptoms independently associate with overall survival in patients with melanoma brain metastases
Authors: Steindl A , Heimbach K , Ressler J , Gatterbauer B , Dieckmann K , Widhalm G , Preusser M , Berghoff A
Published: September 2022

Background

Based on the the rising detection of asymptomatic brain metastases (BM) and the remarkable intracranial responses of targeted- and immunotherapy in specific subgroups of asymptomatic BM patients, we aimed to evaluate the clinical characteristics and prognostic value of neurological symptoms in BM from melanoma.

Material and Methods

670 patients with newly diagnosed melanoma BM were identified from the Vienna Brain Metastasis Registry. We performed retrospective chart review and statistical outcome analyses.

Results

370/670 (55.2%) patients presented with neurological symptoms including neurological deficits (316/370; 85.4%), signs of increased intracranial pressure (126/370; 34.1%) and epileptic seizures (53/370; 14.3%). 57.6% (80/139) of patients with BRAF mutated melanoma presented with asymptomatic BM at diagnosis. Absence of neurological symptoms at BM diagnosis was associated with a longer median overall survival after time of BM diagnosis (7 vs. 5 months; p< 0.001; log-rank test). In multivariate analysis with the diagnosis-specific graded prognostic assessment (DS-GPA: HR:1.4; 95% CI, 1.25-1.48; p<0.001) and the graded prognostic assessment for melanoma using molecular markers (Melanoma-molGPA: HR:0.8; 95% CI, 0.66 -0.92; p<0.001), the presence of neurological symptoms (HR 0.8; 95% CI, 0.69 -0.96; p=0.003/ HR:0.6; 95% CI, 0.59-0.72; p<0.001) was found to be independently associated with survival prognosis from time of BM diagnosis respectively.

Conclusion:

Neurological symptoms at the time of BM diagnosis are an independent and strong prognostic factor in melanoma BM patients. Our results argue for the integration of neurological symptoms into the prognostic assessment of patients with BM from melanoma.
P11.24.A The anisotropic component of the decomposed diffusion tensor predicts overall survival in patients with glioblastoma
Authors: Simon N L , Sinha R , Sravanam S , Mayrand R , Li C , Wan Y , Wei Y , Price S
Published: September 2022

Background

The diffusion tensor can be decomposed into isotropic (DTI-p) and anisotropic (DTI-q) components (Peña et al., 2006). Regions of DTI-q abnormality have a high tumour burden and increased surgical resection of abnormal DTI-q positively correlates with overall survival (OS) (Yan et al., 2017). We aimed to establish if median voxel DTI-q (MVQ) or a distribution measure of DTI-q (DMQ) could act as a neuro-imaging biomarker, to predict OS in patients with glioblastoma.

Material and Methods

Diffusion tensor decomposition was used to create DTI-p and DTI-q maps, using FSL software (FMRIB Software Library, Oxford). MVQ and DMQ (the 95th centile minus the 5th centile of the DTI-q distribution, divided by the MVQ) were calculated from the preoperative whole brain (WB), contrast-enhancing (CE), and non-contrast-enhancing (NCE) hemisphere DTI-q maps, using fslstats, for 33 patients with glioblastoma. Using R Studio, multiple linear regression (MLR) models were computed to establish if MVQ or DMQ of the WB, CE and NCE hemispheres or age, significantly predicts OS. The Breusch-Pagan Test, on package “lmtest” in R, was calculated for all MLR models, to determine if heteroscedasticity was present and, if so, bootstrapped multiple regression (BMR) models were computed using package “boot” in R.

Results

Evidence for heteroscedasticity was present in MLRs that modelled the relationship between DMQ of WB, age, and OS (BP = 6.032, p = 0.014) and DMQ of CE hemisphere, age, and OS (BP = 7.163, p = 0.028). In the BMR of WB DMQ, age, and OS, the 95% bias-corrected accelerated confidence intervals (BCa-CI) for the WB DMQ regression coefficient was 133.5 - 1851.4 and included the WB DMQ estimated coefficient of 803.9. The BMR of CE hemisphere DMQ, age, and OS, computed a 95% BCa-CI for the CE hemisphere DMQ coefficient of 101.8 - 1579.6, containing the CE hemisphere DMQ coefficient estimate of 612.414. For both BMRs, the 95% BCa-CI for age coefficients crossed a value of 0. From computed MLR models, WB MVQ (t = -2.569, p = 0.015), CE hemisphere MVQ (t = -2.143, p = 0.040), NCE hemisphere MVQ (t = -2.567, p = 0.015) and NCE hemisphere DMQ (t = 2.39, p = 0.024) were significant predictors of OS. Age did not significantly predict OS in any models and was not significantly related to WB, CE and NCE hemisphere MVQ or DMQ.

Conclusion

WB, CE and NCE hemisphere MVQ and DMQ predict OS in our tested subgroup of patients with glioblastoma. Age is not a significant predictor of OS and does not significantly correlate with MVQ or DMQ. The median value and distribution spread of DTI-q may act as a prognostic biomarker in glioblastoma, facilitating patient stratification.
P11.29.B Risk factors associated with the presence of brain metastasis at the moment of diagnosis in non-small cell lung cancer patients. Retrospective case series
Authors: Martín-Abreu C M , Fariña-Jerónimo H , Plata-Bello J
Published: September 2022

Background

Lung cancer is the second most frequent neoplasm worldwide and the leading cause of cancer death in both sexes. Furthermore, it is the most common origin of brain metastases. The aim of this study is to identify clinical, histological, and molecular variables associated with a higher risk of presenting brain metastases at the moment of diagnosis in patients with lung cancer.

Material and Methods

A single-center retrospective case series analysis of patients with a new diagnosis of lung cancer (from January 2015 to December 2018) was performed. A total of 723 total patients with a new diagnosis of non-small cell lung cancer (NSCLC) were identified. Only patients with a brain imaging study at the time of diagnosis were included in the analysis. Non-parametric statistical tests were used to compare patients with or without metastases at the moment of diagnosis. A uni- and multivariate analysis were performed to identify risk factors associated with the presence of brain metastases at NSCLC diagnosis. Statistical significance was considered when p<0.05.

Results

We included 135 patients with a new diagnosis of lung cancer and with brain imaging study at the time of diagnosis (mean age at diagnosis of 64.69 years [SD= 10.34]; 71.9% men). The most common histology was adenocarcinoma (67.1%) followed by squamous carcinoma (25.2%). Brain metastases were present in 40% of patients at diagnosis. No significant differences in clinical, histological and molecular variables was identified between patients with or without brain metastases. In any case, as expected, the survival analysis showed that brain metastasis at diagnosis was associated with a worse overall survival (Log-Rank test, p<0.01).The univariate analysis showed that presenting neurological symptoms (OR=19.5, p<0.0001 CI [7.895-47.65]), histology of adenocarcinoma (OR= 2.113, p<0.014 CI [1.160-3.849]) and the presence of visceral metastases (OR= 14.444, p<0.0001 CI [6.161-33.86]) were associated to the presence of brain metastases at diagnosis. The presence of metastases limited to the thorax (OR= 0.019, p<0.001 CI [0.003-0.146] was associated to be free of brain metastasis at NSCLC diagnosis. However, only neurological symptoms (OR= 20.290, p<0.0001 CI [4.953-83.118]), presenting visceral metastases (OR= 4.451, p<0.010 CI [1.458-13.777]) and/or metastases limited to the thorax (OR= 0.066, p<0.024 CI [0.006-0.010]) reached statistical significance in the multivariate analysis.

Conclusion

Neurological symptoms and the presence of visceral metastases are independent predictors or presenting brain metastasis at the moment of diagnosis in lung cancer patients. On the other hand, the presence of lung cancer disease confined in the thoracic cavity is associated with a lower risk to present brain metastasis
P11.33.B Tumour Treating Fields (TTFields; 200 kHz) with chemo-radiation and maintenance TTFields/temozolomide as first-line treatment for newly-diagnosed glioblastoma: The phase 3 TRIDENT Trial (EF-32)
Authors: Shi W , Kleinberg L , Jeyapalan S A , Goldlust S A , Nagpal S , Roberge D , Nishikawa R , Grossman R , Glas M
Published: September 2022

Background

Tumour Treating Fields therapy (TTFields; 200 kHz) is a noninvasive, loco-regional, antimitotic treatment approved for newly diagnosed glioblastoma (ndGBM) and mesothelioma. In the phase 3 EF-14 trial, TTFields/temozolomide (TMZ) significantly increased overall survival (OS) and progression-free survival (PFS) vs TMZ alone in patients with ndGBM. TTFields-related adverse events (AEs) were mainly dermatological with no increases in systemic toxicity. In preclinical models, the addition of TTFields to radiotherapy (RT) increased the therapeutic effect. In 2 clinical pilot phase 2 studies, TTFields added to RT/TMZ was reported as feasible and well-tolerated.

Material and Methods

TRIDENT (EF-32; NCT04471844) is an international, phase 3 randomised trial comparing TTFields (200 KHz, ≥ 18 h/day)/RT/TMZ vs RT/TMZ alone. Eligibility criteria include histologically confirmed ndGBM, ≥ 18 years of age (≥ 22 years of age; US), Karnofsky Performance Status ≥ 70, life expectancy ≥ 3 months, adequate organ function and eligible for RT/TMZ - participants will be stratified by extent-of-resection and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. During the initial 6-week investigational period, patients in the experimental arm will receive continuous TTFields and concomitant RT/TMZ whilst patients in the control arm will receive only RT/TMZ. Subsequently, all patients will receive TTFields and 6 cycles of maintenance TTFields/TMZ. TTFields will continue for 24 months or until second disease progression per Response Assessment in Neuro-Oncology (RANO), whichever occurs first. The primary endpoint is median OS. Secondary endpoints include median PFS (RANO), 1- and 2-year survival rates, overall radiological response (RANO), PFS6, PFS12, severity and frequency of AEs (Common Terminology Criteria for Adverse Events v5.0), post-treatment pathological changes in resected GBM tumours, quality-of-life per EORTC QLQ-C30, OS correlation to TTFields duration-of-usage, and neurological assessment per NANO (Neurological Assessment in Neuro-Oncology) and RANO criteria. Survival will be measured from time-of-randomisation. Sample size (N = 950; randomised 1:1) was powered for a hazard ratio < 0.8 with a 5% type I error. The hypothesis, that first-line TTFields/RT/TMZ can significantly improve OS vs RT/TMZ, will be tested using a stratified log-rank test.

The study is currently open to enrollment in locations in Austria, Belgium, Czech Republic, France, Germany, Israel, Switzerland, and across the US.
P11.35.B The clinical course of long-term survivors after the diagnosis of brain metastasis
Authors: Jünger S T , Meissner A , Ruge M I , Rueß D , Goldbrunner R , Grau S
Published: September 2022

Background

To asses demographic and clinical parameters, treatment, and course of disease in patients surviving longer ≥ 5 years after the diagnosis of brain metastasis (BM).

Material and Methods

We retrospectively identified patients who were treated for BM and survived ≥ 5 years after initial BM diagnosis. We analysed and described clinical and treatment related parameters with respect to histology, time to occurrence and systemic/ BM-specific treatment.

Results

We included 48 patients with a mean age of 55 years (range 33-81, SD 12) at diagnosis of primary tumor and 58 (range 41-84, SD 20) at initial BM diagnosis. Histology was non-small-cell lung cancer in 18 (37.5%), melanoma in 14 (29.2%), breast cancer in 11 (22.9%), renal carcinoma in 2 (4.2%), and small-cell lung cancer, cancer of unknown primary and gastrointestinal cancer in one case each (2.1%). Treatment for primary tumor included resection (83.3%), chemotherapy (43.8%), radiation (33.3%), interferon therapy (18.8%), and immuno-/targeted therapy (25%). Most patients received a combination of latter. The mean interval between primary tumor and BM diagnosis was 36 months (range -2 to 277; SD 57). At the time of BM diagnosis, 50% of patients presented with systemically stable disease, 66.7% showed BM related symptoms, 92% showed a KPS ≥70. Most patients had 1 BM (72.9%), while 20.9% had 2-3 and 6.3% >3. Initial treatment for BM comprised resection (60.4%), stereotactic radiosurgery (27.2%), whole-brain-radiation therapy (8.4%), and interstitial brachytherapy (4.2%). Approximately half of the patients (52.1%) suffered from ≥1 BM relapse at initial treatment site. At the time of the analysis, 13 (27.1%) patients had died; cause of death was mostly unknown, in two patients each, systemic/cerebral cause was confirmed. The mean overall survival (OS) was 131 months (range 64-344, SD 68) and 95 (range 60-246, SD 36) after diagnosis of primary tumor and BM, respectively. All patients suffering from melanoma who had received interferon therapy (n=8) survived. Neither systemic status at BM diagnosis nor the administration of novel treatment agents or chemotherapy after BM diagnosis showed an impact on OS (p=0.642, p=0.177 and p=0.628, respectively). Further survival analysis was omitted due to subgroup sizes.

Conclusion

Despite the usually fatal course after BM development, some patients show long-term survival. Whether specific genetic parameters have a particular impact in this subgroup of patients, warrants further investigation.
P11.40.A Clinicopathological Analysis of High risk Pituitary Adenomas According to the 2017 WHO Classification System for Pituitary Neuroendocrine Tumors (PitNET)
Authors: Kim Y , Ahn S , Jeun S , Lee Y , Park J
Published: September 2022

Background

The 2017 WHO classification of pituitary tumors has revealed “high-risk pituitary neuroendocrine tumors (PitNETs)”, which were known to have high probability for recurrence. Tumor invasion was not included in the pathological grading and classification due to frequent lack of proper pathologic assessment. However, it mentioned tumor invasion as an important prognostic feature in identifying clinically aggressive adenomas.

Material and Methods

We performed a retrospective review of a prospectively collected dataset from January 2018 to March 2021. Patient’s clinical presentation, radiologic features, pathologic findings, and clinical outcome were gathered. Inter-group analysis was performed for high-risk versus low-risk tumors, and invasive versus non-invasive tumors.

Results

Among total 116 cases of PitNETs, high-risk and low-risk tumors were identified in 32 and 84 cases, respectively. The inter-group comparison showed no differences in clinical presentation, radiologic features, pathologic findings, and clinical outcomes.Invasive and non-invasive tumors were identified in 49 and 67 cases, respectively. The invasive group tumors were more symptomatic ( 29 (59.2%) vs. 30 (44.8%), p= 0.031), with larger tumor size over 40mm (9 (18.4%) vs. 1 (1.5%), p = 0.002), and more likely to have Knosp grade higher than 3. The gross-total resection was less achievable (7 (14.3%) vs 26 (38.8%), p = 0.007) However, Ki-67 index showed no significantly difference between the invasive group and non-invasive group (2.0 vs 2.0 , p= 0.556).

Conclusion

According to our study results, the pathologic diagnosis of a high-risk tumor does not necessarily seem to properly reflect the clinical aggressiveness. Tumor invasion, however, seems to better represent the aggressive tumors that requires proper and active treatment.