bluuebunny/crossref_metadata_2025 huggingface dataset:
OS03.5.A Characterization of the inflammatory tumor microenvironment composition in solid cancer patients with brain metastases after progression to immune checkpoint inhibitor therapy
Authors: Starzer A M , Kleinberger M , Feldmann K , Tomasich E , Hatziioannou T , Paiato C , Heller G , Kreminger J , Traint S , Steindl A , Ressler J M , Widhalm G , Gatterbauer B , Dieckmann K , Müllauer L , Preusser M , Berghoff A S
Published: September 2022

Background

Immunotherapy (IO) has changed the treatment landscape of metastatic cancer patients, however, treatment resistance is frequent. We aimed to characterize the inflammatory tumor microenvironment in brain metastases (BM) after IO to gain a deeper understanding of immunologic escape mechanisms.

Material and Methods

Solid cancer patients who had BM resection after IO progression (IO cohort) were retrospectively identified. We analyzed tumor-infiltrating immune cell subsets (CD3, CD8, CD45RO, FOXP3) and expression of immune checkpoint molecules (PD-L1, PD-1, LAG-3) by immunohistochemistry. A control cohort of BM tissue samples without prior IO served for comparison (no immunotherapy cohort, NIO).

Results

Twenty-eight IO patients (12/28, 42.9% females; 16/28, 57.1% males; median 61 years; 14/28, 50% lung cancer; 5/28, 17.9% melanoma; 4/28, 14.3% renal cell carcinoma; 1/28, 3.6% breast cancer; 4/28, 14.3% other cancer entities) and 57 NIO patients (28/57, 49.1% females; 29/57, 50.9% males; median 58 years; 35/57, 61.4% lung cancer; 9/57, 15.8% breast cancer; 4/57, 7.0% melanoma; 3/57, 5.3% renal cell carcinoma; 6/57, 10.5% other cancer entities) were included. IO patients had a median of one (range 0-4) systemic therapy line prior to IO. Median time from last IO application until BM resection was 5.6 months (range 0.2-49.8 months). Patients received a median number of 7 (range 1-56) IO applications (14/28, 50% PD-1-targeting IO; 8/28, 28.6% PD-L1; 2/28, 7.1% CTLA4; 4/28, 14.3% CTLA4+PD-1; 3/28, 10.7% IO+chemotherapy). No statistically significant differences in the densities of investigated TILs or PD-L1 expression between the IO and the NIO cohort were observed. Patients of the IO cohort showed higher PD-L1 expression compared to the NIO cohort (57.1 vs. 42.1%, Chi-square, p>0.05). Overall survival (OS) was similar in both cohorts, with a median OS of 11.0 months (range 5.0-17.0) in the IO cohort and 11.0 months (range 5.5-16.5) in the NIO cohort.

Conclusion

Our findings show an upregulation of PD-L1 in BM occurring after prior IO therapy in the absence of other overt changes in the inflammatory microenvironment. Ongoing analyses in this cohort are investigating possible molecular driver of resistance by analyzing DNA methylation profiles of pre-and post-IO tissue samples of the IO cohort to potentially gain insights on inflammatory IO resistance mechanisms in BM patients.
OS06.6.A Real-World Pattern of Care Study on Glioblastoma in the Austrian Population. Final results from 2014-2020
Authors: Oberndorfer S , Woehrer A , Borkovec M , Marosi C , Payer F , Urbanic-Purkart T , Nowosielski M , Iglseder S , Stockhammer G , Kleindienst W , Florea C , Hager A , Tinchon A , Stultschnig M , Surboeck B , Pichler J , Leibetseder A , Weiss S , Hutterer M , Seebrecht L , Roetzer T , Hainfellner A , Hainfellner J
Published: September 2022

Background

The Austrian ABTR-SANO Glioblastoma Registry is the first population-based assessment of patterns of care for patients with Glioblastoma across Austrian healthcare institutions. The primary aim is to assess the real world effectiveness of administered therapies.

Material and Methods

Clinical data are collected via a common web-based IT platform “ABTR-SANO Net” since 2014. The database and the ongoing evaluation of clinical parameters, as well as interims analysis are provided in cooperation with a review board. First Outcome analysis, including patients from 2014-2020, was performed at the end of 2021.

Results

Eleven centers across Austria are involved, and the data of 1416 patients (m/f ratio: 1,35, median age: 66 years) were recently analyzed in detail. Age, extent of resection, as well as ECOG was associated with improved survival. Methylated MGMT Status also showed a moderate survival benefit. Patients with re-resection and re-radiation also exhibited improved survival, which however may be attributed to a selection bias.Second line treatment manly comprised of antiangiogenic treatment, followed by alkylated agents, re-radiation and re-surgery. Median overall survival of all patients was 344 days and clearly age dependent (best for <50 years, worse for>80 years).

Conclusion

This is the first population based outcome analysis of Glioblastoma in Austria. Results regarding prognostic markers and outcome are mostly comparable with international data. Robust population based data are important in order to monitor quality of health care, and to match the data with results from clinical studies.
OS06.7.A Underlying mechanisms of verbal fluency in glioma patients: language or executive functioning?
Authors: Collée E , Van den Berg E , Visch-Brink E , Dirven C , Vincent A , Satoer D
Published: September 2022

Background Glioma patients often suffer from cognitive deficits, such as in language and executive functioning (EF). A sensitive test to identify these deficits is verbal fluency (VF). In VF, participants are asked to generate as many unique words within a given semantic category (category fluency - CF) or starting with a given letter (letter fluency - LF) within one minute. While both language and EF play a role in VF, the relative contribution of both domains remains unclear. We aim to retrospectively investigate performance on VF and, for the first time, on Non-Verbal Fluency (NVF), requiring to connect 5 points in different patterns within three minutes. Additionally, we aim to explore the influence of language and EF on VF performance in glioma patients.

Materials and Methods 69 adults with gliomas in eloquent areas underwent a comprehensive neuropsychological test-battery at 1-2 months before surgery (T1) and 3 (T2) and 12 months (T3) after surgery. The protocol consisted of VF (CF: animals, professions, LF: D-A-T/K-O-M), language tests (Repetition (Akense Afasie Test), Token Test, Boston Naming Test) and EF tests (Five Point Test, Trail Making Test, Stroop Colour-Word Test, Wisconsin Modified Card Sorting Task). VF and NVF performance were compared 1) to healthy population using one sample t-tests/Wilcoxon rank-tests (all patients), and 2) between T1, T2, and T3 with paired sample t-tests/Wilcoxon rank-tests (31 patients). Linear regression analyses were conducted to investigate the predictive value of language and EF on VF for all patients.

Results Preoperatively, patients were impaired on all VF tasks. Especially CF profession performance was more prone to deterioration after surgery at T2 and T3. In contrast, NVF was intact and even improved after surgery (T1-T3, T2-T3). NVF (p = .032, EF) was a predictor for CF animals while the Token Test (p = .023, language) was a predictor for CF professions. Both NVF (p = .032, EF) and the Token Test (p = .004, language) were predictors for LF.

Conclusion First, glioma patients were preoperatively impaired in VF but were preserved in NVF, as is in line with the literature. Secondly, CF professions appeared to be particularly sensitive to detect long-term postoperative decline. Thirdly, the main result of this study is that both language and EF mechanisms appeared to be responsible for VF performance in glioma patients. These findings are useful for interpreting VF impairment in glioma patients and for therapeutic interventions, suggesting a combination of language and EF training materials.
OS09.5.A The experience of interval scans for adults living with primary malignant brain tumours
Authors: Rudkin S , Booth T C , Absolom K , Latchford G , Short S C , Boele F W
Published: September 2022

Background

People living with primary malignant brain tumours (PMBT) face a complex and unpredictable illness. Throughout the disease course they undergo various treatments and follow-up with regular interval scanning. There are potential costs and benefits to interval scanning, however there is no high-quality evidence to suggest interval scanning is beneficial or whether scans alter outcomes of importance for people living with PMBTs. Yet, interval scanning may exacerbate issues such as uncertainty and anxiety - which impacts on patient quality of life. The aim of this study was to gain an in-depth understanding of how adults living with PMBTs experience and cope with interval scanning.

Material and Methods

Twelve patients with a diagnosis of PMBT (glioblastoma n=10; astrocytoma grade 3 n=1; solitary fibrous tumour of the dura grade 3 n=1) under the neuro-oncology teams at Leeds Teaching Hospital NHS Trust and King's College Hospital NHS Foundation Trust took part in the study. They were interviewed remotely about their experiences of interval scans, following a semi-structured interview guide. An abbreviated version of a constructionist grounded theory approach was used to analyse data.

Results

Five main themes were generated from the data: ‘Living with a PMBT’, ‘Interval scanning: the difficult times’, ‘MRI scan: accepting the discomfort’, ‘Waiting for results: coping with the uncertainty’ and ‘Results: providing some certainty in uncertainty’. Although most participants found interval scans uncomfortable, they accepted that they were something that they had to do and were using various coping methods to get through the MRI scan. All participants said that the wait between their scan and results was the most difficult part. Despite the difficulties they experienced, all participants said that they would prefer to have interval scans than wait for a change in their symptoms. Most of the time, scans provided relief, gave participants some certainty in an uncertain situation, and a short-term sense of control over their lives.

Conclusion

The present study shows that interval scanning is important and highly valued by patients living with PMBT. Although interval scans are anxiety provoking, they appear to help people living with PMBT cope with the uncertainty of their diagnosis.
OS09.6.A Factors predicting mood disorders, health related quality of life and sexual disturbances in adults with glioma: a retrospective study
Authors: Leonetti A , Puglisi G , Rossi M , Conti Nibali M , Sciortino T , Gay L , Vigano' L , Fornia L , Cerri G , Bello L
Published: September 2022

Background

It is not clear whether Mood Disorders (MD) and poor Health Related Quality of Life (HRQoL) in glioma patients correlate with clinical and histomolecular features of the tumor or with secondary symptoms associated with treatment. This study assessed the prevalence of MD and decline in HRQoL (with a specific interest in sexuality) in glioma patients, identifying the clinical, imaging and treatment factors associated with these variables.

Material and Methods

260 glioma patients (190 lower grade) were evaluated. Patients were prospectively followed-up from admission to 12 months after surgery, for MD and HRQoL assessment. 115 were asked to fill a questionnaire for sexual life investigation. Clinical, imaging, histomolecular features as well as cognitive functions were evaluated. Variables associated with MD,low HRQoL and sexual life impairment were identified by bivariate analysis.

Results

Factors associated with MD and low HRQoL were different in LGGs and HGGs over the course of the disease. In LGGs the effect of adjuvant treatments was prominent in determining the prevalence of MD and poor HRQoL from the third month after surgery onward. In HGGs, MD and poor HRQoL were associated with older age. In both, cognitive deficits were associated with MD. 42% of patients showed dissatisfaction for their sexual life and decrease of sexual intercourses, which were linked to a reduction of libido (22%), astenia (39%), pharmacological therapy (23%), and self-image insecurity(22%). Patients undergoing adjuvant treatments showed a lower sexual satisfaction.

Conclusion

Overall the data suggest that worsened quality of life, Incidence of Mood disorder and worsening in sexual life affect a relevant amount of patients affected by glioma. Lack of recovery from functional deficits (language, attentive/executive and motor deficits) and adjuvant therapies (expecially radiotherapy) play a crucial role in determining the emergence of Mood Disorders, low HRQoL and worsened sexual life.
OS10.4.A A macrophage-based drug delivery platform for glioma treatment
Authors: Sun M , Bialasek M , Rygiel T , Król M , Weller M , Weiss T
Published: September 2022

Background

There is an urgent need for more effective treatment strategies against gliomas. At present, even though various drugs have potent anti-tumor activity in vitro, their application in vivo is limited by ineffective delivery and systemic toxicity. Therefore, novel strategies are needed to deliver these drugs effectively and safely to the tumor site. Here, we developed an adoptive transfer strategy against malignant brain tumors utilizing macrophages that are loaded with ferritin-protein cages containing drugs or other proteins and transfer these nanocarriers to cancer cells in vitro and in vivo.

Material and Methods

Live-time imaging, microscopy and flow cytometry were utilized to investigate the transfer of ferritin cages from loaded macrophages to human or mouse glioma cells. Co-cultures of glioma cells and macrophages loaded with ferritin-drug cages were used to study the anti-glioma activity in vitro and orthotopic immunocompetent mouse glioma models were used to study the anti-glioma activity in vivo. Affinity purification-mass spectrometry (AP-MS) was used to elucidate the mechanisms of transfer by characterizing the interactome of ferritin cages within macrophages and cancer cells.

Results

We observed a high transfer efficiency of ferritin-cages from loaded macrophages into human and mouse glioma cells in vitro in co-culture assays and confirmed the transfer from macrophages to glioma cells also in vivo upon intravenous or intratumoral treatment of GL-261 or CT-2A glioma-bearing mice. To study the anti-glioma activity with therapeutically active payloads, we loaded murine/human macrophages with ferritin cages carrying cytotoxic payloads. Co-culture of these loaded macrophages with murine or human glioma cells in vitro revealed a time- and concentration-dependent cytotoxicity to glioma cells. In vivo, intravenous or intratumoral administration of ferritin-drug protein cages was tolerated without toxicities and conferred a survival benefit in two orthotopic murine glioma models (GL-261 and CT-2A). Interactome studies of ferritin-cage-binding proteins revealed phagocytic and cytoskeleton re-arrangement pathways to be involved in uptake and transfer of ferritin-cages from macrophages to glioma cells.

Conclusion

This ‘Trojan Horse’ approach constitutes a promising platform to deliver cytotoxic drugs effectively and safely to gliomas and provides a rationale for clinical translation.
OS10.5.A Modeling immunocompetent tumor microenvironment in glioblastoma patient-derived orthotopic xenografts
Authors: Moreno-Sanchez P M , Oudin A , Yabo Y A , Klein E , Baus V , Poli A , Michelucci A , Niclou S P , Golebiewska A
Published: September 2022

Background

To date, glioblastoma (GBM) remains a fatal disease, with a median overall survival of roughly over a year. There is a crucial need of new treatment options, yet most clinical trials have failed partly due to the lack of predictive preclinical model systems. Currently, most patient-derived preclinical models suffer from the reduction or absence of immune system components, which represents a bottleneck for adequate immunotherapy testing. Humanized mice offer new opportunities here, since they rebuild an adaptive human immune system in a NSG mouse. Derivation of glioblastoma patient-derived orthotopic xenografts (PDOXs) in humanized mice appears thus as a promising tool for testing new treatment strategies targeting the tumor microenvironment (TME).

Material and Methods

We derived PDOXs through intracranial implantation of GBM primary organoids in different immunocompromised mouse strains (Nude, NOD/SCID, NSG). To introduce back the adaptive human immune system, GBM PDOXs were further derived in human CD34+ hematopoietic stem cell-engrafted NSG (HU-CD34+) mice. We applied single-cell RNA-sequencing, multicolor flow cytometry, immunohistochemical analyses and functional studies to examine the heterogeneous TME in a cohort of GBM PDOX models. We further interrogated the contribution and crosstalk between the human and mouse components constituting the brain TME in HU-CD34+ PDOXs.

Results

We show that glioma PDOXs can be derived in mice of different background including Nude, NOD-SCID, NSG and HU-CD34+ mice. Mouse-derived TME created in PDOX models contains tumor-associated macrophages (TAMs) known as major immuno-suppressive components of human GBM tumors. We further show that PDOXs derived in HU-CD34+ NSG mice present human CD45+ immune cells in the bone marrow and blood. Interestingly, we detect an influx of human immune cells in tumors developed in the mouse brain, which interact with the brain-derived immunosuppressive TME of mouse origin.

Conclusion

We here provide a thorough characterization of the heterogeneous brain TME created in GBM PDOX models. We show that human GBM can instruct mouse-derived brain cells towards immune-suppressive TME. The missing adaptive immune component can be introduced by derivation of GBM PDOXs in humanized mice. Such immunocompetent in vivo models will be important for testing novel therapies targeting different immune components in GBM.
OS10.6.A What is the initial cell in the subventricular zone for human glioblastoma genesis?
Authors: Yoon S , Choi R , Cho S , Kim H , Lee J , Kim E , Chang J , Kim S , Kim H , Lee J , Kang S
Published: September 2022

Background

We all have a fundamental question about why glioblastoma (GBM) develops. In order to find the answer to this fundamental question, if you find out what the first cell is, you will get closer to the answer. GBM arises from the subventricular zone (SVZ). GBM is one of the most devastating tumour of human brain as the most optimal treatment barely prolongs the survival, and it does not cure the disease. As the majority of GBM tissues show copy number variations (CNV) of co-altered chromosomal 7 gain and 10 loss, we hypothesized the origin cell (Oc) of SVZ may be traced back with these markers. The cellular identity of the Oc is still unknown and it is different from the tumour-derived progenitor-like cells. We aimed to define these cells from the SVZ that have a potential to get activated into GBM.

Material and Methods

We compared bulk RNA sequencing (RNAseq) data of IDHwt GBM tumor tissue (n=122), tumor free SVZ from GBM patients (n=40), tumor-free control SVZ of non-glial tumor (n=9). Pared single nucleus RNAseq (snRNAseq) or single cell RNAseq (scRNAseq) samples of tumor free SVZ (n=11) and GBM tumor (n=8), were done to see cell specific CNVs. We developed genetically engineered mouse models for GBM genesis introducing three driver mutations (TP53, PTEN, and EGFRviii) into SVZ to isolate mouse Oc (mOc) and mouse cancer cells (mCc). The biological characteristics of separated mOc and mCc were compared. Bulk RNAseq and scRNAseq were performed on these cells (mOc, mCc), and their cellular state was compared with the human gene set.

Results

In this work, we found two types of the Oc in the RNA sequencing of 60 human tumour free-SVZ samples. Furthermore, single-cell level analysis revealed that two Oc types in SVZ harbor ongoing patterns of CNV co-alterations from Oc1 to Oc2, and finally to GBM. The Oc1 type cells contained the CNV signature of Oc2 ancestor with neural progenitor cell (NPC) signature. Oc2 type cells expressed a high level of EGFR than other cells with astrocyte-like cell signature. Both of these cells expressed oligodendrocyte progenitor cell (OPC)-like signatures in the SVZ. We validated the human-based findings by using the P53/PTEN/EGFR-mutant mouse model with EGFR/tdTomato overexpression and P53/PTEN knockout in the SVZ cells. As a result, non-tumourigenic and highly motile Oc-like cell-states are found in the mouse models, supporting the firework-like migration pattern from the SVZ.

Conclusion

Our results demonstrate how members of Oc preoccupy the SVZ, known as the stem cell niche and give rise to the tumour. We anticipate that a new therapy may emerge by targeting the Oc in the SVZ.
OS10.7.A Activation of the CCR8-ACP5 axis by human microglia/macrophage derived CCL18 promotes glioma growth
Authors: Huang Y , Motta E , Nanvuma C , Yuan Y , Kuhrt L , Xia P , Lubas M , Zhu S , Schnauss M , Hu F , Zhang H , Lei T , Synowitz M , Flüh C , Kettenmann H
Published: September 2022

Background

Glioblastoma multiforme is a highly malignant primary brain tumor with an average survival of 14 months and very limited therapeutic options. Glioma associated microglia and macrophages (GAMs) foster tumor growth by releasing several cytokines, which have only partly been identified. Here, we studied the chemokine (C-C motif) ligand 18 (CCL18), a chemokine which is only expressed in human, but not rodent GAMs, in a novel ex-vivo brain slice model including transplantation of human induced pluripotent stem cells (iPSC) derived human microglia (iMGL) and human glioma cells in to murine brain slices, which had been depleted of intrinsic murine microglia before.

Material and Methods

After establishing the humanized ex-vivo brain slice model, we performed immunohistochemical analysis (IHC) of growth and invasiveness, qrtPCR on glioma cells isolated by magnetic-activated cell sorting (MACS), functional assays measuring invasiveness, proliferation, migration and colony formation of glioma cells in vitro and in slice experiments. Corresponding studies on tumor growth and invasiveness were performed after treatment with a CCL18 neutralizing antibody, a CCR8 neutralizing antibodies and knockdown of CCR8, ACP5 (Acid Phosphatase 5) and PITPNM3 with small interfering RNA (siRNA) and short hairpin RNA (shRNA). QrtPCR, IHC and Westernblot analysis were performed on primary glioma specimens. We also conducted bioinformatic analyses, based on the TCGA GBM, GLIOVIS and GEPIA databases.

Results

We observed that CCL18 was highly expressed in GAMs, whereas CCR8 was only expressed in glioma cells. We identified the chemokine (C-C motif) receptor 8 (CCR8) as a functional receptor for CCL18 and ACP5 as an important down-stream signaling component in glioma cells. Activation of the CCL18/CCR8/ACP5 signaling pathway in human glioblastoma was associated with enhanced tumor growth and invasiveness.

Conclusion

GAMs derived CCL18 promoted glioma growth by activation of the CCR8/ACP5 axis in human glioma cells and therefore is a potential therapeutic target.
P01.02.B Case Report: Disruption of Resting-State Networks and Cognitive Deficits After Whole Brain Irradiation for Singular Brain Metastasis
Authors: Kocher M , Jockwitz C , Lerche C , Sabel M , Lohmann P , Stoffels G , Filss C , Motthagy F M , Ruge M I , Fink G R , Shah N J , Galldiks N , Caspers S , Langen K
Published: September 2022

Background

Long-term survivors of whole brain radiation (WBRT) are at significant risk for developing cognitive deficits, but knowledge about the underlying pathophysiological mechanisms is limited. Therefore, we here report a rare case with a singular brain metastasis treated by resection and WBRT that survived for more than 10 years where we investigated the integrity of brain networks using resting-state functional MRI.

Material and Methods

A female patient with a left frontal non-small cell lung cancer (NSCLC) brain metastasis had resection and postoperative WBRT (30.0 in 3.0Gy fractions) and stayed free from brain metastasis recurrence for a follow-up period of 11 years. Structural magnetic resonance imaging (MRI) and amino acid [O-(2-[18F]fluoroethyl)-L-tyrosine] positron emission tomography (FET PET) were repeatedly acquired. At the last follow up, neurocognitive functions and resting-state functional connectivity (RSFC) using resting-state fMRI were assessed. Within-network and inter-network connectivity of seven resting-state networks were computed from a connectivity matrix. All measures were compared to a matched group of 10 female healthy subjects.

Results

At the 11-year follow-up, T2/FLAIR MR images of the patient showed extended regions of hyper-intensities covering mainly the white matter of the bilateral dorsal frontal and parietal lobes while sparing most of the temporal lobes. Compared to the healthy subjects, the patient performed significantly worse in all cognitive domains that included executive functions, attention and processing speed, while verbal working memory, verbal episodic memory, and visual working memory were left mostly unaffected. The connectivity matrix showed a heavily disturbed pattern with a widely distributed, scattered loss of RSFC. The within-network RSFC revealed a significant loss of connectivity within all seven networks where the dorsal attention and fronto-parietal

control networks were affected most severely. The inter-network RSFC was significantly reduced for the visual, somato-motor, and dorsal and ventral attention networks.

Conclusion

As demonstrated here in a patient with a metastatic NSCLC and long-term survival, WBRT may lead to extended white matter damage and cause severe disruption of the RSFC in multiple resting state networks. In consequence, executive functioning which is assumed to depend on the interaction of several networks may be severely impaired following WBRT apart from the well-recognized deficits in memory function.
P01.07.A Neurocognitive outcomes after proton beam therapy for skull base tumours
Authors: Gaito S , Hwang E , Aznar M , France A , Sitch P , Crellin A , Holtsman A L , Pan S , Whitfield G , Smith E
Published: September 2022

Background

Evidence suggests that Proton Beam Therapy (PBT) may lessen the risk of neurocognitive decline (NCD) by reducing the dose to the normal brain as compared to conventional photon radiotherapy (XRT). We report the incidence of moderate-severe (Grade ≥3) NCD in adults treated for skull base chordomas and chondrosarcomas within the United Kingdom’s Proton Overseas Programme (POP).

Material and Methods

Baseline (pre-PBT) and follow-up clinical outcomes data were prospectively collected as part of a national PBT-outcomes registry, which started in 2008 . This registry is curated by a dedicated Proton Clinical Outcomes Unit. Specifically, late toxicities ≥G3 as per CTCAE (Common Terminology Criteria for Adverse Events) v4.0 definition, occurring later than 90 days after treatment completion, were recorded. This study focuses on the incidence of memory impairment (MI) in the adult (≥25 y) cohort.

Results

Between 2008-2018, 141 adult patients were treated for skull base chordomas (77 patients, 54.6%) and chondrosarcomas (64 patients, 45.4%) via the POP (the majority -62.8%- treated at the University of Florida PBT Institute). Median age at treatment was 51 years (range 26-77). Median prescription dose was 73.8 GyRBE (70-75.6), with a median dose per fraction of 1.8 Gy (1.2-2.1). Of note, the median dose for chondrosarcomas was 70.2 GyRBE (70-75.6), whereas the median dose for chordomas was 73.8 GyRBE (72-75.6). Median follow up was 39 months (0-138). On clinical assessment, 4 patients (2 chordomas, 2 chondrosarcomas) were reported with G3 MI after a median time of 43 months (27-49). None of them had impaired memory at baseline, nor relevant neurological comorbidities. Median age of those who developed G3 MI was 63 y (39-70). Median prescription dose was 72.9 GyRBE (70-73.8). Plans were available for 3 of these 4 patients. Relevant dose statistics to hippocampi and temporal lobes were extracted. Dmean to the omo- and contralateral hippocampi in these 3 patient plans were: patient 1) 33.7 and 11.6 GyRBE; patient 2) 28.1 and 24.4 Gy; patient 3) 8.7 and 8.2 GyRBE, respectively. V20 to the omo- and contralateral temporal lobes in the same patients were: patient 1) 47% and 10%; patient 2) 29% and 28.7%; patient 3) 30% and 28%, respectively. Suggested constraints for these structures are: Dmean < 20 Gy to the hippocampi and V20Gy <10% to the temporal lobes.

Conclusion

Our results indicate that adult patients undergoing high dose radiation for radioresistant tumours may experience detrimental effects on memory. Neurocognitive baseline and follow-up assessment is not routinely performed in this age group but might be appropriate to explore which domains of cognitive function are mainly affected. Larger cohorts are warranted to establish predictive factors and better understand dose volume effect of brain structures and neurocognitive sequelae.
P01.14.B Visuospatial selective attention deficit after resection of right hemisphere gliomas: a multivariate lesion symptom mapping and diffusion tractography study
Authors: Puglisi G , Viganò L , Sciortino T , Leonetti A , Rossi M , Conti Nibali M , Gay L , Fornia L , Cerri G , Bello L
Published: September 2022

Background

The ability to select relevant information to current behavioural goals despite concomitant distractors (i.e. selective attention) is crucial for daily life. Despite the implication of fronto-parietal network in sustaining visuospatial selective attention has been considered crucial, the role of subcortical structures is still unclear. Aim of this study was to evaluate the impact of neurosurgical removal of right gliomas on visuospatial selective attention performances.

Material and Methods

The visuospatial selective attention domain was assessed pre- and postoperatively (1 month follow-up) in 73 patients operated for right hemisphere gliomas. Support-vector-regression lesion-symptom mapping and disconnectome analysis (Lesion Quantification Toolkit, HCP 1065 data) were used to evaluate the relationship between the resection cavities and the postoperative performance on a standardized selective attention test. To test and refine the atlas-based results, in a subset of 17 patients with preoperative diffusion tractography, the postoperative outcome was correlated with the percentage of disconnection for different white matter tracts.

Results

Results showed that resection of a cluster enclosing the SMA-complex and the surrounding white matter was significantly associated with a decline in visuospatial selective attention performances (p<.05). Disconnectome analysis at population level revealed that the deficit was significantly correlated with the resection of superior cortico-striatal fibres, superior thalamic radiations, corticopontine projections, callosal connections and fibres of the frontal aslant tract. Within all the cortico-subcortical terminations of these tracts, disconnection of streamlines of the SMA-complex was the most associated with selective attention deficits. Tractography in single patients confirmed the population level results and suggested that ventro-lateral resections in case of inferior frontal or insular tumours significantly disconnecting the frontal aslant tract but sparing superior projection fibres were not associated with any postoperative disturbances.

Conclusion

Results show converging evidence to support a critical role for the SMA/preSMA and its projections in maintaining efficiency of attentive control. The present results reveal the importance of a fronto-medial descending connectivity in mediating the voluntary control of visuospatial selective attention. From a surgical standpoint, to avoid postoperative deficits, it seems crucial to preserve SMA projection pathways, while the disconnection of the frontal aslant tract is feasible without any postoperative decline.
P01.15.A Longitudinal assessment of neurocognition and quality of life in low-grade glioma patients receiving first-line Temozolomide
Authors: Darlix A , Fabbro M , Monnier M , Castan F , Coutant L , Denis E , Carriere M , Menjot de Champfleur N , Rigau V , Duffau H , Guerdoux E
Published: September 2022

Background

While maximal safe resection is the first therapeutic option in patients with newly-diagnosed diffuse low-grade glioma (DLGG), the timing and choice of further treatments (chemotherapy, radiation therapy or combinations of both) remain controversial. Because the expected survival is long in these young patients, the oncological impact of treatments must be balanced with the possible side effects, in particular regarding neurocognitive functioning and quality of life (QoL). Temozolomide (TMZ), an alkylating agent, is widely used in this setting. Here we aimed at evaluating the feasibility of a longitudinal neurocognitive and QoL assessment in DLGG patients receiving TMZ.

Material and Methods

We conducted a prospective study including adult DLGG patients receiving TMZ as first-line treatment after surgical resection(s) or biopsy. Neurocognition and QoL were evaluated longitudinally until progression. The feasibility was evaluated in terms of participation and compliance of a complete neurocognitive and QoL assessment (defined as the completion of these assessments at baseline, 6 months and 12 months). Secondary objectives were the description of the proportion of patients with changes in neurocognitive or QoL scores on TMZ.

Results

Of 29 eligible patients, 26 accepted to enter the study (participation rate 86.7%): 57.7% men, median age 45y. Tumor type was distributed as follows: astrocytoma, IDH-mutant 13/26, astrocytoma, IDH wild-type 1/26 and oligodendroglioma, IDH mutant and 1p19q codeleted 12/26. The compliance rate was 95.6% (evaluable in 23 patients as 3 patients had tumor progression within the first 12 months of TMZ). After TMZ, 13.6% of patients experienced a decline of the MoCA score as compared to baseline (from normal to abnormal). Cognitive complaints according to the FACT-COG assessment were stable for 90.9%. The complete cognitive and QoL evaluations (baseline and after 12 months of TMZ) will be presented.

Conclusion

Our data shows that a longitudinal evaluation of cognition and QoL is feasible in low-grade glioma patients. It suggests that first-line TMZ does not negatively affect neurocognition and QoL. These results must be evaluated in the long-term setting (evaluations ongoing) and confirmed in a larger, multicenter cohort.
P01.16.B Neurocognitive outcome and seizure freedom after awake surgery of gliomas
Authors: Reitz S , Behrens M , Lortz I , Conradi N , Rauch M , Filipski K , Voss M , Kell C , Czabanka M , Forster M
Published: September 2022

Background

Gliomas are often diagnosed due to epileptic seizures as well as neurocognitive deficits. First treatment choice for patients with gliomas in speech-related areas is awake surgery, which aims at maximizing tumor resection while preserving or improving patient’s neurological status. The present study aimed at evaluating neurocognitive functioning and occurrence of epileptic seizures in patients suffering from gliomas located in language-related areas before and after awake surgery as well as during their follow up course of disease.

Material and Methods

In this prospective study we included patients who underwent awake surgery for glioma in the inferior frontal gyrus, superior temporal gyrus, or anterior temporal lobe. Preoperatively, as well as in the short-term (median 4.1 months, IQR 2.1-6.0) and long-term (median 18.3 months, IQR 12.3-36.6) postoperative course, neurocognitive functioning, neurologic status, the occurrence of epileptic seizures and number of antiepileptic drugs were recorded.

Results

Between 09/2012 and 09/2019, a total of 27 glioma patients, aged 36.1 ± 11.8 years, were included. Tumor resection was complete in 15, subtotal in 6 and partial in 6 patients, respectively. While preoperatively impairment in at least one neurocognitive domain was found in 37.0% of patients, postoperatively, in the short-term, 36.4% of patients presented a significant deterioration in word fluency (p=0.009) and 34.8% of patients in executive functions (p=0.049). Over the long-term, scores improved to preoperative baseline levels. The number of patients with mood disturbances significantly declined from 66.7% to 34.8% after surgery (p=0.03). Regarding seizures, these were present in 18 (66.7%) patients prior to surgery. Postoperatively, 22 (81.5%) patients were treated with antiepileptic drugs with all patients presenting seizure-freedom.

Conclusion

In patients suffering from gliomas in eloquent areas, the combination of awake surgery, regular neurocognitive assessment - considering individual patients′ functional outcome and rehabilitation needs - and the individual adjustment of antiepileptic therapy results in excellent patient outcome in the long-term course.
P01.18.B Structural abnormalities related to chemotherapy in cancer survivors: an ALE meta-analysis of neuroimaging studies
Authors: Ahmed Y , Al-Bzour A , Al-Majali G , Ababneh O , Ibrahim R , Al-Khalili A , Hamza A , Alzghoul S , Al-Mannai R , Z Alawneh K , Al-Hayek K , Al Qawasmeh M
Published: September 2022

Background

Chemotherapy induced cognitive impairment (CICI) is a term used for the cognitive dysfunction reported with non-central nervous system cancer patients during or after chemotherapy. Recent neuroimaging studies have shown decreased activation in cancer patients during cognitive tasks post-chemotherapy. Structural changes are sought to be associated with cognitive decline in cancer survivors after chemotherapy. Here we aim to investigate the neuroimaging findings of structural abnormalities and gray matter alterations associated with chemotherapy in cancer survivors.

Material and Methods

A systematic search through PubMed database for peer-reviewed English-language studies yielded a total of 302 studies. Eligible studies were included in the activation likelihood estimation (ALE) meta-analysis if they reported coordinates in a stereotactic format (MNI or Talairach space) for voxel-based morphometric (VBM) studies on gray matter volume and post-chemotherapy cancer survivors compared to matched healthy controls. GingerALE (3.0.2) software from Brainmap.org was used to perform the ALE meta-analysis with threshold settings of uncorrected P-value < 0.001 for multiple comparisons.

Results

The study sample included 299 patients comprised of breast cancer survivors (BCS), childhood acute lymphocytic leukemia (ALL) survivors, ovarian cancer survivors (OCS) and lung cancer with 279 matched healthy controls from 12 studies and 21 experiments. ALE-maps for post-chemotherapy cancer survivors showed reduced gray matter volume in comparison to healthy controls in the left inferior frontal gyrus, right thalamus, right superior frontal gyrus, right medial frontal gyrus and right cerebellum (peak coordinates: [-43,40,-6], [23,-29,2], [14,30,55], [9,57,-16], [9,-78,-41] respectively, and cluster size of 544 mm3, 312 mm3 and 257 mm3, 296 mm3, 297 mm3 respectively).

Conclusion

This is the first ALE meta-analysis that studied the converged areas of reduced gray matter volume in post-chemotherapy cancer survivors. Our findings of reduced gray matter volume in frontal regions and cerebellum might be responsible for the cognitive dysfunction in executive function, attention, and memory observed in cancer survivors. Further studies are needed to assess the impact of different chemotherapeutic regimens related to CICI .
P01.19.A The temporo-parieto-occipital junction in the non-dominant hemisphere as a challenging hub for glioma surgery: functional and oncological outcomes
Authors: Conti Nibali M , Puglisi G , Leonetti A , Rossi M , Gay L , Sciortino T , Mattioli L , Gambaretti M , Viganò L , Bello L
Published: September 2022

Background

The temporo-parieto-occipital junction (TPOJ) in the non-dominant hemisphere is a complex region intersected by multiple white matter bundles (Optic radiations, Inferior-fronto-occipital tract, inferior-longitudinalis-tract, superior-longitudinalis-tract, vertical-occipital-tract, medial-dorsal-longitudinal-tract, parietal-aslant-tract), subserving several high-level neurological functions such as spatial recognition, visual agnosia, visual field, attention and working memory. Few data are available on the optimum brain mapping strategy to be adopted for resecting tumors involving this area. Ideally it should allow surgeon to effectively identify several tracts and safely preserve all functions.

Material and Methods

We developed a proper protocol to approach this complex area integrating, in awake condition, intraoperative visual test (iVT) to mapping visual field, semantic association test (SRAT) to prevent visual agnosia and preserve working memory, hand manipulation task (hMT) to preserve spatial abilities. We reviewed its efficacy in a series of 38 patients with tumors involving non-dominant TPOJ, looking to functional (neurologic-neuropsychological) and oncological (EOR) outcomes. we perform a lesion symptom map and a disconnectome analysis to evaluate what region predict a decline in neuropsychological function and which tract of white brain matter are correlated in the decline of performance.

Results

Feasibility was high and all patients were able to perform and complete the protocol, which lasted, on the average11 min cortically and 25 min subcortically. Specificity was >95%. Immediate post-operative deficits were documented in 87.4% of patients, permanent in 3.9% (visual field, visual spatial abilities). Attentive and emotional domains were those mostly affected in the neuropsychological evaluation. Lesion symptom mapping and disconnectomic analysis showed that the postoperative decrease in neuropsychological performance was associated with resection of a cluster of voxels corresponding to the anterior portion of the temporo-parietal junction. The white matter tracts mainly involved were the anterior and posterior segment of the middle longitudinal fasciculus (aMdLF and pMdLF) and the parietal aslant tract (PAT).

Conclusion

Effective and safe resection of tumors involving non-dominant TPOJ is feasible. The adoption of a specific brain mapping protocol in awake setting is recommended to achieve a full functional preservation and extend tumor resection. Further analysis should be performed to assess the role of this subcortical tracts.
P02.04.A Preoperative neutrophil, thrombocyte and monocyte to lymphocyte ratios as independent prognostic factors for patient survival in WHO 2021 glioblastoma multiforme
Authors: Lyutfi* E , Stoyanov* G S , Dzhenkov D , Ivanov B D , Kaprelyan A , Ghenev P , Georgiev K
Published: September 2022

Background

Glioblastoma (GBM) is the most common malignant primary central nervous system (CNS) tumor. It is a fast-growing and extremely aggressive malignancy with a short postoperative survival time of little more than a year. The tumor-immune system interactions are complex and can be measured as local phenomena - e.g., tumor-infiltrating lymphocytes, or as systemic events - e.g., lymphopenia, neutropenia, etc. with cell numbers allowing for estimation of the type of immune reaction against the tumor.

Material and Methods

A retrospective non-clinical approach was utilized for the means of the study. Patients with a histologically and molecular verified GBM, corresponding to the guidelines of 2021 WHO CNS tumor classification, diagnosed in a three-year interval (February 2018-2021) in a single tertiary healthcare institution were included. Patients with infectious, inflammatory, autoimmune, and hematological diseases, as well as those with malignancy in another location, were excluded. Data regarding patient demographics, and preoperative peripheral blood cell counts (neutrophils, platelets, and monocytes in a ratio to lymphocytes) were compared with postoperative patient survival. Preoperative ratios were calculated as absolute values. For cutoff values we used generally accepted ones - >4 for neutrophil to lymphocyte (NLR), >200 for thrombocyte to lymphocyte (TLR), and >0.25 for monocyte to lymphocyte ratios (MLR). Results were statistically analyzed with MedCalc version 19.7.1 and the Kaplan-Meier method.

Results

A total of 22 patients fit the established criteria, with a male to female ratio of 2.14:1, mean age of 66.23 years, and mean survival of 255.72 days (8.04 months, range 24-801 days). Eight patients had an elevation of NLR and five of PLR, with no statistical correlation to survival. Six patients had an increase in MLR with a statistically significant (p=0.0044) shorter postoperative survival. Synergic increase in NLR and PLR did not show significance, while synergic increase with MLR showed no added benefit, as did comparison within MGMT promoter methylation groups.

Conclusion

Elevation in NLR, PLR, and MLR is a good independent prognostic marker for postoperative patient survival in histologically and mutationally verified GBM.

Acknowledgments

* contributed equally to the work and should be considered co-first authors.Financing: Medical University - Varna Scientific Fund, grant number 19010 and National scientific fund - young researchers (Republic of Bulgaria) grant number 2990/07.06.2021

Ethical approval: Medical University - Varna committee on scientific ethics approval protocol number 93/21.05.2020
P02.05.B Targeted therapies of Glioblastoma using single cell sequencing and drug-response analysis in a phase 2 clinical trial setting
Authors: Lü M , Hendriksen J , Urup T , Hamerlik P , Wennerberg K , Lassen U , Skovgaard H , Weischenfeldt J
Published: September 2022

Background

Glioblastoma is an aggressive brain tumour with a median survival of less than 15 months despite aggressive standard treatment consisting of neurosurgery, radiotherapy plus concomitant and adjuvant chemotherapy with temozolomide. There is no standard treatment at recurrence, and all have limited efficacy. In this study we will enroll glioblastoma patients from the Danish clinical trial “Protarget” to get a better understanding of resistance mechanisms and vulnerabilities in glioblastoma to give personalized medicine to glioblastoma patients at recurrent disease. We hypothesise that two connected factors are responsible for the failure to successfully target glioblastoma: i) intra-tumour heterogeneity and within this ii) cancer stem cells.

Material and Methods

We will use tumour tissue from glioblastoma patients included in the Danish phase 2, prospective, non-randomized clinical trial “Protarget” to establish short-term cultured neurospheres to preserve the heterogeneity of the tumour including cancer stem cells. We will then perform single cell RNA sequencing before and after drug screening. This setup will allow for a new approach to identify drug vulnerabilities at the single cell level. If successful in identifying drugs that leads to a clinical response, according to the "ProTarget" guidelines, we will consider scaling up the effort, to allow broader evaluation of efficacy. Our plan is to enroll 10 patients as a start. Patients will be selected based on ProTarget inclusion criteria and molecular profiling. We will further select patients with the following characteristics:1. IDH wildtype 2. High tumour purity (>50%). 3. High degree of intra-tumour heterogeneity.

Results

Enrollment for "Protarget" began in 2020 and our cohort will be part of this study, which is why enrollment has already started, but the first patient has not been enrolled yet. Clinical trial registry number for "Protarget" is NCT04341181.

Conclusion

This new and flexible approach to identify drug vulnerabilities at the single cell level in glioblastoma in order to find targeted therapies is a promising tool for future treatment of glioblastoma patients.