bluuebunny/crossref_metadata_2025 huggingface dataset:
What are the barriers to medical collaboration in community-based integrated care supporting cancer patients? A qualitative analysis of healthcare and long-term care providers’ perceptions
Authors: Mashiro Erina , Arao Harue , Aoki Miwa , Matsumoto Yoshihisa
Published: September 2023

Background

Patients required comprehensive cancer treatment in the community based on medical collaboration between designated cancer care hospitals and community medical and nursing care facilities to help them live life on their own terms. This study aims to describe the barriers to medical collaboration in community-based integrated care from the perspectives of healthcare providers (HCPs) and long-term care providers (LCPs) supporting cancer patients.

Methods

Semi-structured interviews were conducted with 88 HCPs and LCPs supporting cancer patients. We analyzed interview data to describe barriers to medical collaboration between designated cancer care hospitals and community medical and nursing care facilities using content analysis in MAXQDA.

Results

Participants were mostly HCPs, with physicians accounting for the largest proportion (27.3%). Totally, 299 codes were integrated into seven barriers to medical collaboration in community-based integrated care, including lack of information provision including life perspectives and a delay in sharing cancer patients’ values with HCPs to provide end-of-life care according to the patients’ wishes. Furthermore, insufficient coordination of cancer and non-cancer symptom management was identified as a barrier specific to older adults with cancer.

Conclusions

Barriers related to cancer treatment that integrate lifestyle perspectives, end-of-life care emphasizing patient values, and medical collaboration between cancer and non-cancer care are distinctive. They emphasize the importance of utilizing professionals to connect treatment and lifestyle information, establishing a central coordinating organization led by the DCCH, and developing a community palliative care network. Moreover, connecting cancer and non-cancer care through government and medical collaboration is crucial.
Ctrl-C: a cross-sectional study of the electronic health record usage patterns of US oncology clinicians
Authors: Sinha Sumi , Holmgren A Jay , Hong Julian C , Rotenstein Lisa S
Published: September 2023

Despite some positive impact, the use of electronic health records (EHRs) has been associated with negative effects, such as emotional exhaustion. We sought to compare EHR use patterns for oncology vs nononcology medical specialists. In this cross-sectional study, we employed EHR usage data for 349 ambulatory health-care systems nationwide collected from the vendor Epic from January to August 2019. We compared note composition, message volume, and time in the EHR system for oncology vs nononcology clinicians. Compared with nononcology medical specialists, oncologists had a statistically significantly greater percentage of notes derived from Copy and Paste functions but less SmartPhrase use. They received more total EHR messages per day than other medical specialists, with a higher proportion of results and system-generated messages. Our results point to priorities for enhancing EHR systems to meet the needs of oncology clinicians, particularly as related to facilitating the complex documentation, results, and therapy involved in oncology care.
KS01.7.A ADAPTOR FITC CAR T-CELLS AND OCTO-FLUO ELICIT PROMISING ANTITUMOR ACTIVITY IN MENINGIOMA VIA SSTR2
Authors: Chen J , Pellegrino C , Mastall M , Padevit L , Favalli N , Bassi G , Neidert M , Vasella F , Roth P , Neri D , Manz M , Weller M , Wirsching H
Published: September 2023

BACKGROUND

Effective treatment options for meningioma patients beyond surgical resection and radiotherapy are lacking. Somatostatin receptor (SSTR) 2 is expressed by most meningiomas. Here, we report pre-clinical and translational evidence for the activity of an SSTR2-targeted adaptor CAR T cell system in meningiomas.

MATERIAL AND METHODS

Tissue microarrays of meningioma (N=384) patient samples stained for SSTR2. Fluorescein-linked, octameric cyclic peptide SSTR2 antagonist OCTO-FLUO (kindly provided by Philogen, Otelfingen, Switzerland). Adaptor FITC CAR T-cells generated by lentiviral transduction of healthy donor T-cells. Flow cytometry-based killing assays in vitro in SSTR2-expressing meningioma (Ben-Men-1 IOMM-Lee) cells, and ex vivo utilizing freshly dissociated surgical meningioma specimens, by co-incubation with OCTO-FLUO and adaptor FITC CAR T-cells. Orthotopic growth and mouse survival following subdural implantation of IOMM-Lee cells, genetically engineered to express luciferase, i.v. treated with OCTO-FLUO and intratumoral injection of CAR T-cells.

RESULTS

SSTR2 expression was overall heterogeneous and was high or intermediate in most World Health Organization (WHO) grade 2 (87.8 %) or grade 3 (87.5 %) meningiomas. In vitro, 10 nM was determined as the optimal concentration of OCTO-FLUO, yielding tumor cell killing within 72 hours at effector-target cell (ET) ratios as low as 1:100 in Ben-Men-1 (CAR vs untransduced T-cells [UTT] 47.9 % vs 4.7 %, p < 0.001) and IOMM-Lee (CAR vs UTT 40.2 % vs 4.9 %, p < 0.001) cells. Tumor growth inhibition by the adaptor FITC CAR T-cell system in vivo was confined to SSTR2 expressing cells and was paralleled by prolonged survival compared to UTT in IOMM-Lee (hazard ratio [95% confidence interval], 0.3 [0.1 - 0.9], p=0.030). Preliminary ex vivo killing assays employing freshly dissociated patient samples yielded specific lysis-rates in the range of 15-20% (ET 1:1) at 12 hours. Updated ex vivo results employing optimized protocols will be presented at the conference.

CONCLUSION

Targeting SSTR2 positive meningioma cells with an adaptor FITC CAR T-cell system is feasible. Syngeneic murine models and the use of adaptor molecules directed against murine SSTR2 will be required to explore secondary immune reactions and off-tumor effects prior to proceeding to early phase clinical trials.
KS03.5.A COMPARING VOLUMETRIC GROWTH-RATE AND RANO CRITERIA IN DETERMINING THE RESPONSE OF MENINGIOMA TO BEVACIZUMAB THERAPY
Authors: Borenstein S , Amiel A , Siegal T , Gal O , Limon D , Eliahu R , Yust-Katz S
Published: September 2023

INTRODUCTION

Meningioma is the most prevalent primary tumor in the central nervous system (CNS). Although mostly benign, 15- 20% are aggressive and tend to recur and progress despite surgery and adjuvant radiation. Recent publications show that bevacizumab, a vascular endothelial growth factor inhibitor, effectively treats these refractory meningiomas. The standard method to monitor treatment’s effect on imaging is Response Assessment in Neuro-Oncology criteria (RANO). Recently, an alternative tool called 3D volumetric growth rate (3DVGR) has emerged as a result of significant advancements in the accuracy of volumetric measurement techniques. Our aim is to compare the effectiveness of conventional RANO criteria and the emerging 3DVGR measure in evaluating the response to bevacizumab treatment in patients with refractory meningiomas. We will also assess their correlation with clinical outcomes over a period of up to 9 months.

METHODS

68 MRI scans of 20 patients with aggressive meningiomas that progressed after radiation therapy and then received Bevacizumab were evaluated. Scans were obtained from two tertiary cancer centers. For each tumor both RANO and 3DVGR were conducted in two subsequent head MRI studies acquired prior to the initiation of bevacizumab treatment and then in at least one exam within 6 months post-treatment. Measurements were obtained using PACS and BRAIN LAB software by two radiologists.

RESULTS

A total of 43 lesions derived from 13 males and 7 females were included in the final analysis. The mean age was 65.5; mean number of pre-radiation treatments was 2.66; mean number of pre-surgical treatments was 2.7 and mean number of bevacizumab cycles was 22.7. All lesions showed a decrease or stabilization in growth rate compared to baseline. More specifically, 34 out of 43 lesions (79%) showed a negative growth rate value indicating decrease in tumor size. Comparison of treatment response using RANO criteria was not always in concordance with the 3DVGR measurement and showed inaccurate correlation with clinical outcome.

CONCLUSIONS

Although widely accepted for treatment response evaluation, RANO criteria are not an accurate technique for irregularly shaped lesions. As shown in our study, for atypical meningiomas, the 3DVGR measure seems to be more precise compared to RANO criteria. Furthermore, our results show great promise for treatment of refractory meningiomas with bevacizumab.
JS03.7.A INTERPLAY BETWEEN SELF-REPORTED AND PERFORMANCE-BASED SYMPTOMS IN PATIENTS WITH GLIOMA AND MENINGIOMA - A NETWORK ANALYSIS AND COMPARISON BETWEEN DIAGNOSES
Authors: Butterbrod E , van de Glind M , Rutten G , Sitskoorn M , Gehring K
Published: September 2023

BACKGROUND

Patients with brain tumors show complex symptomatology often involving self-reported complaints, e.g., concerning self-perceived cognitive function (SCF), fatigue or mood, as well as deficits in cognitive performance. Understanding the interplay between symptoms across diagnoses is crucial for intervention, but remains challenging. This study used network analysis to 1) uncover unique relationships between various multidimensional self-reported symptoms and cognitive performances in patients with meningioma and glioma, and 2) investigate differences in symptom networks between diagnoses.

MATERIAL AND METHODS

We used pre-surgical data from patients with meningioma (n=240) and glioma (n=208). Two Gaussian graphical models were constructed to explore conditional relationships among symptoms in the two samples. Included as symptoms in the networks were ten patient-reported measures: SCF (3 nodes), Anxiety, Depression, and Fatigue (5 nodes), and 5 cognitive performance measures: Inhibition, Cognitive flexibility, Verbal memory, Processing speed and Psychomotor speed. We evaluated the importance of the symptoms with three centrality indices; node strength, betweenness and closeness. We compared features of the networks between the diagnoses with a Network Comparison Test.

RESULTS

In both samples, particularly strong connections existed between Anxiety and Depression, Forgetfulness and False Triggering (SCF nodes), and General Fatigue and Physical Fatigue. These positive relationships were significantly stronger than most of the other relationships. The most central symptoms, based on the strength of their connections with other symptoms, were Forgetfulness, General Fatigue and Inhibition in glioma patients, and Forgetfulness, Physical Fatigue and Depression in meningioma patients. Activity-related fatigue appeared as the least central symptom in the glioma network, but it was in the top 5 in the meningioma network. The difference in the number of relationships found (meningioma: 49 vs. glioma: 41), was not significant. Visual inspection of the networks suggested additional connections between multiple fatigue and cognition nodes in meningioma that were absent in glioma. Significant differences were found between the networks regarding strength of the relationships General Fatigue-Physical Fatigue (stronger in glioma), and Physical Fatigue-Activity-related Fatigue (stronger in meningioma), p’s < .01.

CONCLUSION

While symptom networks of patients with glioma and meningioma show similarities, they appear to differ with regard to which symptoms play a more central role and how strongly some symptoms are related. Particularly fatigue subtypes may carry different importance. Information that multidimensional symptom networks provide about how symptoms interact can guide treatment decisions for patients with different diagnoses.
JS04.5.A HEMIZYGOUSCDKN2A DELETION CONFERS WORSE SURVIVAL OUTCOMES IN IDH-MUTANT GLIOMAS
Authors: Kocakavuk E , Johnson K C , Sabedot T S , Reinhardt H C , Noushmehr H , Verhaak R G W
Published: September 2023

BACKGROUND

The tumor suppressor gene CDKN2A is frequently deactivated in cancer. Homozygous CDKN2A deletion is a Grade 4 defining criterion for IDH-mutant gliomas. However, the prognostic value of hemizygous CDKN2A deletions is unclear. We assessed CNV profiles of 1238 initial and 479 recurrent IDHmut gliomas to evaluate the association of CDKN2A hemizygous deletions with overall survival (OS) outcomes.

MATERIAL AND METHODS

The GLASS primary/recurrent glioma dataset was used to infer CDKN2A status with DNAseq (n=210) and DNA methylation array (n=100) data. Validation was conducted using DFCI, MSKCC, TCGA and DKFZ cohorts.

RESULTS

Longitudinal analyses of IDH-mutant gliomas without 1p-/19q-codeletion showed significant increases in CDKN2A homozygous deletion from n=6 to n=23 (5% to 20%, P=0.0001, Fisher’s-exact test) and hemizygous deletion from n=19 to n=34 (17% to 30%, P=0.002) at recurrence. CDKN2A hemizygous deletions were significantly associated with poor OS at initial diagnosis (P<0.0001, log-rank test) and recurrence (P<0.0001), remaining significant in multivariable cox regression model that accounted for age, treatment with radiotherapy and/or alkylating agents, and 1p/19q-codeletion status: HR 2.40 (95%-CI: 1.31-4.37, P=0.004). Validation in independent datasets confirmed increased frequencies of CDKN2A hemizygous deletions in recurrent cases as well as the association between CDKN2A hemizygous deletion and worse OS in IDHmut gliomas. Using the DKFZ DNA methylation profiling dataset we further confirmed that CDKN2A status can be accurately assessed through DNAseq and DNA methylation array profiling.

CONCLUSION

CDKN2A hemizygous deletion is associated with significantly worse OS in initial and recurrent IDHmut gliomas. Similar to CDKN2A homozygous deletion, CDKN2A hemizygous deletion is enriched in post-treatment, recurrent IDHmut gliomas, confirming the value of CDKN2A status (re-)assessment in recurrences. Our results highlight the importance of incorporating CDKN2A status in diagnostic workup to inform prognosis and treatment strategies, revealing the previously unrecognized prognostic value of hemizygous CDKN2A deletions.
JS05.5.A INTRAOPERATIVE MRI-GUIDED RESECTION IS NOT SUPERIOR TO 5-ALA-GUIDANCE IN NEWLY DIAGNOSED GLIOBLASTOMA: A PROSPECTIVE CONTROLLED MULTICENTER CLINICAL TRIAL
Authors: Roder C , Stummer W , Coburger J , Scherer M , Haas P , von der Brelie C , Kamp M , Löhr M , Hamisch C , Skardelly M , Scholz T , Schipmann S , Rathert J , Brand C , Pala A , Ernemann U , Stockhammer F , Gerlach R , Kremer P , Goldbrunner R , Ernestus R , Sabel M , Rohde V , Tabatabai G , Martus P , Bisdas S , Ganslandt O , Unterberg A , Wirtz C , Tatagiba M
Published: September 2023

BACKGROUND

Prospective data suggested a superiority of intraoperative MRI (iMRI) over 5-aminolevulinic acid (5-ALA) for achieving complete resections of contrast enhancement in glioblastoma surgery. We investigated this hypothesis in a prospective clinical trial and correlated residual disease volumes with clinical outcome in newly diagnosed glioblastoma.

MATERIAL AND METHODS

This is a prospective controlled multicenter parallel-group trial with two center-specific treatment arms (5-ALA and iMRI) and blinded evaluation. The primary endpoint was complete resection of contrast enhancement on early postoperative MRI. We assessed resectability and extent of resection by an independent blinded centralized review of pre- and post-operative MRI with 1mm slices. Secondary endpoints included progression-free (PFS) and overall survival (OS), patient-reported quality of life and clinical parameters.

RESULTS

We recruited 314 patients with newly diagnosed glioblastomas at eleven German centers. 127 patients in the 5-ALA and 150 in the iMRI arm were analyzed in the as treated analysis. Complete resections, defined as a residual tumor ≤0.175 cm³, were achieved in 90 patients (78%) in the 5-ALA and 115 (81%) in the iMRI arm (p=0.79). Incision-suture times (p<0.001) were significantly longer in the iMRI arm (316 vs. 215 [5-ALA] minutes). Median PFS and OS were comparable in both arms. The lack of any residual contrast enhancing tumor (0cm³) was a significant favorable prognostic factor for PFS (p<0.001) and OS (p=0.048), especially in MGMT unmethylated tumors (p=0.006).

CONCLUSION

We could not confirm superiority of iMRI over 5-ALA for achieving complete resections. Neurosurgical interventions in newly diagnosed glioblastoma shall aim for safe complete resections with 0 cm³ contrast-enhancing residual disease, as any other residual tumor volume is a negative predictor for PFS and OS.
JS05.7.A SURGICAL RE-RESECTION FOR RECURRENT GLIOBLASTOMA: PROGNOSTIC EVALUATION USING THE NOVEL RANO CLASSIFICATION FOR EXTENT OF RESECTION FROM THE RANORESECT GROUP
Authors: Karschnia P , Dono A , Young J S , Juenger S T , Teske N , Häni L , Sciortino T , Mau C Y , Bruno F , Nunez L , Morshed R A , Haddad A F , Weller M , van den Bent M , Beck J , Hervey-Jumper S , Molinaro A M , Tandon N , Rudà R , Vogelbaum M A , Bello L , Schnell O , Grau S J , Chang S M , Berger M S , Esquenazi Y , Tonn J
Published: September 2023

BACKGROUND

The value of re-resection in recurrent glioblastoma remains controversial as a randomized trial that specifies intentional incomplete resection cannot be justified ethically. Here, we aimed to (I) explore the prognostic role of extent of re-resection using the previously proposed RANO classification (based upon residual contrast-enhancing (CE) and non-CE tumor), and to (II) define factors consolidating the surgical effects on outcome.

MATERIAL AND METHODS

The RANO resect group retrospectively compiled a global, eight-center cohort of patients with first recurrence from previously resected glioblastomas. The combined associations of re-resection and other clinical factors with outcome were analyzed. Kaplan-Meier survival analysis and log-rank test were applied to calculate survival, and Cox’s proportional hazard regression models to adjust for multiple variables (significance level: p ≤ 0.05). Propensity score-matched analyses were constructed to mimic randomized clinical trials comparing the different RANO classes.

RESULTS

We studied 681 with first recurrence of IDH-wildtype glioblastomas, including 310 patients who underwent re-resection. Re-resection was associated with prolonged survival even when stratifying for clinical and molecular confounders on multivariate analysis (HR for re-resection: 0.65, CI: 0.5-0.8; p = 0.001); and ≤1 cm3 residual CE tumor was associated with longer survival than non-surgical management. Accordingly, ‘maximal CE resection’ (class 2) had superior survival compared to ‘submaximal CE resection’ (class 3) (median OS after recurrence: 12 vs. 9 months; p = 0.003). Administration of (radio-)chemotherapy further augmented the survival associations of smaller residual CE tumor. The prognostic role of residual CE tumor was confirmed in propensity score analyses. Conversely, ‘supramaximal CE resection’ targeting also non-CE tumor (class 1) was not associated with prolonged survival but frequently accompanied by post-operative deficits, hampering further adjuvant treatment.

CONCLUSION

The RANO resect classification serves to stratify patients with re-resection of glioblastoma. Complete CE resection according to RANO resect class 1 and 2 is prognostic of outcome. The beneficial effects of re-resection might be consolidated by (radio-)chemotherapy, and avoidance of post-operative deficits hampering such treatment is of critical importance.
JS08.5.A VEGFR2-SPECIFIC CAR T CELLS WITH ANTI-GLIOMA AND ANTI-ANGIOGENIC ACTIVITY AGAINST GLIOBLASTOMA
Authors: Mastall M , Villars D , Silginer M , Rössig C , Weiss T , Weller M , Roth P
Published: September 2023

BACKGROUND

Chimeric antigen receptor (CAR) T cell therapy has emerged as a potent immunotherapy against hematological malignancies. In glioblastoma, however, limited infiltration of the tumor by CAR T cells, tumor heterogeneity, antigen escape and an immunosuppressive tumor microenvironment remain significant obstacles. Vessel-targeting CAR T cells have been shown to infiltrate solid tumors more efficiently and have the additional benefit of co-targeting the tumor vasculature with genomic stability. Therefore, vascular endothelial growth factor receptor 2 (VEGFR2)-CAR T cells may represent a promising strategy by targeting the tumor vasculature as well as VEGFR2-expressing tumor cells. Here, we explored the efficacy of VEGFR2-specific CAR T cells against experimental gliomas as well as the contribution of anti-tumor and anti-vasculature-dependent effects of this strategy.

METHODS

Tissue microarrays of glioblastoma patients (n=113) were stained for VEGFR2 expression. Human CAR T cells were generated by lentiviral transduction to express a second generation CAR construct against either mouse or human VEGFR2 (mVEGFR2 or hVEGFR2). Their activity was assessed in co-culture assays in vitro against murine endothelial and human glioma cells, respectively. Several orthotopic xenograft mouse glioma models were used to test the in vivo activity of the newly generated CAR T cells.

RESULTS

We confirmed high VEGFR2 expression on endothelial cells in glioblastoma tissue of stained tissue microarrays as well as in 20.3% of tissue samples also on tumor cells. In co-culture assays, hVEGFR2-CAR T cells were exclusively active against human glioma cells and mVEGFR2-CAR T cells against mouse endothelial cells, respectively. The specificity of hVEGFR2-CAR T cells was confirmed by a CRISPR/Cas9-mediated knockout of hVEGFR2 in a human glioma cell line. In all three in vivo glioma models, intratumoral treatment of hVEGFR2-CAR T cells significantly prolonged the survival of glioma-bearing mice and cured a substantial fraction of these animals in one model. Additionally, we found that survival was prolonged after mVEGFR2-CAR T cell treatment in one glioma model, which correlated with high vascularization of these tumors.

CONCLUSION

Our dataset demonstrates that VEGFR2-CAR T cells prolong the survival of glioma-bearing mice through anti-glioma and anti-glioma vasculature activity. The results suggest that the magnitude of the vasculature-targeting activity depends on vessel-density within the tumor. VEGFR2 might be a relevant target that could be exploited for a novel CAR T cell-based immunotherapeutic approach against glioblastoma.
JS09.7.A COMBINATION OF APPARENT DIFFUSION COEFFICIENT AND FET PET COMPARED WITH STANDARD IMAGING FOR QUANTITATIVE TUMOR PRESENCE IN DIFFUSE GLIOMAS
Authors: Tjong Tjin Joe K , Wesseling P , Barkhof F , Beliën J , Yaqub M M , Pouwels P J W , Verhaak R , Reijneveld J C , Rozemuller A J M , Vandertop W P , Boellaard R , Barthel F , de Witt Hamer P C , van de Giessen E , Verburg N
Published: September 2023

BACKGROUND

Diffuse glioma local treatment is currently guided by standard MRI sequences. Yet, the combination of apparent diffusion coefficient (ADC) and O-(2-[18F]-fluoroethyl)-L-tyrosine positron emission tomography (FET PET) (ADC/FET) detects histopathological qualitative assessed tumor presence more accurately than standard imaging. It is unknown whether this is similar for quantitative assessed tumor presence. This study compares the diagnostic accuracy of standard imaging and ADC/FET for the detection of quantitative assessed tumor presence in diffuse glioma.

MATERIAL AND METHODS

Fifteen patients with newly diagnosed diffuse glioma were retrospectively included. Pre-operative standard imaging, ADC and FET PET were available. Multiregional image-guided stereotactic biopsies were acquired before craniotomy. Quantitative imaging data from regions-of-interests (ROIs) centered at the biopsy locations was obtained. For each biopsy, sample semi-automatic cellularity and proliferation index, as well as DNA methylation-based tumor purity was determined. Linear mixed models were used to evaluate which modalities were significant independent predictors for each tumor presence marker and fitness was assessed using Bayesian Information Criterium.

RESULTS

125 biopsies were analyzed (75 from eight high grade and 50 from seven low grade gliomas). Cellularity was predicted by T1 weighted MRI (p = 0.033), ADC (p = 0.016) and ADC/FET (p <.001), with ADC/FET as best fit. Both proliferation index (p = 0.003) and tumor purity (p <.001) were only predicted by ADC/FET.

CONCLUSION

Combining ADC and FET PET predicts cellularity, proliferation index and tumor purity better than standard imaging. Further investigation into ADC/FET-guided local treatment of diffuse glioma is therefore needed.
JS09.8.A COMPARATIVE PROGNOSTIC VALUE OF O-(2-[18F]-FLUOROETHYL)-L-TYROSINE PET IMAGING AND DCE MRI BLOOD VOLUME IMAGING IN PATIENTS WITH SUSPECTED RECURRENT IDH-WILDTYPE HIGH-GRADE GLIOMA
Authors: Henriksen O M , Muhic A , Lundemann M J , Larsson H B W , Lindberg U , Andersen T L , Hasselbalch B , Møller S , Marner L , Larsen V A , Poulsen H S , Hansen A E , Law I
Published: September 2023

BACKGROUND

Quantitative blood volume (BV) imaging using dynamic T1-weighted contrast enhanced (DCE) perfusion MRI may be of diagnostic value in patients with suspected recurrent high-grade glioma, but the association of DCE BV measurements with survival is not known. The aim of the study was to compare the prognostic information of DCE BV measurements with that of O-(2-[18F]-fluoroethyl)-L-tyrosine ([18F]FET) PET imaging in treated IDH wildtype high-grade astrocytoma and glioblastoma (2016 WHO classification).

MATERIAL AND METHODS

A total of 94 hybrid [18F]FET PET/MRI scans with DCE from unique adult patients were retrospectively analysed. Scans were obtained after surgery/biopsy (n=94) and radiotherapy (n=93) due to variable suspicion of residual or progressive disease. In each scan the visually BV positive (VOLBV), the [18F]FET PET avid (VOLFET) and the contrast-enhancing (VOLCE) volumes were delineated, and fractional tumour volumes (fVOL) within VOLCE, as well as maximal BV (BVmax) and maximal [18F]FET tumour-to-background ratio (TBRmax) were determined. Accuracy for prediction of 6-month progression free survival and 1 year overall survival were assessed by logistics regression. Associations with overall survival were assessed for each parameter by Cox proportional hazard analysis.

RESULTS

In a univariate analysis, adjusted for age and MGMT, both VOLCE, and all [18F]FET and DCE BV derived metrics were predictive of both 6 month progression free survival, 1 year survival and overall survival. ROC AUC for prediction of 6 month progression free survival and 1 year overall survival tended to be higher for [18F]FET derived metrics, but ROC AUC values were not significantly different between any [18F]FET and DCE BV derived metrics. In Cox models for overall survival (adjusting for age, MGMT and VOLCE) only TBRmax and VOLBV had independent prognostic value among [18F]FET PET and DCE BV derived metrics, respectively. In a final model including both TBRmax and VOLBV, only TBRmax remained significant..

CONCLUSION

DCE BV and [18F]FET PET derived metrics provides prognostic information independent of age, MGMT status and contrast enhancing tumour volume in treated glioblastoma, with volume of increased BV and [18F]FET TBRmax providing strongest associations with overall survival. Accounting for functional imaging biomarkers may be important in balancing future randomized clinical trials.
OS01.4.A A DETECTABLE ANTITUMOR IMMUNE RESPONSE IS PRESENT IN GLIOMAS, BUT IS PROFOUNDLY DAMPED BY CHEMOTHERAPY
Authors: Picca A , Baron M , Labrèche K , Bouzidi A , Rousseau A , Morin V , Bielle F , Touat M , Sanson M , Autran B ,   IDEATION study group
Published: September 2023

BACKGROUND

Until now, immunotherapy has been disappointing in gliomas. Promising results in cancer neoantigen (NeoAg)-directed vaccines have been seen, but final outcomes remain poor. We need a better comprehension of the factors associated with effectively immunogenic NeoAgs along with clinical features that correlate with detectable immune responses.

MATERIAL AND METHODS

We prospectively enrolled glioma patients from our institution in the IDeATIon project (NCT03706625) exploring tumors occurring in immunosuppressed conditions or in immune-privileged sites such as the CNS. We performed whole exome and RNA sequencing of tumor samples along with patients HLA typing. Using state of the art algorithms and personalized filters, we predicted cancer NeoAg sequences and expression. Peripheral blood mononuclear cells (PBMC) were collected in a subset of patients, and their reactivity to NeoAg-derived peptides was assessed ex vivo using ELISpot assays to validate in silico-predicted immunogenicity.

RESULTS

We enrolled 36 prospective glioma patients (IDH mutant, n=10; IDH wildtype, n=26). To test the ability of our pipeline to identify the most immunologically relevant NeoAgs among others, we privileged the inclusion of mismatch-repair (MMR)-deficient (MMRd) gliomas (n=21, of which 12 post-temozolomide and 9 de novo), given their expected high NeoAg burden. The median number of predicted immunogenic NeoAgs from 21 patients with both WES and RNASeq data was 274 and was higher for MMRd gliomas (1540 vs. 58, p<0.001). Tumor mutational burden and the number of predicted NeoAgs were correlated (ρ=0.81, p<0.001). Ex vivo PBMC responses were assessed for best ranked peptides (median 48 peptides/patient, range 12-62) in 18 patients (10 MMRd). NeoAg-specific T-cell responses (>50 spot forming units/10e6 PBMC) were detected in 72% (13/18) of patients, including MMRd cases (8/10). All non-responder patients (5/5) were under treatment with cytotoxic chemotherapies (CHT) at the time of blood sampling, compared to 15% (2/13) of responders (p=0.003). Conversely, NeoAg-specific responses were seen in 100% (11/11) of patients not under CHT.

CONCLUSION

We developed and validated in vitro a robust and reliable pipeline for the identification of effectively immunogenic neoantigens using validated algorithms and personalized filters. Our results suggest that in the absence of CHT, a specific antitumor immune response is present in the majority of gliomas and may represent a therapeutic lever.
OS03.5.A MULTI-ANCESTRY GENOME-WIDE ASSOCIATION STUDY OF 4,069 CHILDREN WITH GLIOMA IDENTIFIES 9P21.3 RISK LOCUS
Authors: Foss-Skiftesvik J , Li S , Rosenbaum A , Hagen C M , Stoltze U K , Ljungqvist S , Hjalmars U , Schmiegelow K , Morimoto L , De Smith A J , Mathiasen R , Metayer C , Hougaard D M , Melin B , Walsh K M , Bybjerg-Grauholm J , Dahlin A M , Wiemels J L
Published: September 2023

BACKGROUND

While recent sequencing studies have revealed that 10% of childhood gliomas are caused by rare germline mutations, the role of common variants is undetermined and no genome-wide significant risk loci for pediatric CNS tumors have been identified to date.

MATERIAL AND METHODS

Meta-analysis of three population-based genome-wide association studies (GWASs) comprising 4,069 children with glioma and 8,778 controls of multiple genetic ancestries. Replication was performed in a separate case-control cohort. Quantitative trait loci analyses and a transcriptome-wide association study were conducted to assess possible links with brain tissue expression across 18,628 genes.

RESULTS

Common variants in CDKN2B-AS1 at 9p21.3 were significantly associated with astrocytoma, the most common subtype of glioma in children (rs573687, p-value 6.974e-10, OR 1.273, CI95 1.179-1.374). The association was driven by low-grade astrocytoma (p-value 3.815e-9) and exhibited unidirectional effects across all six genetic ancestries. For glioma overall, the association approached genome-wide significance (rs3731239, p-value 5.411e-8), while no significant association was observed for high-grade tumors. Predicted decreased brain tissue expression of CDKN2B was significantly associated with astrocytoma (p-value 8.090e-8).

CONCLUSION

In this population-based GWAS meta-analysis, we identify and replicate 9p21.3 (CDKN2B-AS1) as a risk locus for childhood astrocytoma, thereby establishing the first genome-wide significant evidence of common variant predisposition in pediatric neuro-oncology. We furthermore provide a functional basis for the association by showing a possible link to decreased brain tissue CDKN2B expression and substantiate that genetic susceptibility differs between low- and high-grade astrocytoma.
OS07.6.A INVESTIGATING REGIONAL HETEROGENEITY AND PROGRESSION-ASSOCIATED MARKERS IN OLIGODENDROGLIOMAS
Authors: Millner T O , Mikaeili H , Shabbir A , Lowe A , Brandner S
Published: September 2023

BACKGROUND

Oligodendrogliomas are defined by IDH-mutation, 1p/19q-codeletion and TERT promoter mutation. Molecular stratification of oligodendrogliomas has so far proved difficult, despite recent progress in other brain tumours. Loss of H3K27 trimethylation (H3K27me3) is seen in many, but not all oligodendrogliomas, and we have observed that this trimethylation mark is lost predominantly in low-grade oligodendrogliomas, and more often retained in high-grade tumours. The key aims of this project are to establish the downstream effects of H3K27me3 regulation in oligodendrogliomas to identify progression-associated biomarkers.

MATERIAL AND METHODS

78 oligodendrogliomas (CNS WHO grade 2: n=38, and grade 3: n=40) were tested for H3K27me3 expression. These tumours showed either down-regulation (H3K27me3-), retention of expression (H3K27me3+) or intratumoural heterogeneity (H3K27me3Het). 65 regions across these three types were micro-dissected for DNA methylation profiling and RNA sequencing.

RESULTS

Of the H3K27me3- tumours 85% (35/41) were grade 2, of the H3K27me3+ tumours 100% (10/10) were grade 3, and of the H3K27me3Het tumours 87% (20/23) were grade 3. With DNA methylation arrays and derived copy number data we have shown a different breakpoint of the 1p chromosome in H3K27me3+ samples or areas, and in 15 paired samples, 6 gains and 12 losses in H3K27me3+ regions, and overall 24 copy number differences between H3K27me3+ and me3- areas within the same tumours, indicative of spatial genetic heterogeneity. RNA sequencing suggests distinct expression profiles between H3K27me3+ and H3K27me3- areas.

CONCLUSION

We have shown a close correlation between areas with high-grade features and H3K27me3 expression both between and within tumours. We have shown that H3K27me3+ and me3- areas within the same tumours show copy number changes and have differential gene expression. Using pathway analysis we have identified pathways and genes involved in tumour progression and mediation of histone modification. We are currently using these targets for functional studies and protein level validation with the overall aim of developing immunohistochemistry biomarkers.
OS07.7.A GLIOBLASTOMA HYBRID CELL STATE CONVEYS RESISTANCE TO CONVENTIONAL THERAPIES
Authors: Bourmeau G , Anezo O , Ballestin A , Pichol-Thievend C , Reveilles J , Seano G
Published: September 2023

BACKGROUND

Glioblastoma (GB) is a deadly disease and no therapeutic improvements have been made in the last 20 years. High phenotypic plasticity has been recognized as a major obstacle to the efficient treatment of GB. Single-cell sequencing revealed the coexistence of four different cell states within the same tumor. The transition from one subtype (or state) to another, such as from proneural (PN) to mesenchymal (MES), has been suggested as a mechanism for resistance to therapies. However, there is no prognostic value of the current GB states for patients, meaning that mechanisms of resistance may not lie in hardwire identities but in the transition from one subtype to another. Therefore, we investigated the role of the hybrid cell states in GB resistance to therapy.

MATERIAL AND METHODS

To dynamically follow spatiotemporal changes in GB plasticity in real time, we transduced patient-derived GB cells (patient-derived cell lines with different mutational and phenotypic landscapes) using two specific GB-subtype fluorescent synthetic genetic tracing cassettes. To follow the hybrid cell state dynamics and features, we functionally and transcriptionally investigated GB cells labeled with activated reporters for both the PN and MES subtypes. Using a combination of cytofluorimetry, live imaging, preclinical models, bulk and single-cell RNA-sequencing, we visualized the single-cell GB plasticity and studied the changes in the hybrid state subpopulation proportion over time and under therapeutic stress.

RESULTS

We discovered that the PN/MES hybrid state (GB-hybrid) has a definite molecular and phenotypic identity and that it is strongly induced after conventional therapies. The GB-hybrid cell state is highly resistant to therapy and more proliferative. Importantly, when implanted in mice the GB-hybrid cells were more aggressive than the rest of the cells, which is consistent with the marked prognostic power for the GB-hybrid geneset signature when tested in the TCGA database. Mechanistically, we showed that GB-hybrid cells were characterized by broad chromatin remodeling, an important increase in overall mRNA quantity per cell and intensification of the nuclear import/export machinery.

CONCLUSION

Here, we present a novel GB transition cell state between PN and MES subtypes/states. The GB-hybrid is at the same time highly proliferative and resistant to therapy, making it an interesting target to slow down GB recurrence after therapy.
OS08.5.A UNDERSTANDING THE ASSOCIATION BETWEEN FATIGUE AND COGNITION IN GLIOMA PATIENTS: AN OBSERVATIONAL MULTINATIONAL STUDY
Authors: Röttgering J G , Taylor J W , Brie M , Luks T , Hervey-Jumper S L , Phan S , Bracci P M , Smith E , De Witt Hamer P C , Douw L , Weyer-Jamora C , Klein M
Published: September 2023

BACKGROUND

Both fatigue and cognitive impairment are highly prevalent in individuals with glioma and have been associated with diminished health-related quality of life. Although the two are thought to be related, evidence remains sparse, in part, due to the limited availability of data. Therefore, we aimed to investigate the relationship between fatigue and cognition in adult glioma patients.

MATERIAL AND METHODS

We analyzed cognitive data from adult patients with diffuse glioma at the University of California San Francisco (UCSF, n=100) and Amsterdam UMC (n=127). Comparable cognitive tests were combined by domain: attention, information processing, mental flexibility, semantic fluency, verbal learning, verbal memory, and visual search. Z-scores of ≤ -1.5 SD were considered impaired. Fatigue was assessed with the Fatigue Symptom Inventory (UCSF) and the Checklist Individual Strength (Amsterdam UMC). Linear mixed models were used to assess associations between cognitive domains and fatigue adjusted for site, grade, histology, sex, radiotherapy, and chemotherapy. Latent profile analysis was used to identify distinct fatigue-cognitive phenotypes.

RESULTS

UCSF patients were older (50.3 vs. 44.9 years, p=0.002), more likely to have grade 4 tumors (32% vs. 18%, p=0.025), and more years since diagnosis (2.72 vs 1.27, p<0.001). Interestingly, though UCSF patients were more impaired across nearly all cognitive domains, there was no difference in fatigue between institutions (-0.0457 vs. -0.178, p=0.60). Attention and impaired semantic fluency were associated with fatigue severity in univariate models. Using backward selection, the best-fit model included only impaired semantic fluency (estimated effect = 0.35, p= 0.014, r2=0.03). We identified four distinct cognitive phenotypes in the pooled dataset, which validated across sites, though fatigue severity did not contribute to these phenotypes.

CONCLUSION

Although fatigue and cognitive symptoms can overlap, the association between cognitive impairment and fatigue severity is weak. Interestingly, this important finding was validated across institutions and glioma subtypes. Further study is needed to address questions regarding the longitudinal change of symptoms. Given the limited relational overlap, fatigue and cognitive impairments should both be explicitly assessed and treated with targeted therapies.

SUPPORT/DISCLOSURE

Stichting Anita Veldman Foundation CCA-2019-2-21; Amsterdam University Fund 4056-2022-7-8; CCA travel grant 2022-10-10; Prins Bernhard Cultuurfondsbeurs 40042576/NOD; R.A. Laan fonds 2022-10-24; The loglio Collective; Sheri Sobrato Brisson Brain Cancer Survivorship Program.
OS08.6.A QUALITY OF LIFE IN PATIENTS AND CAREGIVERS FOLLOWING RADIOTHERAPY FOR BRAIN METASTASES: LOWER HEALTH STATUS AND MORE SYMPTOMS OF ANXIETY
Authors: van Grinsven E , Cialdella F , Vrolijk T G G , Philippens M E P , Verhoeff J J C , van Zandvoort M J E
Published: September 2023

BACKGROUND

The incidence of brain metastases (BMs) has been rising due to improvements in cancer treatment. Although survival rates are typically 3-4 months, more and more long surviving patients and their families are confronted with physical, practical, emotional, and cognitive consequences of disease and more effective treatments. Therefore, we investigated quality of life (QoL) in both patients and caregivers in the six months following radiotherapy (RT).

METHODS

To understand the impact of BMs on QoL for both patients and caregivers, we implemented the prospective Cohort for patient-reported Outcomes, Imaging and trial inclusion in Metastatic BRAin disease (COIMBRA) to examine all patients with BMs who received RT. 94 adult patients with BMs and their informal caregivers completed the same QoL-questionnaires for themselves (including EQ-5D-3L, EQ-VAS and HADS) before RT, one month, three months and six months after RT. Individual changes in QoL were evaluated using minimal clinically important differences as reported in previous literature. Trajectories of changes in QoL were assessed using mixed linear models with a growth curve approach.

RESULTS

On the group-level, growth models indicated stable QoL for both patients and caregivers over the six months following RT. However, individual trends showed variability in baseline levels and rate of change. That is, patients with higher baseline QoL, tend to experience larger decreases in QoL over time. A comparison of the trajectories of QoL indicated no differences between patients and caregivers. A closer inspection of the data, showed patients reported a lower health status (EQ-5D and EQ-VAS), while caregivers reported more symptoms of anxiety (HADS-anxiety) at all investigated time points (all p < .05). Over all time points considered, 37% of caregivers experienced clinically relevant symptoms of anxiety. Highest individual differentiated rates of change were seen in the first month following radiotherapy, with 34% of patients improving on the EQ-5D-3L whereas 42% of patients declined on the EQ-VAS.

CONCLUSION

Overall, in the six months following brain radiotherapy QoL remained stable in both patients and caregivers. Individual analyses highlights differentiated trajectories, with the majority of patients and caregivers showing the largest changes within the first month. Since a relatively large group of caregivers experienced symptoms of anxiety, this suggests a potential benefit for of offering psychological support to caregivers throughout the treatment process could potentially be beneficial.

GRANT INFORMATION

E.G was supported by research funding from the Dutch Cancer Society “Koningin Wilhelmina Fonds (KWF)” (#11110).
OS10.6.A GLIOBLASTOMA CELLS IMITATE NEURON’S EXCITABILITY IN ACUTE AND ORGANOTYPIC HUMAN BRAIN SLICES
Authors: Tong T , Ozsvar A , Hou W , Capogna M , Korshøj A R
Published: September 2023

BACKGROUND

Glioblastoma (GBM) is a highly lethal cancer with a low treatment success rate due to its inter- and intra-patient molecular and physiological heterogeneity, and its complex interaction with brain tissue. Neuron-to-brain tumor-synaptic-communications (NBTSCs) are believed to contribute to glioma progression and tumor-induced epilepsy. However, the physiology of these synaptic interactions in the tumor-infiltrated human neocortex remains largely uncharacterized. In this study, we investigated the intrinsic electrical properties of cells and NBTSCs in the tumor-infiltrated human cortex.

MATERIAL AND METHODS

We established a unique experimental workflow that enables us to investigate glioma cells in acute and cultured human tumor-infiltrated brain slices. We utilized an adeno-associated virus-assisted gene delivery technique to selectively express fluorescence proteins in a cell-type specific manner. By performing fluorescence-guided whole-cell patch clamp recording, we characterized the electrophysiological properties of glioma cells and neurons under the tumor microenvironment.

RESULTS

We observed that glioma cells from tumor-infiltrated human brain samples display relatively depolarized -32.59 + 3.16 mV resting membrane potential and high input resistance of 1.73 + 0.43 GΩ, with 44.44% of glioma cells exhibit spikelets or distorted-action potentials upon current injection. Consistent with previous studies, some glioma cells (11.8%) from both acute and cultured human brain slices exhibit spontaneous excitatory postsynaptic currents (sEPSC). In addition, the tumor-infiltrated microenvironment significantly influences the proximal neurons’ physiology and the neuronal microcircuitry. Neurons within the tumor region show abnormal intrinsic electrical properties, depolarized resting membrane potential (-37.66 + 4.32 mV), and a significant reduction in spontaneous synaptic input frequency.

CONCLUSION

Collectively, we consolidate the existence of NBTSCs in human cancer patients and unprecedentedly reveal that glioma cells exhibit neuron-like excitability, which is contrary to the common understanding that they are considered as non-excitable. Under the tumor microenvironment, neurons display hyperexcitability. Our newly established organotypic human brain slice culture platform provides potential grounds for exploring further the biological characteristics of gliomas.

SUPPORT/DISCLOSURE

This study is supported by grants to AK (DCCC Consortium grant number R295-A16770 funded by the Danish Comprehensive Cancer Center); to MC (Lundbeck-NIH grant number R325-2019 funded by the Lundbeck Foundation, DFF-1 project 37741 funded by the Independent Research Fund Denmark).
OS10.7.A TUMOR-ASSOCIATED ASTROCYTES PROMOTE TUMOR PROGRESSION OF SONIC HEDGEHOG MEDULLOBLASTOMA BY SECRETING LCN2
Authors: Chang Q , Li H
Published: September 2023

BACKGROUND

Sonic Hedgehog (SHH) subgroup of medulloblastoma (MB) accounts for about 25% of all subgroups of MB. Tumor microenvironment (TME) may play a key role in the tumor progression and therapeutic resistance. Tumor-associated astrocytes (TAAs) are reshaped to drive tumor progression through multiple paracrine signals. However, the mechanism by which TAAs modulate MB cells remains elusive.

MATERIAL AND METHODS

We explored the function of TAAs of SHH-MB in transgenic mouse model and co-culture system by a series of molecular biological techniques. To illuminate the TAAs distribution pattern during tumor progression of MB, we firstly detected MB transgenic mice bearing tumor at different time points by nuclear Magnetic resonance imaging (MRI). Histologic sections were then evaluated under microscope after H&E staining. The RNA-sequencing was also performed to evaluate differential expression between normal astrocytes (ASs) and tumor-associated astrocytes (TAAs). Bio-informatic analysis was followed to find the specific gene expressed in TAAs. Drug treatment of TAA inhibitor was finally applied in the animal model to clarify its effects on tumor progression.

RESULTS

We illuminated that TAAs showed a specific and dynamic pattern during SHH-MB development. Most TAAs gathered to the tumor margin during the tumor progression, rather than evenly distributed in the early-stage tumors and dissemination foci. We further demonstrated that LCN2 secreted by TAAs could promote the tumor growth and was correlated with the poor prognosis of MB patients. Knocking down LCN2 in TAAs in vitro impeded the proliferation and migration abilities of MB cells. In addition, we identified that TAAs accelerated the tumor growth by secreting LCN2 via STAT3 signaling pathway. Accordingly, blockade of STAT3 signaling by its inhibitor WP1066 in TAAs abrogated the effects of LCN2 on tumor progression in vitro and in vivo.

CONCLUSION

We for the first time clarified that LCN2, secreted by TAAs, could promote MB tumor progression via STAT3 pathway and has potential prognostic value. Our findings unveiled a new sight in reprogramming the TME of SHH-MB and provided a potential therapeutic strategy targeting TAAs.