bluuebunny/crossref_metadata_2025_split huggingface dataset:
KS01.3.A Tumoral MHC class II expression in gliomas drives T cell exhaustion
Authors: Chih Y , Sahm K , Sadik A , Bunse T , Trautwein N , Pusch S , Stevanovic S , Opitz C , Deimling A , Wick W , Sahm F , Bunse L , Platten M 
Published: September 2021

Abstract

BACKGROUND
Neoepitopes are presented on major histocompatibility class II (MHCII) molecules. In glioma, for instance, the recurrent driver mutation IDH1R132H was shown to bear an MHCII-restricted epitope in preclinical and clinical vaccine studies. The general relevance of MHCII expression in glioma for antitumor immunity, however, remains unknown. Here we evaluate stromal and tumoral MHCII expression, functionality, and its association with survival in gliomas.

MATERIAL AND METHODS
Immunostaining of human glioma tissues was used to identify tumoral, endothelial, and microglial MHCII expression and to enumerate T cell infiltrates. To gain insights into tumoral MHCII expression, bulk transcriptomic data from TCGA and single-cell transcriptomic data from publicly available datasets were analyzed. MHC ligandome analyses of an MHCII+ glioma cell line and human glioma tissues were used to determine the functionality of MHCII in vitro and ex vivo. Functional in vitro co-culture assays with an HLA-DR-matched tetanus toxoid (TT) epitope-overexpressing glioma cell line and in vitro-expanded TT-reactive T cells from healthy donors were used to examine direct target recognition by T helper cells. CRISPR-Cas9-mediated knockout of MHCII in preclinical hypermutant glioblastoma cell line GL261 was employed to further validate the consequences of tumoral MHCII expression and to probe potential clinical intervention with existing therapies.

RESULTS
MHCII is expressed in the majority of gliomas and associated with increased infiltration of T cells. In 10% of the analyzed glioma tissues and a subset of single cells, tumoral MHCII expression is detected. Clinical and transcriptomic data reveal that tumoral MHCII is associated with poor prognosis, cytokine responses, immune inhibition and T cell differentiation. Ligandome analyses evidence presentation of peptides by MHCII molecules on glioma cells. In in vitro assays, TT-reactive T helper cells specifically produce IFNg when co-cultured with MHCII+ glioma cells upon the presence of co-stimulation. In agreement with the clinical data, preclinical murine models demonstrate that tumoral MHCII expression leads to reduced survival. Co-culture assay shows that tumoral MHCII results in upregulation of PD-1 on T helper cells antigen-specifically. Concordantly, immune checkpoint blockade (ICB) therapy slows the disease progression of mice carrying MHCII+ tumors.

CONCLUSION
MHCII is expressed in gliomas by a subset of tumor cells. Although tumoral MHCII is functional, it is associated with poor survival in both clinical data and preclinical models. T cell exhaustion induced by tumoral MHCII expression can, in part, be overcome by ICB in vivo. Further experiments are required to decipher tumor cell intrinsic and microenvironmental consequences of tumoral MHCII expression.
OS03.5.A Corelation between longitudinal t2 MRI radiomic primary texture feature values and radiation dose in non-tumoral regions of the brain in paediatric brain tumours
Authors: Sakhavalkar P , Avula S , Pizer B , Thorp N , Jenkinson M 
Published: September 2021

Abstract

BACKGROUND
Paediatric brain tumour survivors may have treatment toxicity associated with signal change on follow-up MRI. Quantitative MRI texture features can potentially be used as surrogates of the underlying tissue changes following radiation therapy.

MATERIAL AND METHODS
Longitudinal retrospective study in 51 paediatric primary brain tumours treated with photon (N=30) and proton (N=21) radiotherapy (RT). T2 MRI scans at baseline and multiple time point from the date of surgery to 2 years following radiotherapy were selected for the textural analysis. Scans were bias corrected, registered with the CT dose maps and with baseline scan for each patient using 3Dslicer. Regions of interest (ROI) of fixed diameter were drawn in 11 predetermined non-tumoral regions of brain including in peri-tumoural region (PTV). ROIs were placed in homogenous white/grey matter. Radiation dose was calculated in each of these 11 ROIs and texture features were extracted using pyradiomics. Data were analysed using machine learning and statistical analysis. General linear multivariate model was used to corelate primary texture features over period of 24 months and radiation dose, time, effect of dose*time together at each ROI separately.

RESULTS
There were Brainstem 4, Cerebellar19, Hemispheric cerebral 7 and Supratentorial midline 10 tumours. Median age at diagnosis was 8.26 years (range: 0–20). Median RT treatment dose was 28.52Gy (0-60Gy). Multivariate analysis shows significant corelation (p &lt; 0.001) between radiation dose and longitudinal primary texture features in all 11ROIs. Time showed corelation with feature values only in 3 ROIs and dose* time showed corelation in 5ROIs. Primary (statistical) feature values showing consistent correlation with dose in all 11 ROIs over 24 months are total energy, 10%, 90%, energy, entropy, mean, median, and minimum.

CONCLUSION
Radiomic texture analysis is a promising modality to understand dose related textural changes in the normal part of brain in paediatric brain tumour patients treated with radiation therapy. Radiomic changes need to be related to neurological outcomes in future research.
P06.01 Pediatric non-pontine diffuse midline glioma H3K27M mutant: a monoinstitutional experience
Authors: Schiavello E , Biassoni V , De Cecco L , Pecori E , Filippo S , Gandola L , Massimino M 
Published: September 2021

Abstract

BACKGROUND
The new entity “diffuse-midline-glioma H3K27M-mutant”(DMG) was defined in the 2016 WHO classification. This tumor subtype, regardless of histological features, is associated with an aggressive clinical behavior and poor prognosis, sharing the same outcome as DIPG.

MATERIAL AND METHODS
We report our experience from 2016 to 2018 in treating patients with radiotherapy and concomitant Nimotuzumab/Vinorelbine, as already published for DIPG’s patients (DOI10.1007/s11060-014-1428-z). All patients’ parents provided written informed consent for treatment.

RESULTS
Patients were 9: 7/9 females, median age at diagnosis 13 years (range 1–26); 8 with localized disease, 1 with spinal fluid (CSF) dissemination. Five patients had thalamic disease (1 bithalamic), 2 ponto-cerebellar (one with 2 lesions), 1 pineal gland and one with disseminated CSF disease at diagnosis. 3/9 were biopsed in thalamus, the others had partial resection. Central neuropathological review with confirmed histopathological diagnosis of DMG mutated was necessary for inclusion. At the first pathological evaluation tumors had been classified according to the fourth edition of the WHO 2007 as glioblastoma (n=4), anaplastic astrocytoma grade III (n=1), diffuse astrocytoma grade II (n=1), and 1 glial tumor with oligodendroglial features; 2 patients already had DMG at the first pathological evaluation. Immunohistochemical analysis revealed p53 mutation in 3 patients. All 9 patients were evaluated on serial plasma samples with NGS targeted panel (Pan-Cancer) and 6/9 presented p53 mutation in at least one of the samples. 8/9 expressed MAP2K1 gain of function at liquid biopsy. The small number of patients did not allow correlations with the prognosis. Two patients completed the scheduled 2 years of treatment: one had a local relapse at 37 months after diagnosis, the other is alive without evidence of progression at 30 months. With a median follow up of 14.4 months, PFS and OS were 33% and 77% at 1 year; OS was 22% at 2 years, with 2 patients long survivors at 36 and 40 months after diagnosis.

CONCLUSION
The molecular and phenotypic pattern of DMG allows to include patients in clinical trials/registry shared with patients suffering from DIPG. Our knowledge is still limited about this entity; new insights into molecular profile should help us to study new drugs directed against the effects of the H3K27M mutations and to define new diagnostic/prognostic approach as liquid biopsy able to correlate treatments and prognosis
P10.03 Establishment and validation of clinical prediction model in WHO grade II glioma
Authors: Xue X , Gao Q 
Published: September 2021

Abstract

OBJECTIVE
WHO grade II glioma has the characteristics of heterogeneity, and this disease progresses rapidly in some patients, in whom the malignant degree is equivalent to that of high-grade glioma. In order to accurately predict the prognosis of patients, an effective clinical prediction model based on relevant risk factors is needed which could provide a theoretical basis for optimization of clinical individualized treatment.

METHODS
According to the inclusion and exclusion criteria, eligible patients from January 2010 to December 2018 in our hospital were selected, and those who met the criteria were randomly assigned 4:1 to the training group and the validation group, respectively. The predictors were screened by univariate and multivariate Cox regression analysis, the prediction model was established, and the model was verified and evaluated.

RESULTS
A total of 258 patients with WHO grade II glioma were recruited, including 208 patients as the training group and 50 patients as the validation group. Six independent risk factors, including patient age, preoperative Karnofsky performance status (KPS) score, preoperative seizure symptoms, surgical resection range, tumor size and IDH status, were selected and included into the prediction model by univariate and multivariate Cox regression analysis, and were visualized in the form of Nomogram. The concordance index (C index) was used to evaluate the predictive ability of the model. Results showed that the C-index was 0.832 in the training group and 0.853 in the validation group, respectively, indicating good performance for the prediction model. The calibration charts were drawn in both groups respectively, which showed that the calibration lines were in good agreement with the standard lines, indicating good consistency between the two groups.

CONCLUSIONS
In this study, a clinical prediction model for WHO grade II glioma was established, and it was verified that the model has good predictive ability, which may be beneficial for clinical work.
P11.03 Sleep analysis of accelerometer data from High Grade Glioma patients in the BrainWear study
Authors: George M , Dadhania S , Williams M 
Published: September 2021

Abstract

BACKGROUND
Sleep disturbance is a common symptom in patients with high grade glioma (HGG). Existing self-reported and uni-dimensional data from questionnaires are of limited value. The observational phase 2 trial, BrainWear (ISRCTN 34351424) provides the first objective analysis of sleep in HGG patients.

MATERIAL AND METHODS
Patients with HGG were asked to wear an AX3 Axivity tri-axial accelerometer throughout treatment. The study employed a wear-as-long-as-possible approach to accelerometry data collection, and we used age-sex matched controls from the UK Biobank as comparators. Baseline was established as a 7 day period of wear prior to surgery or at least 7 days post-surgery. The dataset for this analysis consists of 21 patients with data at baseline and 15 patients during chemo-radiation. Only 16 of the 21 HGG patients at baseline were included for initial comparisons with healthy controls due to age limitations of the UK Biobank cohort for matching. Raw accelerometer data was processed using the GGIR package, with non-imputation of missing data, exclusion of days with &lt;16 hours of wear time and removal of algorithm-identified problematic data. Mann-Whitney U-tests and unpaired T-tests were used to compare 7 sleep-related features between HGG patients and healthy controls at baseline, with choice of statistical test based on shapiro-wilk derived normality. Secondly, to assess changes in sleep in HGG patients across treatment period, K-means clustering of 5 sleep parameters, available longitudinally, was conducted to explore sleep behaviours at baseline (n = 21) and during chemo-radiation.

RESULTS
HGG patients (n = 16) exhibited greater daytime inactivity than healthy controls (n = 32) (p &lt; 0.0001, 2.2 vs 0.5 hrs) and more variation in their 24 hour activity rhythm from day to day (p &lt; 0.0001, 0.12 vs 0.18). We identified 5 sleep features which allowed us to cluster patients’ sleep behaviour, and most (62.5%) of HGG patients have a poor sleep profile. This sleep profile was characterised by an average of 5.4 hours of night-time sleep, 2.1 hours of daytime inactivity and disturbed sleep quality. However, evaluation of HGG patient sleep cluster designation at baseline and during chemoradiation, showed HGG patients with data at both timepoints (n = 9) demonstrate stability or improvement in sleep profile.

CONCLUSION
Patients with HGG have objective evidence of poor sleep compared to healthy matched controls. Further work will explore changes in sleep over time.
P11.05 Evaluation of a dialogue support tool tailored to support patients with brain tumors in identifying areas for improvement in a new proton clinic
Authors: Lund M H , Simonsen H , Kristensen A W 
Published: September 2021

Abstract

BACKGROUND
Proton therapy has been available in Denmark in the recent 2 years. The aim of this project was to evaluate the course of treatment with proton therapy from a patient perspective and thereby identify areas for improvement.
A secondary aim was to test the use of a dialogue support tool when interviewing patients with brain tumors. The tool supports the oral questions with visual pictograms.

MATERIAL AND METHODS
During 2020, structured interviews based on a dialogue support tool were conducted with 17 adult patients (&gt;18 years) with brain tumours at the end of their treatment with proton therapy. Three radiation therapists (RTTs) conducted individual interviews in quiet surroundings in the clinic. The dialogue support tool consisted of the following elements; a poster showing the course of treatment, pictograms of activities during the treatment course. Furthermore, green, yellow and red smileys representing a satisfied, neutral or unsatisfied evaluation of the treatment pathways reported by the patients. During the interview the RTT placed the pictograms on the poster one by one. The patient evaluated each pictogram as satisfied, neutral or unsatisfied. If the patient evaluated a pictogram as neutral or unsatisfied, the RTT asked the patient for suggestions on improvements related to the specific activity. The last pictogram represented an evaluation of the dialogue support tool. The patient evaluations were documented systematically, collected and analysed. The emerging areas for improvement were discussed by the authors until consensus was reached.

RESULTS
The following topics were identified as areas for improvements of the course of treatment: A need for more detailed information on proton therapy in the referring clinics before initiation of treatment. Lack of shared decision between patient and doctor regarding choice of radiotherapy modality. Barriers to understand patient information on website due to reading difficulties, reduced cognitive function or visual impairment. A need for detailed information on the possibilities regarding transportation, accommodation and accompanying relatives. Patients reported confusion with being assigned a doctor responsible for their treatment because the patients met many doctors during the course of treatment. Evaluation of the dialogue support tool: The patients experienced that the dialogue support tool made it easier to understand the oral questions.

CONCLUSION
The structured interviews supported by the dialogue support tool was a suitable approach to detect areas of improvement in the course of treatment with proton therapy. The poster helped to visualise the course of treatment and the pictograms clarified the questions. The findings represent patient-identified topics relevant for further development in clinical practice.
P12.02 Symptoms of patients with diffuse glioma during stable disease as a potential target for treatment
Authors: Röttgering J G , Belgers V , Kouwenhoven M C M , Schuur M , Postma T J , Nijboer C M , van Linde M E , de Witt Hamer P , Douw L , Klein M 
Published: September 2021

Abstract

BACKGROUND
Patients with diffuse glioma experience many tumor- and treatment-related symptoms, including fatigue, cognitive deficits, and anxiety. It remains unclear how the frequency and burden of these symptoms change over time and specifically which symptoms patients experience during the stable phase of the disease. We assessed the frequency and burden of common symptoms in glioma patients during stable disease and whether patients were willing to undergo treatment for those symptoms. We suggest a top five of potentially treatable symptoms.

METHODS
Patients with a diffuse glioma during stable disease completed a questionnaire on symptoms they experienced during the past two weeks, such as irritability, fatigue, stress, pain, depressive thoughts and relationship problems. They rated the frequency and burden of seventeen symptoms on a seven-point numeric scale ranging from ‘never’ to ‘continuously’ and from ‘no burden’ to ‘unbearable’, respectively. Also, they stated whether they were willing to undergo treatment for each symptom. Data was collected retrospectively. The median values of the frequency and burden dimension were calculated for each symptom. We composed a top five of most frequent and burdensome symptoms. We used Kendall’s Tau to correlate frequency, burden and willingness to undergo treatment per symptom.

RESULTS
Fifty-two patients were included, 77% had a KPS score of 90–100, 23% a KPS score of 70–80 and 40% had a glioblastoma. The top five most frequent and burdensome symptoms were fatigue, memory problems, reduced physical fitness, concentration problems and drowsiness. Fatigue had the highest median value on the frequency (median 4.5, IQR 2.5) and burden (median 4.0, IQR 3.00) dimension and 21% of the patients were willing to undergo treatment for fatigue. Overall 35% of the patients were willing to undergo treatment for at least one symptom. Frequency and burden of symptoms correlated well (median Kendall’s Tau of 0.84 with a range of correlations of 0.73–0.95). Frequency and willingness to undergo treatment correlated less (median Kendall’s Tau of 0.35, range 0.24–0.57), as well as burden and willingness to undergo treatment (median Kendall’s Tau, range 0.28–0.61).

CONCLUSION
The top five symptoms most often reported by patients with diffuse glioma during stable disease were: fatigue, memory problems, reduced physical fitness, concentration problems and drowsiness. These symptoms may serve as a roadmap for future research on treatment strategies to alleviate these symptoms.

SUPPORT/DISCLOSURE
This project is funded by The Anita Veldman Foundation (CCA-2019-2-21).
P13.09 Inconsistent effect of temozolomide exposure on cell viability in glioblastoma cell line models - a systematic review
Authors: Bruce M M C , Poon M T C , Brennan P M 
Published: September 2021

Abstract

BACKGROUND
The alkylating agent temozolomide is part of standard care for patients with glioblastoma. Potential novel therapeutic agents are often first evaluated against temozolomide in glioblastoma cell line models. Despite the importance of this step in compound development, there is no standard concentration or exposure duration of temozolomide in laboratory research, and consistency in the effect of temozolomide on glioblastoma cell lines has not been assessed. This systematic review aimed to summarise the concentration and exposure duration of temozolomide and its effect on cell viability in studies using glioblastoma cell lines.

MATERIAL AND METHODS
We searched Medline and Embase Jan 1994 - Feb 2021 for studies that used at least one glioblastoma cell line and reported a measure of cell viability associated with temozolomide exposure. Studies were excluded if they used modified cell lines or did not report a cell viability measure associated with temozolomide as monotherapy. One reviewer screened all records and two reviewers assessed potentially eligible studies for inclusion. The main data items included the cell lines used, the concentration and exposure duration to temozolomide, and cell viability measures. We summarised findings using descriptive statistics.

RESULTS
Of 1,533 potentially eligible studies we included 213 studies reporting 209 different cell lines. The most common cell lines were U87, U251 and T98G, used in 61%, 41%, and 27% of studies, respectively. Twenty-five (12%) studies used patient-derived cell lines. The concentration of temozolomide used ranged from 0 to 8000μM. The temozolomide exposure duration ranged from &lt;24 hours to &gt;96 hours, with 29% studies using 72 hours. The most common cell viability measure was half maximal inhibitory concentration (IC50), which was reported in 183 (86%) studies. The median IC50 in 32 studies using the U87 cell line was 180μM (interquartile range [IQR]: 52–254μM) at 48-hour temozolomide exposure and 202μM (IQR 52–518μM) at 72-hour exposure. The median IC50 in 31 studies using U251 cell line was 84μM (IQR: 34–324μM) at 48-hour exposure and 102μM (IQR: 35–358μM) at 72-hour exposure.

CONCLUSION
Experimental setup of temozolomide and its effect on cell viability vary widely between studies using similar glioblastoma cell lines. This inconsistency of response to temozolomide questions reproducibility and the translational value of study findings.
P14.20 Quality of life of patients with newly diagnosed glioblastoma during TTFields therapy in routine clinical care: first results of the TIGER study
Authors: Bähr O , Tabatabai G , Fietkau R , Goldbrunner R , Glas M 
Published: September 2021

Abstract

BACKGROUND
Glioblastoma (GBM) is an aggressive primary tumor of the central nervous system. Current interdisciplinary treatment strategies outside clinical trials include maximal safe resection, followed by treatment with radiation and an alkylating chemotherapy. Based on the results of the positive phase III trial EF-14, the addition of Tumor Treating Fields (TTFields) to temozolomide (TMZ) maintenance therapy brought an additional treatment method to clinical routine. The prospective non-interventional study TIGER (TTFields In GErmany in Routine Clinical Care) documents the use of TTFields in routine clinical care with a particular focus on health-related quality of life (HRQoL) within 4 months after starting therapy, treatment compliance and duration.

MATERIAL AND METHODS
This multi-center prospective non-interventional study in Germany (NCT03258021) included ndGBM patients eligible for TTFields therapy. Following their consent to participate in the study, patients received a comprehensive introduction to the therapy and their baseline demographic data were collected. Information on TTFields therapy decision is evaluated based on a dedicated TTFields questionnaire at baseline in both arms, follow-up information on how patients cope with the therapy is collected two months after TTFields treatment start, if applicable. HRQoL was assessed in patients deciding for TTFields therapy at baseline as well as at 2 months and 4 months thereafter using the EORTC-QLQ-C30/BN-20 questionnaires.

RESULTS
Between August 2017 and November 2019, 710 patients (259 female/451 male) were enrolled at 81 participating centers. The mean age was 58.5 years (range: 19.0–85.0; Cut-off: August 31, 2020). The overall baseline characteristics of the study group reflects a typical GBM population. Of these, 582 (82%) decided to start TTFields and 128 (18%) refused TTFields treatment. Health-related QoL did not decline during TTFields therapy except for itchy skin, comparable to the results of the EF-14 phase 3 trial. A detailed analysis of the cohort as well as their reported QoL will be presented.

CONCLUSION
The TIGER study is the largest non-interventional trial on the use of TTFields in routine clinical care. The use of TTFields in patients with ndGBM did not impair HRQoL during the follow-up period, except for more itchy skin.