bluuebunny/crossref_metadata_2025_split huggingface dataset:
OS1.1 Plasma PD-L1 levels over time differ between glioblastoma and lower-grade glioma patients
Authors: Mair M , Ilhan-Mutlu A , Pajenda S , Widhalm G , Dieckmann K , Hainfellner J A , Marosi C , Wagner L , Preusser M , Berghoff A S 
Published: September 2019

Abstract

BACKGROUND
Immune modulating therapies are a promising treatment approach in patients with primary brain tumors, however their clinical efficacy is still under investigation as the systemic inflammatory responses are potentially challenged by the brain’s tight immune regulatory mechanisms. Here, we aimed to investigate soluble PD-L1 (sPD-L1) in the plasma of recurrent glioblastoma (GBM) and recurrent WHO grade II - III glioma (LGG) patients over their course of disease.

MATERIAL AND METHODS
30 patients with recurrent GBM and 10 patients with recurrent LGG were treated with bevacizumab (400mg, q14 days) as a salvage therapy at the Medical University of Vienna. EDTA plasma samples were drawn prior to each treatment cycle. sPD-L1 was analyzed using a sandwich ELISA (Millipore ABF133 and clone 5H1). The lower limit of detection was 0.050 ng/ml as determined by serial dilutions of recombinant human PD-L1.

RESULTS
sPD-L1 values could be retrieved in a median of 6 timepoints per patient (range: 2 - 24). No significant difference in sPD-L1 concentrations between GBM and LGG patients was present at baseline (p > 0.05). After 2 weeks of bevacizumab treatment, LGG patients presented with statistically significant lower sPD-L1 concentrations as compared to baseline (p = 0.036, Wilcoxon signed rank test), while no difference in sPD-L1 concentration was observed in GBM patients. Significantly higher sPD-L1 intra-patient variability was evident in LGG patients compared to GBM patients (p = 0.012, Mann-Whitney-U). In LGG patients, sPD-L1 correlated with leukocyte count (Spearman’s r = 0.397, p = 0.001) as well as with C-reactive protein level (Spearman’s r = -0.424, p = 0.001), while in GBM patients no correlation of sPD-L1 and systemic markers of inflammation was evident (-0.3 < Spearman’s r < 0.3).

CONCLUSION
sPD-L1 as a systemic marker of inflammation was lower in recurrent LGG patients compared to recurrent GBM patients after bevacizumab-based treatment, arguing that the glioma-immune system interactions differ between LGG and GBM.

SUPPORT/DISCLOSURE
This project was funded by the research budget of the Medical University of Vienna.
OS1.2 Development and Validation of a RNA-Seq Based Prognostic Signature in Neuroblastoma
Authors: Zhou J , Ma H 
Published: September 2019

Abstract

BACKGROUND
Credible prognostic stratification remains a challenge for neuroblastoma (NBL) with variable clinical manifestations. RNA expression signatures might predict the outcomes; notwithstanding, independent cross-platform validation is still rare.

MATERIAL AND METHODS
expression data were obtained from NBL patients and then analyzed. In TARGET-NBL data, an RNA-based prognostic signature was developed and validated. Survival prediction was assessed using a time-dependent receiver operating characteristic (ROC) curve. Functional enrichment analysis of the RNAs was conducted using bioinformatics methods.

RESULTS
A total of 1,119 differentially expressed RNAs and 149 prognosis-related RNAs were identified sequentially. Then, in the training cohort, 12 RNAs were identiﬁed as signiﬁcantly associated with overall survival (OS) and were combined to develop a model that stratified NBL patients into low- and high-risk groups. Twelve RNA signature high-risk patients had poorer OS in the training cohort (n = 105, Hazard Ratios (HR)= 0.10 (0.05–0.20), P < 0.001) and in the validation cohort (n = 44, HR = 0.25 (0.09–0.69), P = 0.008). ROC curve analysis also showed that both the training and validation cohorts performed well in predicting OS (12-month AUC values of 0.852 and 0.438, 36-month AUC values of 0.824 and 0.737, and 60-month AUC values of 0.802 and 0.702, respectively). Moreover, these 12 RNAs may be involved in certain events that are known to be associated with NBL through functional enrichment analysis.

CONCLUSION
This study identiﬁed and validated a novel 12-RNA prognostic signature to reliably distinguish NBL patients at low and high risk of death. Further larger, multicenter prospective studies are desired to validate this model.
OS1.7 Plasmatic differential scanning fluorimetry profiles discriminate glioma patients from healthy controls
Authors: Tabouret E , Tsvetkov P , Eyraud R , Peel T , Malesinski S , Figarella-Branger D , Chinot O , Devred F 
Published: September 2019

Abstract

BACKGROUND
differential scanning fluorimetry (DSF) has been recently proposed to be used to perform high throughput biofluids profiling by following protein denaturation. Our objective was to discriminate patients with glioma from healthy controls using plasmatic DSF profiles.

MATERIAL AND METHODS
We included 78 glioma patients and 44 healthy controls. Plasmas were collected using EDTA tubes and analyzed in duplicate using nanoDSF Prometheus NT.Plex instrument (Nanotemper). The following DSF data were analyzed: protein fluorescence at 330 and 350 nm, first derivation of the ratio of fluorescence at 330 and 350 and the absorbance at 350 nm. Then we ran several machine learning algorithms to differentiate gliomas from healthy controls: Logistic Regression (LR), Support Vector Machine (SVM), Neural Networks (NN), Random Forest (RF) and Adaptive Boosting (AdaBoost). All these methods have been tested using a leave-one-out approach where each datum is used once as test while the other are used to train the automatic classifiers.

RESULTS
We included 78 patients with a median age of 57.8 years (range, 21.8 - 89.9). Thirteen patients (17%) presented with a 1p/19q codeleted IDH mutated oligodendroglioma, 12 patients (15%) with an IDH mutated astrocytoma and 53 patients (68%) with an IDH wild-type astrocytoma, including 26 patients with a recurrent grade IV IDH wild-type astrocytoma. DSF data were independent from classical prognostic factors or patient characteristics: age, Karnofsky Performans Status, IDH mutation status, 1p19q codeletion, grade, initial or recurrent setting, steroid doses, patient size and weight, tumor size and location. The different datasets of the DFS output were tested independently and in combination as input of the machine learning algorithms. Results were obtained using the tuned best parameters on 157 data. The best obtained accuracy was 95.54% with 2% of fake positives and 5% of fake negatives (algorithm: SVM). Others achieved ≥ 90% of correct classification: LR accuracy was 89.17%, NN accuracy was 92.99%, RF accuracy was 91.72% and Adaboost accuracy was 92.36%.

CONCLUSION
DSF profiles analyzed by machine learning algorithms could allow us to identify glioma patients from healthy controls with an accuracy of more than 95%. These results suggest that DSF of biofluid could be a useful and non-invasive tool to monitor glioma patients. Further investigations, including longitudinal profile analyses are ongoing.
OS3.2 Relevant topics for brain tumor patients in the Distress Thermometer, first results of the HEAT study
Authors: Renovanz M , Coburger J , Tabatabai G , Ringel F , Wirtz C , Mehdorn M , Goebel S 
Published: September 2019

Abstract

BACKGROUND
Patient-centered assessments and disease-adjusted patient-reported outcome measures (PROMs) are crucial in neuro-oncology. The Distress Thermometer (DT) is a well-accepted screening tool for cancer patients including a numerical rating scale (1–10, cut-offs indicating relevant distress ≥4–6) and 40 items describing possible problem categories (emotional, social, physical, practical and spiritual). The aims of the first part of the “Adaption of the Distress Thermometer in patients with intracranial tumors” (HEAT) study were to evaluate the importance and relevance of items for brain tumor patients (BTP).

MATERIAL AND METHODS
The multicenter study included three University hospitals. After given informed consent patients were prospectively evaluated either during their hospital stay or in the outpatient setting using DT as well as the 40 item problem list. Clinical and demographic data were recorded. We performed an analysis regarding frequency of indicated topics and evaluated their relevance for patients’ psychosocial well-beings via Pearson correlations with the DT score.

RESULTS
Data of n = 670 patients were analyzed. Mean age was 52 years (SD = 14, range 18–81), most of the patients harbored WHO°I tumors (37%) and WHO°IV tumors (28%). Male to female ratio was 1:1, 17% were assessed preoperatively, 40% postoperatively and 43% during adjuvant therapy or follow-up. 14% of the patients faced a tumor recurrence at assessment. Mean score of DT was 5.23 (SD = 2.9, range 0–10). Applying a cut-off score ≥ 4, 61% reported distress (≥ 5: 46% and ≥ 6: 37%). Regarding the relevance of the problem list for BTP, emotional problems (e. g., anxiety, depression) were most frequently reported. A total of 14/40 (35 %) of items were endorsed by less than 10% of patients. With exception of emotional problems all areas were reflected: practical problems (e. g., problems with child care or insurance), social problems (e. g., problems with children), spiritual concerns (e. g., loss of faith), and physical problems (e. g., breathing, fever). However, some of these rarely reported problems were of relevance for patients’ psychosocial well-being as indicated by significant correlations between the respective item and the DT score. This was, for example, the case for problems with childcare (r = .106; p < .01) or breathing (r = .125; p = .001).

CONCLUSION
Tools developed for cancer patients do not yet perfectly reflect all needs of BTP. Based on our data, we suggest further adjustments of available tools. Yet, it should be taken into account that subgroups of BTP may require different problem lists in the DT, as we observed some topics (e.g. breathing) probably be related to BTP under chemotherapy or steroids only. Moreover, our data require cross-cultural validation as especially results regarding practical problems and insurance might differ in cultures with different social security systems.
OS4.1 MEVITEM: A European, randomized, open-label, Phase I/II study of vismodegib in combination with temozolomide versus temozolomide alone in adult patients with recurrent or refractory medulloblastoma presenting an activation of the Sonic Hedgehog (SHH) pathway
Authors: Frappaz D , Barritault M , Montané L , Laigle-Donadey F , Chinot O , Le Rhun E , Bonneville-Levard A , Meyronnet D , Garin G , Pérol D 
Published: September 2019

Abstract

BACKGROUND
Vismodegib (V) suppresses sonic hedgehog (SHH) signaling. We postulated that vismodegib together with chemotherapy may be more efficient than chemotherapy alone in patients (pts) relapsing of a SHH-activated medulloblastoma (MB).

MATERIAL AND METHODS
Adult pts with recurrent SHH-MB not previously exposed to temozolomide (T) were randomly assigned (2:1 ratio) to Arm A (V daily 150mg/d, po) + T (D1-5: 150 mg/m2 for cycle 1 and 200 mg/m2 thereafter; n=up to 25pts) or Am B (T alone; n=up to 13pts). Identification of SHH activation was performed centrally by IHC (GAB1, β-catenin, filamin A, and YAP1). NGS analyses were performed to identify the mutations responsible for SHH activation. Primary objectives were to assess the incidence of severe toxicities (safety run-in based on a 3 + 3 design) and the 6-month non-progression rate (NPR-6m) according to WHO criteria and based on central read tumor assessment (Phase II). A Minimax Simon’s two-stage design was used to detect NPR-6m of 55% (p0: 30%, type I error rate of 5%, power of 80%). At first stage, ≥ 3/9 pts without progression at 6m were required for the accrual of 16 additional pts in Arm A. A 3rd independent and parallel arm with V as single agent (Arm C, n= up to15pts) was added for pts previously treated by T.

RESULTS
24 SHH-MB pts were enrolled (Arm A: 10, Arm B: 5 and Arm C: 9; median age: 37 y [21–55]). At the end of the safety run-in; no major safety concerns were reported. At the end of Stage I: no objective response were reported and 2 pts among 10 were free of progression at 6m among in Arm A. According to statistical rules, the study was definitively closed to enrolment. NGS analyses showed a PTCH1 inactivating mutation in 6 pts (n=4 in arm A; n= 2 in arm B); a SMO activating mutation in 4 pts (n= 3 in Arm A; n=1 in Arm B). For 1 pt in each arm, no tumor sample was available for analysis, for 1 pt in Arm A DNA quality was insufficient, and for 1 patient in each arm no mutations of SMO, PTCH1, SUFU or SHH were found. Out of the 4 pts in Arm A with an inactivating PTCH1 mutation, only 1 was progression free at 6m. PFS and OS data will be presented at the meeting.

CONCLUSION
The combination of vismodegib with monthly T failed to demonstrate superior activity as compared with T alone. Further studies are warranted to refine therapeutic indication for vismodegib
OS4.2 Phase 0 trial of Ceritinib in brain metastasis and recurrent glioblastoma
Authors: Fiorelli R , Li J , Bao X , DeRogatis A , Pennington-Krygier C , Kim S , Mehta S , Sanai N 
Published: September 2019

Abstract

BACKGROUND
Ceritinib is an orally bioavailable, small molecule inhibitor for ALK/IGFR1/FAK, which are highly expressed in glioblastoma and brain metastases. Preclinical and clinical data suggest that ceritinib has activity in central nervous system (CNS) malignancies, but to date there is no direct evidence in patients. This study assessed the pharmacokinetics (PK) and pharmacodynamics (PD) of ceritinib in recurrent glioblastoma and brain metastasis patients.

MATERIALS AND METHODS
Three brain metastasis and seven glioblastoma patients with high expression of pSTAT5b/pFAK/pIGFR1 were enrolled and treated with oral ceritinib daily (750 mg) for 10 days prior to tumor resection. Plasma, tumor, and cerebrospinal fluid (CSF) samples were collected at ~ 4 and 24 h following the last dose. Total and unbound drug concentrations were determined using LC-MS/MS. PD response was assessed by immunohistochemical analysis of pALK, pFAK, pIGFR1, and pIRS1 staining in treated tumor and matched archival tissues.

RESULTS
Ceritinib was highly bound to human plasma protein (median fraction unbound (Fu), 1.4%) and to brain tumor tissue (median Fu, 0.073% and 0.14% in enhancing and non-enhancing regions respectively). There was a large interindividual variability in drug CNS penetration, with the median unbound concentrations in enhancing, non-enhancing, and CSF of 0.040, 0.006, and 0.012 µM, respectively. The median unbound tumor-to-plasma ratio was 2.44 and 0.33 in enhancing and non-enhancing areas, respectively. In one patient with brain metastasis, drug binding to enhancing tumor was significantly lower (Fu, 1.62%), resulting in a higher unbound drug tumor concentration and CSF concentration as compared to those in glioblastoma patients. In all patients, no changes in PD markers were detected.

CONCLUSION
Ceritinib is highly bound to plasma proteins and tumor tissues. Unbound drug concentrations achieved in brain metastasis and glioblastoma are unlikely sufficient for target modulation.
OS5.5 Characteristics of high-grade gliomas with H3 G34 mutation in adults
Authors: Picart T , Barritault M , Tabouret E , Idbaih A , Izquierdo Gracia C , Poncet D , Honnorat J , Meyronet D , Guyotat J , Ducray F 
Published: September 2019

Abstract

BACKGROUND
H3 G34-mutant high-grade gliomas occur primarily in children but can also be encountered in adults. The aim of the present study was to describe the characteristics of H3 G34-mutant high-grade gliomas in adults.

MATERIAL AND METHODS
We analysed the characteristics of 17 adult H3 G34-mutant high-grade gliomas and compared them with those of adult grade IV gliomas with H3 K27M mutation (n=21), IDH mutation (n=42) and TERT promoter (pTERT) mutation (n=88).

RESULTS
Median age at diagnosis in H3 G34-mutant gliomas was 25 years (range: 19–33 y). All tumors had a hemispheric location. The radiological presentation was suggestive of a high-grade glioma in 6 patients but in 10 patients it initially suggested another diagnosis due to absent or faint contrast enhancement (n=9) or the presence of an initial intratumoral haemorrhage (n=1). In non- or faint contrast-enhancing cases, diffusion-weighted imaging (DWI) was more helpful to suspect an aggressive tumor than MR spectroscopy and perfusion MRI. All H3 G34-mutant gliomas were classified as IDH wildtype glioblastomas. PNET-like foci were observed in 8 cases and most cases were immunonegative for ATRX (92%) and Olig2 (81%) and demonstrated MGMT promoter methylation (82%). The clinical, radiological and histological presentation of H3 G34-mutant gliomas was different from that of midline H3 K27M-mutant diffuse gliomas and from that of IDH-mutant and IDH-wildtype pTERT-mutant glioblastomas. Median overall survival of G34-mutant gliomas was 23.9 months compared to 19.6 months (p=0.16), 13.7 months (p=0.45) and 58 months (p=2.3x10-10) in H3 K27M-mutant diffuse gliomas, IDHwt pTERT-mutant and IDH-mutant glioblastomas, respectively.

CONCLUSION
Adults H3 G34-mutant high-grade gliomas are associated with distinct characteristics and a poor prognosis. DWI seems helpful to identify cases that present as non-contrast enhancing lesions and can wrongly suggest another diagnosis in these young patients.
OS6.4 The hypoxia-induced glioma derived exosome miRNA-199a-3p promotes glioma cells proliferation and increased ischemic injury of the para-tumor neurons by inhibiting mTOR pathway— A pivotal ischemic mechanism in the proliferation and growth of glioma
Authors: Zhao J , Hu J , Xie R 
Published: September 2019

Abstract

BACKGROUND
Growth of glioma cells can be promoted by hypoxia, but its underlying molecular mechanisms are not clear. Exosomes and miRNAs were reported to play crucial roles in tumor progression. Effects of exosomes and exosomal miRNAs, induced by hypoxia, on glioma cells were still unclear.

MATERIAL AND METHODS
Glioma samples were analyzed by HE and HIF-1α staining. Image data of these patients were also retrospectively analyzed. HT22 and C6 cell lines were co-cultured in both direct and indirect system. Hypoxia (1% oxygen) and oxygen and glucose deprivation (OGD) were applied to evaluate hypoxia effects on the growth and proliferation of cell lines, and such effects were assessed by C6/HT22 ratio, MTT and LDH assay. Hypoxia-induced glioma derived exosomes (HIGDE) and non-HIGDE (NHIGDE) were isolated and were administrated to normal culture medium to evaluate their effects on cell growing. The target miRNA was selected by performing miRNA microarray analysis. MicroRNA mimics and shRNA were constructed to overexpress or inhibit the microRNA expression. MTOR signal pathway was activated by utilizing phosphatidic acid. The RNAs expression were detected by RT-qPCR and the proteins expression was evaluated by western blotting.

RESULTS
Para-tumor hypoxia area shared a same region with cytotoxic edema around the glioma lesion and can be easily detected by PET/CT. The density of positive HIF-1αstaining was higher in tumor area than that in para-tumor and normal parenchyma area. In hypoxia direct co-culture system, the cell number ratio of C6/HT22 was significantly higher than that without hypoxia pretreatment; while in hypoxia mono-culture and indirect co-culture systems, the proliferation ability of HT22 was statistical lower than C6. After applying OGD, neuron cells cultured with HIGDE showed a statistical higher LDH release level than with NHIGDE or normal culture medium. The miRNA microarray analysis revealed that miRNA-199a-3p was the highest expressed in HIGDE than in NHIGDE (p < 0.05; Fold Change > 2). Transfected with mimics or shRNA, it was indicated that upregulation of miR-199a-3p aggravated HIGDE-induced OGD injury in HT22 cells. Moreover, we interfered mTOR signal pathway and the expression of HIF-1αin C6 cells. We found that miRNA-199a-3p aggravated HIGDE-neuron cell injury via suppressing mTOR signal pathway, and hypoxia related upregulation of miRNA-199a-3p in HIGDE was induced by the activation of HIF-1α in C6 cells.

CONCLUSION
The Hypoxia-Induced Glioma Derived Exosome miRNA-199a-3p can be upregulated by the activation of HIF-1α, and is able to promote glioma cells proliferation and increase ischemic injury of the para-tumor neurons via inhibiting mTOR pathway.
OS7.4 Calculating the net clinical benefit in brain tumor clinical trials by combining survival and health-related quality of life data using two methods: quality adjusted survival effect sizes (QASES) and joint modelling (JM)
Authors: Coomans M , Dirven L , Bottomley A , van den Bent M , Sloan J , Stupp R , Weller M , Reijneveld J C , Taphoorn M , Aaronson N , Baumert B G , Brandes A A , Chinot O , Coens C , Gorlia T , Herrlinger U , Keime-Guibert F , Malmström A , Martinelli F , Talacchi A , Wick W 
Published: September 2019

Abstract

BACKGROUND
The impact of treatment on both the quality and the quantity of life, i.e. the ‘net clinical benefit’, should be considered to inform glioma patients and facilitate shared decision making. We applied two methods (i.e. Quality Adjusted Effect Sizes (QASES) and Joint Modelling (JM)) that combine survival and health-related quality of life (HRQoL) data into one outcome, to gain insight in the net clinical benefit of a treatment strategy. In addition, we assessed if both methods result in similar interpretations.

MATERIAL AND METHODS
We calculated the net clinical benefit in one randomized controlled trial, EORTC 26951 comparing radiotherapy (RT) + PCV chemotherapy versus RT alone, as a proof of concept for other trials. With the QASES method, effect sizes for differences in survival and HRQoL between treatment arms were calculated. Next, the combined effect size can be determined by weighing the emphasis put on survival or HRQoL (e.g. survival more important). JM allows simultaneous modeling of a longitudinal outcome (HRQoL), and a time-to event outcome (survival). HRQoL scales/items that were selected for primary analysis in the main study were also selected for this analysis: fatigue, global health, social functioning, communication deficit, seizures, physical functioning, and nausea/vomiting.

RESULTS
288/386 patients completed baseline HRQoL forms and were included in the analysis. Overall survival (OS) was significantly longer with combined treatment (difference of 10.8 months). In contrast, the percentage of patients who experienced a clinically relevant deterioration (≥10 points) in nausea/vomiting, fatigue, social functioning and global health up to one year after treatment compared to baseline was larger in the RT+PCV arm. The QASES corresponded to a reduction in the median OS difference from 10.8 months to 6.8 months when adjusted for the HRQoL scales/items, when given equal weights to OS and HRQoL. JM analyses resulted in a theoretical loss of treatment effect in OS of 2–6% when adjusting for HRQoL.

CONCLUSION
Both methods showed that adjusting for the impact of treatment on a relevant HRQoL parameter reduced the survival benefit in the experimental treatment arm compared to standard treatment arm. Applying these methods may facilitate communicating the impact of treatment to patients in clinical practice.