bluuebunny/crossref_metadata_2025_split huggingface dataset:
P06.05 The Sitting Position in the Very Young Pediatric Population: Pearls and Pitfalls of a 10-Years’ Experience
Authors: Linsler S , Teping F , Oertel J 
Published: September 2021

Abstract

BACKGROUND
To investigate pearls and pitfalls of the sitting positioning in the pediatric population with special focus on related morbidity and surgical practicability.

MATERIAL AND METHODS
A retrospective analysis of a prospectively maintained internal database was performed. All pediatric patients younger than 18 years at date of surgery, who underwent procedures in sitting position between 01/2010 and 10/2020 were included into this analysis.

RESULTS
A total of 42 of posterior fossa surgeries were performed in 38 children between 01/2010 and 10/2020. Mean age at surgery was 8.9 years (13 months - 18 years). Mean height and weight were 134.4 (± 30.2) cm and 36.6 (± 21.7) kg respectively. Three children (7.9%) were diagnosed with persistent foramen ovale. Electrophysiologic monitoring was unremarkable during positioning in all cases. Mean time needed for anesthesiologic preparation and positioning was 84.5 (± 20.6) minutes. Perioperative blood transfusion was needed in 5 cases (11.9%). Incidence of VAE was 11.9%. There was no VAE related severe complication. One child (2.4%) showed postoperative skull fracture and epidural bleeding due to skull clamp application. Clinical status immediately after surgery was favorable or stable in 33 of the cases (78.6%).

CONCLUSION
Attentive performance and an experienced surgical team provided; the sitting position remains a safe variant for posterior fossa surgery in the pediatric population. Precautious skull clamp application and appropriate monitoring is highly recommended. Considering eloquent aspects, the sitting position offers excellent anatomical exposure and is ideal for combination with endoscopic techniques.
P07.04 Rapid-CNS2: Rapid comprehensive adaptive nanopore-sequencing of CNS tumors, a proof of concept study
Authors: Dogan H , Patel A , Herold-Mende C , Pfister S , Wick W , Loose M , von Deimling A , Sill M , Jones D , Sahm F 
Published: September 2021

Abstract

BACKGROUND
The WHO classification 2021 includes multiple molecular markers for routine diagnostics in addition to histology. Sequencing setup for complete molecular profiling requires considerable investment, while batching samples for sequencing and methylation profiling can delay turnaround time. We introduce RAPID-CNS2, a nanopore adaptive sequencing pipeline that enables comprehensive mutational, methylation and copy number profiling of CNS tumours with a single third generation sequencing assay. It can be run for single samples and offers highly flexible target selection requiring no additional library preparation.

MATERIAL AND METHODS
Utilising ReadFish, a toolkit enabling targeted nanopore sequencing, we sequenced DNA from 22 diffuse glioma patient samples on a MinION device. Target regions comprised our Heidelberg brain tumour NGS panel and pre-selected CpG sites for methylation classification by an adapted random forest classifier. Pathognomonic alterations, copy number profiles, and methylation classes were called using a custom bioinformatics pipeline. Results were compared to their corresponding NGS panel-seq and EPIC array outputs.

RESULTS
Complete concordance with the EPIC array was found for copy number profiles from RAPID-CNS2. 94% pathognomonic mutations were congruent with NGS panel-seq. MGMT promoter status was correctly identified in all samples. Methylation families were detected with 96% congruence. Among the alterations decisive for rendering a classification-compatible integrated diagnosis, 97% of the alterations were consistent over the entire cohort (completely congruent in 19/22 cases and sufficient for unequivocal diagnosis in all).

CONCLUSION
RAPID-CNS2 provides a swift and highly flexible alternative to conventional NGS and array-based methods for SNV/Indel analysis, detection of copy number alterations and methylation classification. The turnaround time of ~4 days can be further shortened to &lt;12h by altering target sizes. It offers a low-capital approach that would be cost-efficient for low throughput settings and invaluable in cases requiring immediate diagnoses.
P09.01 Radiomics-based machine learning approach in differentiation between vestibular schwannoma and meningioma in the cerebellopontine angle
Authors: Zhang Y , Chen C , Xu J 
Published: September 2021

Abstract

BACKGROUND
Vestibular schwannoma (VS) and meningioma are the most two common tumors in the cerebellopontine angle (CPA). Accurate preoperative differentiation of the two lesions is important due to their different surgical approaches and outcomes for the preservation of hearing and facial nerve function. Magnetic resonance (MR) scan is commonly performed to preoperatively evaluate CPA tumors and to differentiate VS from meningioma in clinical routine. However, in some cases, overlaps of conventional MR imaging patterns between the two lesions could make preoperative diagnosis challenging. The purpose of this study is to investigate the ability of radiomics, a novel method providing objective and quantitative information beyond visual assessment, in differentiation between VS and meningioma located at CPA using machine learning technology.

MATERIAL AND METHODS
This retrospective study enrolled eligible patients who were diagnosed with VS (N = 50) or meningioma (N = 41) in the CPA. A set of mineable three-dimensional radiomic parameters were extracted from preoperative contrast-enhanced T1-weighted images. Optimal features were selected first with three selection methods including distance correlation, least absolute shrinkage and selection operator (LASSO) and gradient boosting decision tree (GBDT). Then three machine learning classification algorithms, namely linear discriminant analysis (LDA), support vector machine (SVM) and random forest were employed to build discriminative models. Area under the curve (AUC), accuracy, sensitivity and specificity were calculated to assess the performance of each model.

RESULTS
Nine models were established with different combinations of selection methods and machine learning classifiers. Three classifiers with the suitable selection method all represented feasible ability in differentiation with AUC more than 0.86 in the validation set, and LDA-based models seemed to show better diagnostic performance than those based on the other two classifiers. The combination of LASSO and LDA classifier was found to show the highest AUC of 0.942 in the validation set.

CONCLUSION
Radiomics-based models via machine learning approaches could potentially be utilized to assist in preoperative differentiation between VS and meningioma in the CPA.
P13.04 Survival analyses for determining clinical relevance of molecular markers in translational glioblastoma research - a systematic review
Authors: Fitt B , Loy G , Christopher E , Brennan P M , Poon M T C 
Published: September 2021

Abstract

BACKGROUND
Pre-clinical glioblastoma studies can assess the relevance of their findings to patient survival using integrated clinical and genomic data. Validity of univariable analyses requires an assumption that molecular markers are randomly distributed across patient characteristics to mitigate the confounding effects of clinical variables. Multivariable survival analyses adjusting for clinical variables do not change the association if this assumption holds. We aimed to assess this by summarising the types of survival analyses and their results in translational glioblastoma research.

MATERIAL AND METHODS
We systematically searched Medline and Embase Jan 2008 to Feb 2021 for glioblastoma cell line or animal studies validating their molecular markers in The Cancer Genome Atlas (TCGA) or the Chinese Glioma Genome Atlas (CGGA) using survival analyses. Studies that exclusively used genomic data without laboratory findings were excluded. Two reviewers independently assessed study eligibility and extracted data. Data items included patient inclusion criteria, characteristics of survival analyses, and whether molecular markers had statistically significant association with overall survival.

RESULTS
Of 1,047 potentially eligible studies, we included 59 pre-clinical glioblastoma studies that tested the association between their molecular markers and survival using TCGA or CGGA data. All studies used TCGA data and 2 also used CGGA data. Sixteen (27%) studies specified their patient inclusion criteria from TCGA for survival analysis. Eight studies exclusively investigated sets of molecular markers, leaving 51 studies reporting 126 molecular markers. Eighteen (31%) studies used multivariable survival analysis in addition to univariable analyses. All molecular markers underwent univariable analyses, of which 12 (10%) molecular markers had additional multivariable survival analyses. In the 13 multivariable analyses on 12 molecular markers, four (31%) markers were associated with survival in the univariable analyses but not in the multivariable analyses.

CONCLUSION
Most pre-clinical studies used univariable survival analyses alone in public genomic repositories to assess the relevance of their results to patient survival. Our findings demonstrated that multivariable analyses are needed to account for confounding effects of clinical variables. Using relevant components from reporting guidelines for observational studies can improve the transparency and quality of translational studies.
P13.07 Cysteine induces glioblastoma cytotoxicity through mitochondrial reductive stress
Authors: Noch E , Palma L , Yim I , Barnett D , BHinder B , Benedetti E , Krumsiek J , Elemento O , Cantley L 
Published: September 2021

Abstract

BACKGROUND
Glioblastoma (GBM) remains a poorly treatable disease with high mortality. Tumor metabolism in GBM is a critical mechanism responsible for accelerated growth because of upregulation of glucose, amino acid, and fatty acid utilization. However, therapies targeting GBM metabolism, whether through the use of small-molecule compounds or dietary interventions to limit nutrient sources, have failed in clinical trials. Metabolic bypass is an important mechanism that is often overlooked in GBM trials, since many trials have focused instead on combining anti-metabolic therapy with cytotoxic treatments. The goal of this research is to use a multi-pronged treatment approach with targeted drug and dietary therapy to leverage metabolic susceptibilities in GBM.

MATERIALS AND METHODS
We first interrogated the TCGA database and a cancer metabolite database for alterations in glucose and amino acid signatures in GBM relative to other human cancers and relative to low-grade glioma. We identified the amino acid cysteine as contributing to a novel metabolic susceptibility pathway in GBM. To study the role of cysteine in GBM pathogenesis, we treated patient-derived GBM cells with a variety of FDA-approved cysteine-promoting compounds in vitro, including N-acetylcysteine (NAC). We measured cell proliferation, energy production, mitochondrial metabolism, and reactive oxygen species to study mechanisms of oxidoreductive stress. Results: From our TCGA and cancer metabolite database analyses, we found that GBM exhibits the highest levels of cysteine and methionine pathway gene expression of 32 human cancers and that GBM exhibits high levels of cysteine-related metabolites compared to low-grade gliomas. Cysteine compounds, including NAC, reduce growth of GBM cells, which is exacerbated by glucose deprivation. This growth inhibition is associated with reduced mitochondrial metabolism, manifest by reduction in ATP generation, NADPH/NADP+ ratio, mitochondrial membrane potential, and oxygen consumption rate. Through measurement of mitochondrial hydrogen peroxide, we found that NAC-treated cells exhibit a paradoxical increase in mitochondrial hydrogen peroxide levels, likely due to inhibition of thioreductase and glutathione reductase systems. Through genetic and pharmacological studies, we found that induction of thioredoxin-2 rescues NAC-mediated cytotoxicity and that inhibition of thioreductase and glutathione reductase exacerbates mitochondrial toxicity and reductive stress.

CONCLUSIONS
We show that cysteine compounds reduce cell growth and induce mitochondrial toxicity in GBM through reductive stress. This metabolic phenotype is exacerbated by glucose deprivation. This pathway is targetable with FDA-approved cysteine-promoting compounds and could synergize with glucose-lowering treatments, including the ketogenic diet, for GBM.
P13.22 Menglia: an innovative approach to liquid biopsies in glioma patients
Authors: Truffelli M , Petretto A , Candiano G , Giunti D , Vigo T , Gaggero G , Bennicelli E , Grassi M , Zona G , Fiaschi P 
Published: September 2021

Abstract

BACKGROUND
Gliomas are the second most frequent primary brain tumor. Since 2016 gliomas are classified according to histological, and molecular features such as IDH status and 1p19q codeletion. Recently oncological research has focused on liquid biopsies to reduce the need for invasive diagnostic tests. Cerebrospinal fluid (CSF) is the principal source of brain tumor biomarkers. Modern technologies currently allow us to analyze proteomic and metabolomic tumor profiles, in order to find new biomarkers without being constrained by a priori hypothesis. Several data from the literature also suggests that inflammatory cells and cytokines in tumors contribute to tumor growth, progression and immunosuppression. The possibility of simultaneously testing different inflammatory molecules on the biological fluids could lead to the identification of new biological markers with prognostic and predictive value for treatment response.

STUDY OBJECTIVES
- Identification of protein and/or lipid biomarkers specific to the glioma subgroup among those under analysis. - Identification of tumor group- and subgroup-specific CSF and/or serum inflammatory biomarkers among those tested. - Correlation of biomarkers with Progression Free Survival (PFS), Overall Survival (OS).

ELIGIBILITY CRITERIA
- Patients with a radiological suspected diagnosis of glioma eligible for surgery. - Age ≥ 18 years. - Availability of histological samples, CSF, blood and urine. - Patients with unconfirmed histological diagnosis of glioma will be excluded. - Patients who have never received any systemic or local treatment for CNS diseases.

STUDY DESIGN
This is a prospective monocentric study involving mass spectrometry analysis for characterization of proteins and metabolites and ELISA analysis for the characterization of different cytokines in parallel anonymized biological samples consisting of tumor tissue, CSF, blood and urine from glioma patients, divided into three different molecular subtypes: 1p19q codelet/IDH mutated, 1p19q non-codelet/IDH mutated and 1p19q non-codelet/IDH wt. Biological samples will be taken at surgery, at 24–48 h after surgery and every 3 months up to 1 year. The control group will include patients with subarachnoid hemorrhage or hydrocephalus, either undergoing external ventricular shunting or undergoing ventricular catheter placement/revision surgery.

STUDY ANALYSIS
Data interpretation will be based on a statistical analysis of the data, applying tools such as Principal Component Analysis (PCA) Weighted Correlation Network Analysis (WGNCA), Multiple Venn Diagram, T-Test, ANOVA, Clustering and Gene Ontology Enrichment, non-parametric Mann-Whitney test. For the assessment of clinical outcome, survival curves will be compared between different groups of patients who share a similar protein/metabolomic/inflammatory profile.
P13.23 Study of migration characteristics of human glioma cells in vitro
Authors: Pavlova G , Pavlova S , Drozd S , Savchenko E , Zakharova L , Shamadykova D , Golbin D , Potapov A , Revishchin A 
Published: September 2021

Abstract

BACKGROUND
Gliomas are still one of the most aggressive human cancers, and even despite modern therapeutic approaches, the prognosis for patients with this disease is not favorable. It is known that glioma cells are capable of local invasiveness, when glioma cells migrate into healthy brain tissue. A lack of any definite markers, characterizing migrating glioma cells and allowing them to be distinguished from healthy brain cells, requires a thorough investigation. In case it would be possible to characterize invasive glioma cells, then a development of targeted therapy could be feasible.

MATERIAL AND METHODS
Cell cultures of human gliomas Gr II, III and IV were developed with 5 cultures for each Grade. MTT, RT-PCR, Western and Nosern blot, transcriptome analysis were applied.

RESULTS
Three cultures of human gliomas had a high degree of migration, within the range of 6% - 14%. These cultures were developed from gliomas of Grade III and Grade IV, and with IDH1- (minus) phenotype. Moreover, cell cultures with IDH1 + (plus) phenotype had a low migration rate within 1%. An intensity of migration correlated with the degree of malignancy, and an average rate decreased with a decrease of the Grade. Moreover, an analysis of the proliferative activity of cell cultures of human gliomas of various degrees of malignancy did not reveal a relationship with a migratory properties of cultures. A number of actively proliferating cultures did not show high migration, while cultures with medium proliferative activity could show a high level of migration. The low level of proliferation of cultures of gliomas of Grade II and I at the beginning of cultivation, in some cases, subsequently increased, but an inherent low migration activity did not change. In actively migrating cultures, a significant decrease in the expression of Sox2 and Nestin is detected. A positive correlation was found between migration abilities of human glioma cell culture cells and the marker Ki67, GFAP, Sox2, and Oct4. The difference was statistically significant by the one-sided Mann-Whitney test.

CONCLUSION
Conclusions: Cell cultures derived from glioma tumor tissue can be used to predict invasive properties of the tumor. High tumor invasiveness is characteristic for Grade III and Grade IV, and with IDH1- (minus) phenotype, and it also correlates with elevated expression of GFAP, Sox2 and Oct4The reported study was funded by RFBR according to the research project № 18-29-01012 and by the Ministry of Science and Higher Education of the Russian Federation, grant number 075-15-2020-809 (13.1902.21.0030).
P14.11 Severe treatment-induced myelosuppression is more frequent in female malignant glioma patients and associated with reduced overall survival
Authors: Zeiner P S , Filipski K , Forster M , Voss M , Fokas E , Herrlinger U , Harter P N , Steinbach J P , Ronellenfitsch M W 
Published: September 2021

Abstract

BACKGROUND
An association of treatment-related myelotoxicity with female gender has been previously suggested. However, a systematic analysis of the prognostic relevance of radiochemotherapy-related cytopenia involving the different blood cell lineages is lacking.

MATERIAL AND METHODS
We retrospectively analyzed cytopenia during temozolomide-based concomitant radiochemotherapy (RCT) in 493 glioma patients. Histological grading, molecular pathology, surgical procedures and median overall survival (OS) were recorded. The extent of cytopenia was correlated with gender and outcome.

RESULTS
Treatment-induced severe cytopenia (leuko-, lympho-, neutro- and thrombocytopenia) occurred much more often in female than in male glioma patients (40.8 vs. 13.9%, p-value &lt;0.0001). In female patients with IDH-wildtype high-grade astrocytomas there was a negative correlation of severe leuko-, lympho- and thrombocytopenia during temozolomide RCT with OS (36 vs. 54, 37 vs. 54 and 36 vs. 57 weeks, respectively; all p-values &lt;0.05). In male patients there was also a trend for this unfavorable effect. Additionally, severe cytopenia correlated with reduced temozolomide dose exposure during RCT (all p-values &lt;0.05 in total cohort) and reduced dose exposure was independently associated with worse OS (p-values &lt;0.05 in the total and female cohort).

CONCLUSION
Our data confirm that women are at higher risk for treatment-induced cytopenia during RCT which is associated with a significant decrease in OS. From our data, it appears plausible that reduced temozolomide dose exposure during RCT is at least in part responsible for this finding. Immunosuppression of patients with severe cytopenia may be an independent contributor to adverse outcome.
P14.58 Efficacy and safety of lomustine versus fotemustine as first and second line treament in relapsed glioblastoma patients
Authors: Domènech M , Fabregat C , Hernández A , del Barco S , Panciroli C , Garcia-Illescas D , Vieito M , Vilariño N , Mesia C , Balañà C 
Published: September 2021

Abstract

BACKGROUND
Glioblastoma (GB) is the most aggressive primary brain tumour. Despite the survival benefit associated with adjuvant therapy, most of patients (pts) relapse after initial therapy. Nitrosoureas (NU) are the standard treatment at relapse in Europe. Both fotemustine (FM) (Addeo schema) and lomustine (LM) (administered orally every 6 weeks) are used in this context.

MATERIAL AND METHODS
This retrospective cohort study included pts diagnosed with GB treated with NU at relapse in four Catalonia hospitals from 2010 to 2020. Clinical and pathological data were collected from medical records. We analysed 6months-progression-free survival (6m-PFS), progression-free survival (PFS) and overall survival (OS) from the start of NU to progression or death respectively. Differences in toxicity grade using CTCAE v5.0 were analysed globally as ‘non-toxicity’, ‘mild toxicity (grade 1 or 2)’ and ‘high toxicity (grade 3 or 4)’.

RESULTS
We identified 236 GB pts with a median age of 58 years old. 29% of the pts presented MGMT promotor methylation and only 3%(n=7) had IDH mutation. After a median follow-up of 20 months, 94% of the pts were dead at the time of the analyses. At first line, 83 pts were treated with FM and 18 with LM. Pts treated with FM had better performance status (PS) than those treated with LM (p=.010). Median PFS was 2 months and 6m-PFS was 12% vs 6% in FM and LM group respectively (p=.87). Median OS was 3 months with LM vs 6 months with FM, with no statistically significant differences even adjusted for prognostic factors (p=.79 HR:0.9 CI 95% 0.41–1.96).At second line, 78 were treated with FM and 24 with LM, no differences between groups. Median PFS was 2 months in both groups and median OS was 3 vs 5 months for pts treated with LM vs FM respectively, with no significant differences. 6m-PFS was 13% for LM vs 0% for the FM group (p=.39).Pts received a mean of 1.7 cycles (every 6 weeks) and 4.1 cycles (every 2 weeks) in LM and FM group, respectively. Thrombocytopenia was the most common serious side-effect, with a higher proportion of grade 1–2 toxicity in the FM group (p=.03) that also required more treatment delays (p=.01).

CONCLUSION
Despite being retrospective study and a few pts were treated with LM, there were no differences neither in PFS nor in OS in pts treated with LM vs FM at first or second line. Higher G1-2 thrombocytopenia was shown in the FM group probably due to a higher number of hematology samples collected.