bluuebunny/crossref_metadata_2025_split huggingface dataset:
P11.40 Development of an implantable multifunctional biodevice (GlioGel) in the treatment of recurrent glioblastoma
Authors: Déry L , Charest G , Akbari M , Fortin D 
Published: September 2019

Abstract

BACKGROUND
Glioblastoma (GBM) is a devastating disease with a median survival of 14–16 months. This poor prognosis can be explained by 3 factors. First, the infiltrative nature of the disease prohibits a complete removal of the tumor. Second, some of the tumor cells are brain tumor stem cells, which are highly migratory and highly resistant to treatments. Finally, the presence of the blood-brain barrier prohibits entry of therapeutics. This situation implies that new treatment approaches must be directed toward the infiltrated brain surrounding the resection cavity. To bypass this problem and improve the potency of adjuvant treatment, we have designed a new “GlioGel-device” that will have the ability to: 1- attract the migrating tumor cells into or nearby the device, and 2- subsequently deliver chemotherapy to the locally pooled tumor cells and 3- irradiate these cells with radioisotopes embedded in the GlioGel.

MATERIAL AND METHODS
In vitro proof of principle of chemoattraction was investigated by agarose drops method releasing chemokines molecules (CCL2, CCL11, CXCL10) with F98 and U87MG GBM cells. In vivo experiments evaluated the efficiency of chemokines and doxorubicin released by the implanted GlioGel on the tumor behaviour in our Fischer-F98 rat glioma model. An histology of tumour behaviour exposed to chemokines and survival of GBM rats treated with doxorubicin were analysed.

RESULTS
In vitro preliminary results for chemoattraction assays show that up to 2 times more cells invade the gel when it releases chemoattractant compared to PBS. The In vivo chemotherapy experiments with a fast, medium and slow release of doxorubicin from the GlioGel show that a local dose that represent a 1300-fold smaller dose than a normal intravenous systemic dose gave a significant reduction in tumour growth (median survival) compared to a control group. We investigated the effect provided by the GlioGel impregnated with chemokines on tumor cells migration, after implantation in the Fischer-F98 rat glioma model.

CONCLUSION
This preliminary study shows the ability of GlioGel releasing chemokines and doxorubicin to respectively attract and kill orthotopic glioblastoma cells. These encouraging results will be completed with a combination of short-range (high LET) radiation by embedded radioisotope into the GlioGel aiming for synergistic combination to eradicate as much tumour cells as possible, while limiting systemic side effects.
P11.47 Generation, characterisation and drug screening of patient-derivedIDH1-mutated glioma cell lines
Authors: Verheul C , Kers T V , Van Der Ploeg A , Van Der Kaaij M , Aghababazadeh M , De Wit M , Hoogstrate Y , Struys E , Dirven C M F , Leenstra S , French P J , Lamfers M L M 
Published: September 2019

Abstract

BACKGROUND
Despite considerable scientific efforts, endogenous in vitro isocitrate dehydrogenase (IDH)-mutated glioma models remain scarce. Availability of these models is key to understanding underlying molecular mechanisms and vital for the development of new therapeutic interventions. We established and characterized a set of seven cell lines derived from IDH1-mutated gliomas and utilized them to investigate IDH-mutant glioma drug-response in vitro.

MATERIAL AND METHODS
Fresh tumor material was collected directly from the operating room, mechanically and enzymatically dissociated and cultured under serum-free culture conditions. IDH mutation status was verified at several passages with Sanger sequencing, as well as with whole exome sequencing. D-2-hydroxyglutarate (D2-HG) levels were determined with mass-spectrometry. Genome-wide methylation profiling was performed using the Infinium MethylationEpic BeadChip array. Cell viability was measured using the ATP-based CellTiter-Glo assay. Cell proliferation was determined through cell counting. Drug screens were performed with an FDA-approved anti-cancer drug set from the NIH as well as two IDH-mutant specific inhibitors.

RESULTS
Over the last decade our lab processed over 800 glioma samples from all WHO grades and IDH mutational status. Optimisation of culture conditions led to the establishment of seven IDH1-mutant glioma cell lines. The IDH1-mutation was present during all tested passages in these cell lines. Whole exome sequencing showed a high concordance between tumor and cell lines with regard to driver gene mutations. Similarly, copy-number changes based on genome-wide methylation data also show a close resemblance between the parental tumor and resulting cell lines. The Heidelberg methylation profiler classified each cell line and its parental tumor as IDH mutant glioma. When exposed to an IDH1-mutant specific inhibitor, all cell lines showed a concentration-dependent decrease of D2-HG levels. The inhibitors showed little to no effect on viability up to 10uM during 8 days, however, long term treatment up to 4 weeks revealed a decrease in cell doubling time in 2 of 6 cultures. Drug screen results either alone or in combination with an IDH1-mutant specific inhibitor identified several interesting candidates that are currently followed up in additional experiments.

CONCLUSION
We established a unique set of patient-derived IDH1-mutant glioma cell lines that closely resemble their respective tumors and can be used to identify new therapeutic strategies.
P11.57 A 3D brain organoid coculture system delineates the invasive cell components in glioblastoma
Authors: Zhou W , Klink B , Dittmar G , Nazarov P , Garcia E M , Han M , Lunavat T R , Joesph J V , Saed H S , Bahador M , Wang J , Bjerkvig R 
Published: September 2019

Abstract

BACKGROUND
Glioblastoma (GBM) cell infiltration into the surrounding normal brain tissue where the blood brain barrier is intact, represents a major problem for clinical management and therapy. There is a vital need to understand the molecular mechanism that drives tumor cell invasion into the surrounding brain. We have previously developed a 3D coculture model where mature brain organoids are confronted with patient-derived glioblastoma stem-like cells (GSCs). In such a coculture system, single cell invasion into the normal brain tissue can be studied in detail. Here, we first describe in detail, by RNA-seq and proteomics, the differentiation of various neural cell lineages into mature brain organoids as well as their cellular organization. By real-time confocal microscopy and imaging analyses we also determine the speed of tumor cell invasion into the brain. Finally, we used this coculture system to delineate in detail the cellular heterogeneity within the invasive compartment and their gene expression.

MATERIAL AND METHODS
Immunohistochemistry and immunofluorescence were used to determine the expression and distribution of mature neurons, astrocytes, oligodendrocytes, and microglia within the brain organoids. Proteomics and RNA-seq were used to determine brain development ex-vivo. To assess the clonal composition of the GBM-invasive compartment, we used cellular (RGB) barcoding technology. By advanced imaging, we tracked in real time the invasion of barcoded cells into the brain organoids. Finally, we isolated invasive cells and non-invasive cells from our coculture system and used single cell sequencing to analyze their gene expression profiles and molecular phenotypes.

RESULTS
Immunohistochemistry and immunofluorescence showed that brain organoids, after 21 days of differentiation, display a highly cellular and structural organization. RNA-seq and proteomics, performed at different time points of organoid differentiation, revealed that the brain organoids develop into mature brain structures after 21 days as verified by a comparative analysis to normal rat brain development in vivo. Imaging analyses showed that multiple clones within the GBMs have the capacity to invade into the brain tissue with an average speed of ~ 20 μm/h. RNA-sec analysis of the invasive compartment revealed a strong up-regulation of genes and pathways associated with anaerobic respiration (glycolysis).

CONCLUSION
We describe a highly standardized brain organoid coculture system that can be used to delineate GBM invasion ex-vivo. We demonstrate that this platform can be used to unravel the mechanisms that drive GBM invasion into the normal brain.
P11.64 Specialized neurooncologial biorepository of the N.N. Burdenko National Medical Research Center for Neurosurgery: high-quality tumor bank for personalized medicine
Authors: Golbin D , Pavlova G , Shifrin M , Shugay S , Tsukanova T , Korochkina A , Danilov G 
Published: September 2019

Abstract

BACKGROUND
Specialized biorepositories in neurooncology serve for storage of tissue samples derived from patients with central nervous system (CNS) tumors. In 2016 the new facility was launched for collection of CNS tumor specimens. The principal aim of the repository is preparation of frozen CNS tumor samples accompanied by associated clinical, pathological, molecular, and follow-up data.

MATERIAL AND METHODS
Each surgical biopsy was divided into several aliquots (usually three), registered, and stored in LN2. Since August 2018 from all aliquots a lesser fragment was separated for paraffin block processing. This histological control was applied for quality assurance of frozen samples. Each specimen record was accompanied with demographic, clinical, perioperative, and histological data. In the follow-up, oncological treatment and response to therapy were added to the databank as well as molecular data. All tumor samples are characterized, passportized, stored, and systemically revised. The following biomarkers were evaluated: Cdk4, Cdk6, FGFR, NANOG, OCT4, SOX2, MELK, Nestin, Notch2, Olig2, GFAP, MAP2, β-III-tubulin, PDGFRA. Dedicated original flexible electronic data storage system was designed for information support of tumor collection. Specimen acquisition, procurement, and storage was encoded using SPREC 2.0 coding system.

RESULTS
Between March 2016 till January 2019 a total of 596 biopsy samples were stored in the repository. All of them were obtained from the patients operated on in N.N. Burdenko National Medical Research Center for Neurosurgery. Among all entities brain gliomas prevailed and comprised 539 biopsy specimens (90,4%). Specimen quality control using histology, immunohistochemistry, fluorescent in situ hybridization, and molecular methods was performed. The frequency of appropriate aliquots is as high as 83,4%. Tumor sample collection included primary and recurrent cases including those, which underwent primary and secondary in N.N. Burdenko National Medical Research Center for Neurosurgery.

CONCLUSION
Specialized neurooncological biorepository is advantageous due to possibility of tumor tissue collection at different stages of the disease. The associated databank contains patients’ data, tumor tissue data, treatment data, response to treatment, and follow-up data. Further development of the facility will provide collection of the larger spectrum of neurooncological entities, creation of tumor cell culture bank, and experimental therapies for the development of personalized neurooncological treatment.
P12.08 Immunocytokines are a novel immunotherapeutic approach against glioblastoma
Authors: Weiss T , Puca E , Weller M , Neri D , Roth P 
Published: September 2019

Abstract

BACKGROUND
Glioblastoma is the most common malignant primary brain tumor in adults with an urgent need for novel treatment options. The administration of pro-inflammatory cytokines could be a potent immunotherapeutic approach to shift the balance between tumor-associated immunosuppression and immune activation. However, the systemic administration of therapeutically active doses of pro-inflammatory cytokines is not feasible due to toxic side effects and there is a need for strategies that enable a targeted delivery of pro-inflammatory cytokines to the tumor site.

METHODS
We investigated different antibody-cytokine fusion products that enable a targeted delivery of interleukin (IL)-2, IL-12 or tumor necrosis factor (TNF)-α to the tumor site by binding to a tumor-specific epitope of fibronectin. We investigated the expression of this tumor-specific epitope ex vivo in tumor-bearing mouse brains and human glioblastoma samples. Subsequently, we assessed the anti-tumor activity of IL-2, IL-12 or TNF-α fused to an antibody targeting this tumor-specific epitope in orthotopic syngeneic mouse glioma models.

RESULTS
The tumor-specfic extra domain B of fibronectin is expressed in murine glioma models and human glioblastoma samples. A fluorochrome-labeled antibody targeting this tumor-specific epitope accumulated at the tumor site in the brain in vivo upon systemic administration. IL-2, IL-12, or TNF-α fused to this antibody conferred a survival benefit in orthotopic tumor-bearing mice and cured a fraction of tumor-bearing mice. Mechanistically, antibody-fused TNF-α induced tumor necrosis and increased the activation of tumor-infiltrating natural killer (NK) cells, whereas antibody-fused IL-12 mainly boosted an anti-tumor immune response mediated by NK cells and T cells.

CONCLUSION
We demonstrate the expression of a tumor-specific epitope of fibronectin in glioblastoma and exploit this for the targeted delivery of IL-2, IL-12 or TNF-α to the tumor site. Our preclinical assessments indicate potent anti-tumor activity in orthotopic, syngneic glioma mouse models and reveal the mode of action for the different immunocytokines. Based on these findings, we initiated a phase I/II clinical trial in patients with recurrent glioma to investigate the targeted delivery of TNF-α (ClinicalTrials.gov identifier NCT03779230).
P13.02 Conventional MRI radiomics in the diagnosis of early- and pseudo-progression
Authors: Bani Sadr A , Eker O F , Berner L , Ameli R , Hermier M , Barritault M , Meyronet D , Guyotat J , Jouanneau E , Honnorat J , Ducray F , Berthezène Y 
Published: September 2019

Abstract

BACKGROUND
After radiochemotherapy, 20% to 30% of patients with early worsening MRI experience pseudoprogression (Psp) which is not distinguishable from early progression (EP). We aimed to assess the diagnostic performance and survival predictive ability of radiomics in patients with suspected EP or Psp.

MATERIAL AND METHODS
Radiomics features (RF) of 76 patients (53 EP and 23 Psp) retrospectively identified were extracted from conventional MRI based on four volumes-of-interest. Subjects were randomly assigned into training and validation groups. Classification model (EP versus Psp) consisted of a random forest algorithm after univariate filtering. Overall (OS) and progression-free survivals (PFS) were predicted using a semi-supervised principal component analysis and, forecasts were evaluated using C index and integrated Brier scores (IBS).

RESULTS
Using 11 RFs, radiomics classified patients with 75.0% and 76.0% accuracy, 81.6% and 94.1% sensitivity, 50.0% and 37.5% specificity, respectively in training and validation phases. Addition of MGMT promoter status improved accuracy to 83% and 79.2% and, specificity to 63.6% and 75%.
OS model included 14 RFs and stratified low- and high-risk patients both in the training (hazard ratio (HR), 3.63, p=0.002) and the validation (HR, 3.76, p=0.001) phases. Similarly, PFS model stratified patients during training (HR, 2.58, p=0.005) and validation (HR, 3.58, p=0.004) phases using 5 RF. OS and PFS forecasts had C index of 0.65 and 0.69 and IBS of 0.122 and 0.147, respectively.

CONCLUSION
Conventional MRI radiomics has promising diagnostic value, especially when combined with MGMT promoter status, but specificity remains moderate. In addition, our results suggest a potential for predicting OS and PFS.
P13.14 Use of Foundation one CDx for molecular screening in patients with primary brain tumors: Gustave Roussy Experience
Authors: Baldini C , Boulfoul W , Lacroix L , Rouleau E , Scoazec J , Varga A , Hollebecque A , Ribrag V , Soria J , Massard C 
Published: September 2019

Abstract

BACKGROUND
Patients with primary brain tumors usually have poor prognosis and few therapeutic options. However recent report showed that they may benefit from molecular screening to improve treatment benefit and enrollment in clinical trials. We aimed to evaluate if molecular screening using Foundation One Dx may help therapeutic strategies in primary brain tumor patients.

MATERIAL AND METHODS
Between October 2018 and December 2018, we enrolled prospectively patients in the MOSCATO (Molecular Screening for cancer Treatment Optimization) 02 trial using the Foundation One Dx test. Patients were eligible if they had good Performans status (PS) (0 or 1) and tumor tissue material available. Results were reviewed during a molecular multidisciplinary meeting weekly at the Drug Development Department at Gustave Roussy to decide on orientation and matched therapy according to molecular alterations.

RESULTS
Finally thirty-three patients were enrolled in the study. Twenty six tumor tissues were analysed and 7 patients were screen failures due to tumor tissue unavailability. Median age was 49 years old (19 - 72). Patients had a good PS with a median of 1 (0–2) and were mostly males (76%). The most common tumor type was glioblastoma (79%). Five patients had a high grade tumor including 2 medulloblastomas. Median time between consent and multidisciplinary meeting was 70 days (49 - 156). Median percentage of tumor cells was 78% (30–80%). The tumor mutational burden (TMB) was available in 26 patients. The median TMB was 4 mutations per megabase (0 - 277). The most frequent alterations were TERT promoter mutation 22/26 (85%), CDKN2A loss 14/26 (54%), MTAP loss 11/26 (42%), EGFR amplification (38%) including 4 EGFRvIII amplification, TP53 mutation and PTEN deletion 9/26 (35%) respectively, PIK3CA mutation 5/26 (19%), CDK4 or 6 amplification 4/26 (15%), NF1 mutation 3/26 (12%), 2 IDH1 mutations, 2 MET amplifications, 2 HGF amplifications, 1 FGFR2 mutation, 1 BRAF V600E mutation, 1 PDGFRA amplification, 1 EZH2 mutation and 1 SMARCA4 mutation. Finally 11 patients (42%) were oriented according to molecular alterations (EGFR amplifications, BRAF mutation), 1 patient was treated and is ongoing with a BRAF inhibitor and 1 patient is in screening in atrial with an EGFR inhibitor.

CONCLUSION
Molecular screening with Foundation One Dx test is feasible in patients with primary brain tumors and can help therapeutic strategies. However the time between consent and multidisciplinary meeting was the main limitation to our study and affected enrollment in clinical trials.
P14.10 Endoscopic skull base surgery for tumors invading internal carotid artery
Authors: Geng S 
Published: September 2019

Abstract

BACKGROUND
Internal carotid artery (ICA) injury is a disaster in endoscopic skull base surgery, so protection of internal carotid artery is an essential task. We use 3-dimensional multimodal imaging (3D-MMI) and intraoperative navigation (ION) in endoscopic skull base surgery to locate ICA and decrease ICA injury.

MATERIAL AND METHODS
26 patients underwent endoscopic skull base surgery (pituitary adenomas, chordomas, neurinomas and other tumors invading internal carotid artery) guided by 3D-MMI and ION techniques to locate ICA.

RESULTS
In all patients, the 3D-MMI and ION techniques enabled adequate visualization of vascular structures stereoscopically, especially the relationship between lesion and ICA, and suplly real-time navigation to locate ICA during endoscopic skull base surgery. No ICA injury happened and neurosurgeons removed tumors with relaxed mind.

CONCLUSION
3D-MMI and ION techniques were found to be helpful to locate internal carotid artery and decrease ICA injury during endoscopic skull base surgery.
P14.27 The significance of multicentric noncontrast-enhancing lesions distant from surgically resected glioblastoma: Case series of 3 patients
Authors: Hwang J , An H , Yoon S , Park K 
Published: September 2019

Abstract

BACKGROUND
Glioblastoma is the most malignant primary brain tumor. The tumor location and multiplicity plays an important role in surgical and further treatment. The incidence of multiple lesions at the time of diagnosis was known as 1–20%, which showed a poor prognostic factor. Most researches has focused on multiple contrast-enhancing lesions, however, multicentric non-enhancing lesions distant from glioblastoma has been rarely evaluated. The authors reported the case series of the patient who showed multicentric non contrast-enhancing lesions without connection to histologically-proven glioblastoma.

MATERIAL AND METHODS
Multicentric non contrast-enhancing lesions were defined as areas of FLAIR hyperintensity and mass effect without post-contrast enhancement, separated from the histologically-proven glioblastoma in a newly diagnosed disease. Three patients who showed distant non-enhancing lesions with appearance of a multicentric low-grade glioma were included in this study. The typical enhancing lesions were surgically resected and standard chemo-radiotherapy was followed in all patients.

RESULTS
All patients were male and their age was 38, 60 and 65 years old respectively. Multicentric tumor location was as follows: Case 1, left frontal lobe with non-enhancing lesion in left parahippocampal gyrus; Case 2, left parietal with non-enhancing lesion in left anteromedial temporal lobe; Case 3, left thalamus with non-enhancing lesions in both basal frontal and right temporal lobe. Pathologically, the resected enhancing tumor revealed glioblastoma in 2 patients and diffuse midline glioma in 1. All tumors were IDH-wild type. The resected enhanced lesion showed no progression but all non-enhancing lesions developed contrast-enhancing tumors at 3, 13 and 17 months after initial treatment, with high tracer uptake on 18FDG-PET or 18FDOPA-PET. Despite multidisciplinary treatment, two patients died from disease progression at 30 and 32 months after diagnosis and one patient is still alive with overall survival of 15 months.

CONCLUSION
The appearance of multicentric non-enhancing lesions distant from a typically enhancing tumor showed an uncommon finding in glioblastoma and poor prognostic features. These lesions progress faster than expected for a low-grade glioma. These lesions should be distinguished from typical low-grade glioma and should be considered more advanced lesions than their appearances suggest.