bluuebunny/crossref_metadata_2025 huggingface dataset:
P04.17 Differential diagnosis of gliomas using Digital Holographic Microscopy
Authors: Calin V L , Petrescu G E D , Mihailescu M , Brehar F M , Lisievici M , Comanescu B , Tarba N , Gorgan M R , Savopol T , Moisescu M G
Published: September 2019

BACKGROUND

The clinical course and prognostic of gliomas depend on the tumor histological and molecular features. The histopathological diagnosis requests well-trained specialists and multi-step operational procedures for sample preparation. Faster and more objective protocols should be implemented in support of pathologists. The Quantitative Phase Imaging based methods are biologically proved to be efficient in revealing, without any labeling, important characteristics of the living specimens having different structural complexity. We used Digital Holographic Microscopy (DHM) to acquire QPIs and to analyze glioma samples in order to discriminate glioma tissues of various malignancy grades.

MATERIAL AND METHODS

Grade II glioma (GM) and grade IV glioblastoma (GBM) tissues were collected from patients who underwent surgery. For each sample, two consecutive slices were fixed with formalin, embedded in paraffin and cut at 4 µm thickness. One slice was stained using hematoxylin and eosin (H&E) and the other slice was left unstained. The pathologist diagnosed H&E slides as GM or GBM and the corresponding unstained slides were accordingly labeled. Holograms of unstained sections were acquired using a LyncéeTec DHM®-R1000 digital holographic microscope (at 664.5 nm). QPIs were reconstructed using the Koala dedicated software, and then the distribution of the phase shift values in the image was characterized by various statistical parameters (mean, variance, kurtosis, skewness, energy, entropy).

RESULTS

A total of 78 images were analyzed, 33 for grade II gliomas and 45 for grade IV glioblastomas, the areas being randomly selected, as the tissue is highly homogeneous. Lower values of Mean, Variance and Energy and higher values of Kurtosis and Entropy were found for GM compared to GBM (Mann-Whitney test was performed for proofing the statistically significance). No statistical difference was observed for Skewness. As the thickness of the samples was constant, variations of these parameters may be attributed to different distributions of the refractive index within the samples, which in turn is directly related to the protein content and structural features of the tissue.

CONCLUSION

The analyze of unstained biopsies of glioma tumors based on DHM could be used for faster and more accurate diagnosis, offering efficient optical markers to distinguish between levels of malignancy with high statistical confidence. Our findings can be further exploited for automatic evaluation and classification of malignant tissues, parameters provided by QPIs being used as classifiers for a supervised machine algorithm. This method can be adapted for fresh samples, being thus a promising method for intraoperative diagnostic.
P05.06 Phase 2 study to evaluate the safety, pharmacokinetics and clinical activity of PI3K/mTOR inhibitor GDC-0084 given to glioblastoma (GBM) patients with unmethylated O6-methylguanine-methyltransferase (MGMT) promoter status
Authors: Wen P Y , de Groot J , Battiste J D , Goldlust S A , Garner J , Simpson J , Olivero A , Cloughesy T
Published: September 2019

BACKGROUND

GDC-0084 is a potent, oral, selective small molecule inhibitor of class I phosphoinositide 3-kinase and mammalian target of rapamycin (PI3K/mTOR). The PI3K pathway is activated in ≥ 70% of tumors, making it a compelling target for the treatment of GBM. GDC-0084 crosses the blood-brain barrier and achieves a brain / plasma ratio of approximately 1.0. GDC-0084 was given as once daily oral dosing in a phase 1 study (Wen et al, J Clin Oncol 34, 2016(15) suppl.2012) in 47 patients with recurrent high-grade gliomas. The adverse events were generally consistent with the established PI3K/mTOR inhibitor class-effects. The MTD identified was 45 mg once daily.

MATERIAL AND METHODS

This study has a 2-part design consisting of an open-label, multicenter dose-escalation study with expansion to assess the safety, tolerability, RP2D, PK, and clinical activity of GDC-0084 at QD dosing in patients with newly-diagnosed GBM with unmethylated MGMT promotor status. In the escalation phase the first cohort is completed without DLT. At the identified MTD, 20 subjects will be recruited in an expansion cohort and patients will be randomized to take GDC-0084 in fed and fasted states. Subjects in the expansion cohort will also have serial fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging.
P08.01 Impact of cannabis use on quality of life in patients with central nervous system tumors
Authors: Rodriguez Almaraz J E , Butowski N A , Chang S M , Oberheim-Bush N A E , Clarke J R , Taylor J W , Buerki R A , Berger M S
Published: September 2019

BACKGROUND

Nearly 80,000 new cases of primary brain tumors are expected to be diagnosed this year in the United States: 32% of CNS tumors are malignant. Anecdotally, patients who report use of cannabis, frequently describe higher quality of life scores (QOL) in standardized instruments. However, the lack of available tools that allow systematic documentation of cannabis use results in a barrier to accurately assess efficacy and potential benefits and risks.

MATERIAL AND METHODS

We conducted a single center, observational study: patients with primary brain tumors answered a previously validated instrument to explore cannabis use. QOL was assessed using the instruments from the European Organisation for Research and Treatment of Cancer(EORTC): QLQ-C30 and its complementary module BN-20 as well as the EuroQol group’s instrument EQ-5D-5L. Eligible participants were identified as cannabis users or non-users, completing the instruments in a self-administered fashion.

RESULTS

To date, 45 patients who signed informed consent were enrolled and answered the questionnaires, mean age was 51 (SD 13.5) years, 31 were male, 25 were considered active cannabis users (624% males and 36% females). At baseline, the mean Global Health score in the QLQ-C30 instrument was 68.6 (SD: 20.6) among cannabis users and 82 (SD: 18.05) among non-users. The mean difference in Global Health QOL scores between users and non-users was 13.35 (95%CI: 1.34, 25.35; p=0.03). In contrast the difference between cannabis users and non-users in QOL index in the EQ-5D-5L instrument was 0.13 (0.77 vs 0.91; p=0.002). Among cannabis users, patients perceive their symptoms as moderate before using cannabis and mild after using cannabis (p>0.001).

CONCLUSION

In our analysis, patients who use cannabis have, on average, lower QOL scores signaling that sicker patients resort to cannabis to improve their symptoms and ultimately their quality of life. Patients’ perception is one of improvement in the overall quality of life when using cannabis. Our findings provide background support to perform prospective studies in the impact of cannabis in quality of life of patients with central nervous system tumors.
P08.05 Cognitive impairment in patients with newly-diagnosed high-grade gliomas
Authors: Ribeiro M , Durand T , Jacob J , Psimaras D , Noel G , Feuvret L , Hoang-Xuan K , Roussel M , Godefroy O , Bernier M , Ricard D
Published: September 2019

BACKGROUND

Cognitive dysfunction is frequent in patients with primary brain tumor, impairing attention, memory and executive function. It compromises functional independence, decision making capacity and psycho-social well-being. Cognitive functioning is highly correlated to disease progression and quality of survival, thus cognitive follow-up is essential in the management of the disease. Cognitive screening tools are often used, since a comprehensive battery may be time consuming and challenging for patients. The objective of this study was to identify a pattern of cognitive dysfunction in patients with newly-diagnosed high-grade gliomas and evaluate the sensitivity and specificity of the MoCA (Montreal Cognitive Assessment) as a cognitive screening tool in the clinical practice.

MATERIAL AND METHODS

We compared performances in tests of memory, action speed, visuospatial ability and executive function of 156 patients with newly-diagnosed WHO Grade III and IV gliomas, after surgery and prior to radiochemotherapy, to those of a group of healthy controls (n=1003). Relatives assessed behavior through a questionnaire of behavioral dysexecutive syndrome. A stepwise logistic regression was performed to select cognitive domains better discriminating patients from healthy controls and we tested the sensitivity and specificity of the MOCA using ROC curve analysis.

RESULTS

The stepwise logistic regression analysis identified the 3 following factors better discriminating patients from controls: TMT-B completion time (OR: 0.673; 95% CI: 0.511–0.886; p=0.0005), a verbal memory index (OR:0.507; 95% CI: 0.358–0.718; p=0.0001) and a behavioral dysexecutive score (OR:0.616; 95% CI: 0.468–0.812, p=0.001). Prevalence of cognitive-behavioral impairment was of 35.94%; 95% CI: 28.3 - 43.5. The ROC curve analysis for the assessment of the MoCA sensitivity and specificity in detecting impairment yielded 0.795 (95%CI: 0.714–0.875) for the MoCA raw score, and 0.804 (95%CI: 0.727 - 0.881) for the adjusted z score. The optimal discrimination was obtained for a raw score ≤ 25 (sensitivity of 0.526; specificity of 0.832). For the adjusted score, optimal discrimination value was observed with a -0.603 z score (sensitivity of 0.716; specificity of 0.768).

CONCLUSION

Cognitive impairment and behavioral dysexecutive syndrome is frequent in patients with newly-diagnosed high-grade glioma. The MoCA lacks sensitivity in screening cognitive impairment to discriminate patients from healthy controls in this setting, and a comprehensive neuropsychological assessment is still recommended.
P11.15 Exosomal MicroRNA expression profiling altered by high TRAP1 expression in glioblastoma
Authors: Wu J
Published: September 2019

BACKGROUND

Tumor necrosis factor receptor-associated protein 1 (TRAP1) is a mitochondrial molecular chaperone, which regulates the steady state transition between cellular aerobic glycolysis and oxidative phosphorylation. In contrast to normal brain, Glioblastoma multiforme (GBM) shows increased TRAP1 expression. However, the mechanisms responsible for metabolic switch mediated by TRAP1 have not been fully elucidated. Exosomes have been recently implicated in an emerging hallmark of cancer, the cancer cell metabolism. In this study, we studied whether the high expression of TRAP1 can affect the expression profile of miRNAs in the exosomes released by GBM, thus affecting the cell metabolism in the tumor microenvironment.

MATERIAL AND METHODS

We examined the expression profile of miRNAs in exosomes secreted by T98G GBM cell lines or T98G GBM cell lines depleted of TRAP1. The cancer-secreted exosomes were isolated by ultracentrifugation of the culture supernatant, and total RNAs, including miRNAs, were extracted from the isolated exosomes and subjected to miRNA microarray, and 3 miRNAs were further validated using qPCR. Target genes of differentially expressed miRNAs were the intersection predicted with 3 databases(Targetscan,microRNAorg,PITA). GO analysis and KEGG analysis were applied to determine the roles of these target genes.

RESULTS

Expression profiling of exosomal miRNA revealed significant downregulation of 237 miRNAs and upregulation of 134 miRNAs after deletion of TRAP1 in T98G GBM cell lines, while 3 of the upregulated miRNAs were further validated using qPCR. We found that these 3 miRNAs (hsa-miR-30e-5p,hsa-miR-1291,hsa-miR-300) showed a correlation with tumor cell glycolysis through literature searching and cross-searching of three microRNA databases.

CONCLUSION

We demonstrate high expression of TRAP1 can affect the expression profile of miRNAs in the exosomes released by GBM, that might reprogram the metabolic machinery following their uptake by other cells in the tumor microenvironment.
P11.23 Oncolytic adenovirus Delta-24-RGD exerts a potent anti-tumor effect in preclinical models of atypical teratoid/rhabdoid tumors
Authors: Garcia Moure M , González Huarriz M , Marrodán L , Patiño-García A , Alonso M M
Published: September 2019

BACKGROUND

Atypical teratoid/rhabdoid tumors (AT/RTs) are rare pediatric brain tumors affecting mainly infants and young children. However, AT/RTs encompass almost 10% of death caused by pediatric brain tumors, and the 2-year overall survival for these children remains below 20%. For this reason, AT/RT ranks among the deadliest pediatric brain tumors. Therefore, it is clear we need to find out new therapeutic options for these children. Delta-24-RGD is an oncolytic adenovirus that has already demonstrated its efficacy as in Phase I/II clinical trials in adult patients affected by high grade gliomas with no evidence of severe side effects. Of interest for pediatric brain tumors, the safety of Delta-24-RGD is has also been demonstrated in an ongoing Phase I clinical trial for the treatment of DIPGs (NCT03178032). For these reasons, we propose to evaluate the anti-tumor effect of Delta-24-RGD in preclinical models of ATRT.

MATERIAL AND METHODS

Our studies have been carried out in three stablished AT/RT cell lines (BT-12, CHLA-06 and CHLA-266). In vitro, AT/RT cultures were infected with Delta-24-RGD-GFP to confirm the infectivity of the virus by flow cytometry. Replication of Delta-24-RGD was ensured by titrating the PFUs generated in AT/RT infected cultures. In regard to cytolytic effect, viability assays (MTS) were conducted in AT/RT cultures infected at increasing MOIs of Delta-24-RGD. In vivo, AT/RT cell lines were engrafted in Rag-2 mice in supratentorial and infratentorial locations, and the animals were treated with Delta-24-RGD at 107 or 108 PFU/animal (intra-tumor administration), or PBS. The therapeutic benefit of Delta-24-RGD was evaluated comparing the overall survival obtained for treated and untreated animals using the Log-rank test. We have also generated models of disseminated disease through intraventricular injection of the tumor cells, thus mimicking the lesions found in patients. AT/RT cell lines were transduced with a luc-expressing lentivirus to facilitate the follow up of these tumors. Mice bearing disseminated AT/RT were treated with Delta-24-RGD at 107 or 108 PFU/animal, or PBS (control). The therapeutic effect was monitored by bioluminescence and by comparison of the survival curves (Log-rank).

RESULTS

The virus was able to infect and replicate in tumor three different cell culture models of AT/RT, inducing a potent cytotoxic effect that resulting in IC50 values below 1 PFU/cell. Administration of the virus in mice bearing localized AT/RT (supratentorial and infratentorial) extended significantly the survival the animals, leading to up to 20% of long-term survivors. In disseminated AT/RT models, light emission reveals reduction of tumor growth in virus treated animals, resulting in an increased overall survival.

CONCLUSION

In conclusion, these results demonstrate that Delta-24-RGD could be a feasible therapeutic choice for patients affected by AT/RT.
P11.32 Combined effects of niclosamide and temozolomide against human glioblastoma tumorspheres
Authors: Kim E , Oh H , Shim J , Kang S
Published: September 2019

BACKGROUND

Glioblastoma (GBM) is the most aggressive type of brain tumor and has poor survival outcomes, even after a combination of surgery, radiotherapy, and chemotherapy. Temozolomide is the only agent that has been shown to be effective against GBM, suggesting that combination of temozolomide with other agents may be more effective. Niclosamide, an FDA approved anthelmintic agent, has shown anti-cancer effects against human colon, breast, prostate cancers as well as GBM. However, the efficacy of the combination of niclosamide with temozolomide against GBM tumorspheres (TSs) has not been determined. We hypothesized that the combined treatment could effectively suppress GBM TSs.

MATERIAL AND METHODS

Effects of niclosamide and/or temozolomide on GBM TSs were evaluated. Viability, stemness, and invasive properties of GBM TSs were examined. In vivo anticancer efficacy was tested in a mouse orthotopic xenograft model.

RESULTS

The combination of niclsoamide and temozolomide significantly inhibited the viability, sphere formation, expression of stemness-related proteins, and invasive properties of GBM TSs. This combination significantly down-regulated the expression of epithelial mesenchymal transition-related proteins. Bioluminescence imaging further showed that compared with either agent alone, combination of niclosamide and temozolomide significantly reduced the tumor burden in orthotopic xenograft models.

CONCLUSION

The combination of niclosamide and temozolomide effectively decreased the stemness and invasive properties of GBM TSs, suggesting that this regimen may be therapeutically effective in treating patients with GBM.
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

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

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

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

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

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

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

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

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

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.
P14.28 First report on the combination of axitinib and Tumor Treating Fields (TTFields) in three patients with recurrent glioblastoma
Authors: Keßler A F , Weiland J , Linsenmann T , Ernestus R , Hagemann C , Löhr M
Published: September 2019

BACKGROUND

Adding Tumor Treating Fields (TTFields) to first-line therapy in glioblastoma (GBM) demonstrated significantly improved survival in the EF-14 trial. Furthermore, in a post-hoc analysis of the EF-14 trial, median overall survival increased significantly upon recurrence (rGBM) for patients treated with bevacizumab (Bev) and TTFields compared to Bev monotherapy. Axitinib (Axi) is an orally available tyrosine kinase inhibitor which is approved for the treatment of metastatic renal cell carcinoma. It has a high affinity and specificity for vascular endothelial growth factor receptors, thereby acting similar to Bev. In phase 2 trials, Axi improved response rate and progression free survival in rGBM patients compared to historical controls with a manageable toxicity profile. We report on three rGBM patients treated with TTFields and Axi (AxiTTFields).

METHODS

A 53-year-old male patient (#1) presented with a multifocal and consistently progressing GBM after initial surgery, radiochemotherapy (RCT) and after 4 cycles of temozolomide (TMZ), combined with TTFields. To meet the urgent need of an alternative treatment, Axi (5mg twice a day) was added to the treatment regimen. In a 46-year-old male patient (#2), an early progress occurred after surgery, RCT and 3 cycles of TMZ combined with TTFields. Similarly to #1, Axi was added to the treatment regimen. In a 61-year-old male patient (#3) with a rGBM after surgery and RCT at the time of the 6th cycle of TMZ, TTFields therapy was initiated at recurrence and treatment regimen was adapted to AxiTTFields.

RESULTS

In these three patients, AxiTTFields was safe and feasible. #1 and #2 were on AxiTTFields therapy for more than 8 months, presenting an improved neurological status with a partial response in the MRI 3 months initiating the combined treatment of AxiTTFields. #3 declined in his neurological status without any change in the MRI monitoring and died 2.4 months after initiating AxiTTFields. Although, Axi as well as TTFields may cause skin irritations, none were observed in this case series. With an average of 77 % in these three patients, the TTFields usage rate was above the independent prognostic threshold of 75 %, underlining the feasibility of this approach. There were no additional adverse events due to the combined therapy of AxiTTFields.

CONCLUSION

In summary, AxiTTFields was feasible and safe in three rGBM patients. As the addition of Axi to TTFields therapy is a promising approach, we plan to investigate the safety and feasibility of this combination in a pilot trial. Further studies might explore effects on outcome and survival of AxiTTFields in rGBM.
P14.33 Adult brainstem gliomas in neurofibromatosis type 1 (NF1)
Authors: Guillamo J , Wang A , Ducray F , Barbarot S , Chinot O , Frappaz D , Bauchet L , Wolkenstein P , Laigle-Donadey F
Published: September 2019

BACKGROUND

The brainstem is the second location of brain tumors after optic pathways in NF1. In NF1 children, brainstem gliomas are usually indolent and have a better prognosis than their counterparts in non NF1 children. In contrast, the natural history and prognosis of adult brainstem gliomas in NF1 are nearly unknown.

MATERIAL AND METHODS

We conducted a retrospective analysis of medical records and MRI of adult NF1 patients followed for a brainstem glioma in 8 centers over a 17 years period (2000–2017). Clinical and imaging characteristics, management and outcome were analyzed.

RESULTS

Twenty five patients were included in the study (13 males and 12 females) with a median age of 32 (range 17–58). The epicenter of the tumor was located into the pons n=13 (52%), the mesencephalon n=7 (28%), the medulla oblongata n=5 (20%). On MRI, contrast enhancement was seen in 19 tumors (76%). Pathological examination was available in 13 tumors (52%) and showed a high grade astrocytoma (III or IV) in 9 tumors. Five patients were asymptomatic, 3 remained asymptomatic during the follow-up (median follow-up: 86 months, range 22–124). Twenty patients were symptomatic with a median duration of symptom of 2.5 months (range 1–10) before diagnosis. Among these symptomatic patients, 15 died from tumor progression despite treatment with radiation therapy and or chemotherapy. The median overall survival of symptomatic patients was 36 months.

CONCLUSION

Brainstem gliomas are rare tumors in adults with NF1. Unlike children, adult brainstem gliomas seem to have an unexpected poor prognosis, suggesting the disease may be different in adulthood.
P14.37 Depression in patients with primary brain tumors: Relation to clinical variables and tumor characteristics
Authors: John F , Barger G R , Mittal S , Juhasz C
Published: September 2019

BACKGROUND

Patients with brain tumor have an increased risk for depressive disorder, however, the association between depression and clinical or tumor-related variables remains mostly unclear. In this study, we analyzed the relation of depression to several clinical and tumor-related characteristics in patients with primary brain tumors.

MATERIAL AND METHODS

Sixty patients with newly-diagnosed (n=34) or recurrent (n=26) primary brain tumors (50 gliomas, 10 meningiomas) underwent testing with the Beck Depression Inventory-II (BDI-II). Relation of BDI-II scores to clinical and tumor-related characteristics, including age, Karnofsky Performance Status (KPS) scores, presence of antiepileptic, antidepressant, or steroid treatment, as well as tumor grade, lateralization, and lobar localization, were analyzed. In a subset of recurrent malignant glioma patients, the prognostic value of BDI-II scores on overall survival was also analyzed.

RESULTS

The mean total BDI-II score was 10±8 (range: 0–37); while 27% of patients (n=16) had BDI-II scores indicating at least mild depressive disorder (≥13), only a portion of them (17%) was on antidepressant treatment. No BDI-II difference was found between gliomas vs. meningiomas or newly-diagnosed vs. recurrent tumors; also, no association was found with any tumor-related characteristics. Antiepileptic or steroid therapy had no association with BDI-II scores, while higher BDI-II scores were observed in patients with ongoing antidepressant therapy (15±10 vs. 8±7, p=0.017). Higher BDI-II total and somatic subscale scores correlated with lower KPS scores (r=-0.32, p=0.014 and r=-0.31, p=0.017, respectively). In recurrent malignant glioma patients (n=18), higher depression scores were associated with shorter survival (hazard ratio: 3.7; 95% confidence interval: 1.0–13.6; p=0.048).

CONCLUSION

Depression affected more than ¼ of patients with primary brain tumors in this single-center cohort and was independent from most clinical and tumor-related characteristics, except KPS scores. Although most of these patients have mild depression that is often overlooked without targeted screening, higher BDI-II scores may predict shorter overall survival in recurrent malignant glioma patients. These data reinforce the importance of early recognition and treatment of depressive symptoms in patients with primary brain tumors.