bluuebunny/crossref_metadata_2025_split huggingface dataset:
OS12.3 L3MBTL3 is a novel suppressor of medulloblastoma tumorigenesis
Authors: Rual J 
Published: September 2019

Abstract

BACKGROUND
Medulloblastoma is the most common malignant brain tumor of childhood. Therapeutic approaches to medulloblastoma have led to significant improvements but are achieved at a high cost to quality of life. Alternative therapeutic approaches are needed and molecular stratification of patients with medulloblastoma has yet to be routinely implemented in the clinic. TheNotchpathway governs cell proliferation in many biological contexts, including SHHand Group#3medulloblastoma tumorigenesis. Using our proteomic platform, we discovered an interaction between RBPJ, a key co-factor of Notch for the modulation of Notch signals, and L3MBTL3, a methyllysine reader.L3MBTL3 is recruited by RBPJ on chromatin at the enhancers of Notch/RBPJ target genes to repress their expression.Deletions ofthe L3MBTL3locus are observed in patientswith WNTand Group#3medulloblastomaand expression of L3MBTL3 in the SHHmedulloblastoma-derived cell DAOY inhibits cell growth, suggesting a putative tumor suppressor role for L3MBTL3 in medulloblastoma.

METHODS
To further investigate the putative role of L3MBTL3 as a suppressor of medulloblastoma tumorigenesis, we used our novel L3mbtl3KO mouse in combination with a genetically engineered ND2:SmoA1mouse model of SHHmedulloblastoma in a survival analysis.

RESULTS
Our survival analysis validated in vivoour hypothesis that L3mbtl3is a tumor suppressor in this disease context. Indeed, our data show that [ND2:SmoA1; L3mbtl3+/-] mice have a significantly lower survival rate than ND2:SmoA1 mice (P= 0.0322; Log-rank test). Hence, the RBPJ-L3MBTL3 interaction is at the heart of a molecular mechanism governing the repression of Notch/RBPJ target genes and malfunction of this molecular mechanism contributes to L3MBTL3’s tumor suppressor role in medulloblastomathrough aberrant “de-repression” of Notch/RBPJ target genes.

CONCLUSION
L3MBTL3 is a novel suppressor of medulloblastoma tumorigenesis. Our discovery providesinsights into the role of the L3MBTL3 inmedulloblastomathat could be harnessed in the future for the therapeutic benefit of patientswith medulloblastoma.
P03.03 Dynamics of brain metastasis cavities between resection and adjuvant stereotactic radiotherapy and impact of the delay on local control
Authors: Mousli A , Bihin B , Gustin T , Koerts G , Mouchamps M , Daisne J F 
Published: September 2019

Abstract

BACKGROUND
Adjuvant stereotactic radiotherapy (SRT) to the surgical cavity of brain metastases (BM) improves the local control. An early post-operative irradiation is desirable to limit the risk of recurrence while delaying it might reduce the risk of radionecrosis by reducing the size of the target volume (TV) thanks to the cavity constriction. The purpose of our study was to examine cavity dynamics after resection to determine if delaying SRT influences cavity size as well as local progression (LP).

MATERIAL AND METHODS
We reviewed 70 BM resection cavities treated with adjuvant SRT. A preoperative, immediate postoperative and at the time of SRT, 3D T1-weigthed MRI, were available for all patients. The volumes were retrospectively calculated with the PACS software Telemis® version 4 and the iPlan RT image software. For all cavities, the TV was obtained by expanding the cavity by a median margin of 2mm to account for microscopic spread. The surgical track and edema areas were not included in the TV. The dynamic evolution of cavities and LP according to the delay of SRT were analyzed.

RESULTS
The median time from surgery to SRT was 27 days (3–99). The median preoperative and SRT cavity volumes were 7.2 cc (ranges: 0.5–29.5) and 8 cc (ranges: 0.8–31), respectively. After margin expansion, the TV was increased to a median of 14.8 cc. The volumetric cavity changes were an increase by 2 cc in 35 %, whereas only 22.5 % decreased by 2 cc and 42.5% cavities were stable (defined as a change ≤2 cc). We noted that 11% of volume change were attributable to the delay (r2 = 0.11). forty-seven patients were treated within a delay of 30 days and experienced early LP in 10.6 % against 20 % beyond 30 days (p= 0.6).

CONCLUSION
In the interval between surgery and SRT, BM cavities dynamics are inconstant and unpredictable in function of time. Furthermore, delaying SRT may compromise local control, though the difference was not statistically significant due to the small size of our population. A preoperative SRT strategy looks more promising by alleviating the problem of time and reducing the volume of irradiated brain.
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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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.