bluuebunny/crossref_metadata_2025_split huggingface dataset:
P11.36 Ribosome hydroxylase Mina53 is required for Glioblastoma and is involved in regulation of translation rateand fidelity by regulating ribosomal biogenesis
Authors: Pandey D , Mohammad F , Weissmann S , Hallenborg P , Blagoev B , Helin K 
Published: September 2019

Abstract
Glioblastoma multiforme (GBM) is one of the most aggressive types of tumors with a poor response to standard treatment and a median 5-year survival of less than 5%. Therefore, there is an urgent need for new treatments. Recently, a large number of genome-wide studies have shown that the epigenetic modifiers are frequently deregulated in cancer. Using a mouse GBM model, we performed in vitro and in vivo shRNA screens to identify epigenetic regulators required for the tumorigenic process in GBM. Among these regulators is a ribosome hydroxylase Mina53 which hydroxylates His-39 of ribosomal protein, RPL27a. We have found that the knock-down (KD) of Mina53 reduces the in vitro proliferation and colony forming ability of mouse glioma initiating cells (mGIC) and this is dependent on the catalytic activity of Mina. Knock-down of Mina resulted into a small but significant reduction in the global protein synthesis rate. A tandem affinity purification experiment to identify proteins associated with Mina revealed that it is associated mainly with ribosomal proteins, including its substrate RPL27a. Global proteomic analyses revealed that final amounts and de novo protein synthesis of many ribosomal proteins were reduced upon Mina depletion. Isolation and identification of different polysome fraction bound mRNAs using high-throughput sequencing found that mRNAs encoding many ribosomal proteins have lower number of ribosomes loaded on them in the Mina depleted samples compared to the control. Taken together, this study has found that Mina53 is required for glioblastoma and it regulates translation through regulation of ribosomal biogenesis
P11.43 Deletions on Y chromosome are associated with shorter survival in glioblastoma
Authors: Lysiak M , Malmström A , Roodakker K R , Sandberg E , Dimberg A , Mudaisi M , Bratthäll C , Strandéus M , Milos P , Hallbeck M , Smits A , Söderkvist P 
Published: September 2019

Abstract

BACKGROUND
Apart from few exceptions, men are more likely to be diagnosed with cancer during their lifetime, including glioblastoma (GBM), but the gender-related differences in GBM are poorly understood. Loss of chromosome Y (LOY) in peripheral blood cells is associated with physiological ageing, but also with disorders like cardiovascular disease, Alzheimer’s disease and different cancer types. In this study, we determined deletions on Y chromosome in tumor tissue of male patients with GBM, and studied the impact of LOY on survival.

MATERIAL AND METHODS
Ten genes, serving as markers, were selected on both arms of chromosome Y for copy number analysis with droplet digital PCR (ddPCR), enabling detection of loss of a marker in a fraction of the tumor cells used for DNA extraction. A total of 114 tumor samples from male patients were used, derived from a cohort of IDH wild type GBM patients treated with standard radio-chemo therapy. For 61 of these 114 patients, corresponding blood samples were available and analyzed. Different cut-off values were tested for each marker and Kaplan-Meier log-rank analysis was used to estimate overall survival. The mRNA expression for nine of the ten tested genes was available in TCGA, and 225 IDH wild type male GBM were included in a separate survival analysis, where median value of expression was used as group separator.

RESULTS
Fractional loss, as well as gain of markers was detected. Decreased copy number of the following markers was associated with significantly shorter survival; amelogenin Y-linked (AMELY) (13.5 vs. 19.3 months, p=0.017), neuroligin 4 Y-linked (NLGN4Y) (11.8 vs. 18.9 months, p=0.03) and sex determining region Y (SRY) (10.3 vs. 18.7 months, p=0.002). Additional analysis of SRY in the blood samples verified that copy number alterations were predominantly present in tumors. Survival analysis using mRNA expression data from TCGA showed that reduced expression of SRY was associated with significantly shorter OS (13.8 vs. 19.8 months, p=0.008), but no significant correlation with OS for any of the other markers.

CONCLUSION
Our data suggests a clonal or at least sporadic occurrence of fractional loss of Y chromosome markers in GBM, as detected with ddPCR. Interestingly, such dosage changes may contribute to shorter survival in men and explain some of the sex disparity seen in GBM. More research is needed to elucidate the molecular mechanisms of LOY and the role of specific Y-linked genes in GBM but also other diseases.
P11.56 Oncolytic virus and tumor microenvironment modulators an alliance to fight glioblastoma
Authors: Puigdelloses M , Martinez-Velez N , García-Moure M , Gonzalez-Huarriz M , Iñigo I , Marta A M , Gallego Perez-Larraya J 
Published: September 2019

Abstract

BACKGROUND
Glioblastoma is the most common and malignant brain tumour in adults with a dismal overall survival. Several works demonstrated that its tumoral microenvironment is enriched of immunosuppressive cell populations resulting in a challenge for its treatment. In this study, we propose to use an oncolytic adenovirus (Delta-24-RGD) with an inhibitor of myeloid derived suppressor cells (MDSCs; pexidartinib). Therefore, we hypothesis that we will act on two arms of the immune response: the efector arm (with the virus) and the inhibitor arm (with the Pexidartinib) resulting in a greater antitumor immune response.

MATERIAL AND METHODS
We examined the benefit in survival of the combination Delta-24ACT with pexidarnitib (MDSC inhibitor) or a complement inhibitor in C57BL/6 mice bearing the CT-2A or the GLS61-5 murine glioblastoma models orthotopically. Three viral doses (1x108 pfu/mouse) were administered at 4, 8 and 11 days post cell implantation and the tumor microenvironment immunomodulators were administered following different schedules. Survival in different treatment groups were compared using the log-rank test.

RESULTS
We observed that the combination of Delta-24-ACT and pexidartinib, led to an increase in the median survival of the treated mice when compared with single treatments (PBS=24 days, pexidartinib=24 days, Delta-24-ACT= 35 days and Delta-24-ACT+Pexidartinib= 36 days). Moreover, the treatment led to 8 long-term survivors; Pexidartinib=1, Delta-24-ACT=3 and Delta-24-ACT+Pexidartinib=4. These data underscore that the combined treatment increase significantly the number of long-term survivors. These long-term survivors were subjected to a rechalleng experiment to assess the generation of immunological memory which is currently on going. We have observed that the combined treatment increase the tumor infiltratrion of CD4, CD8 and led to a less immunosuppressive microenvironment. Immunohistochemistry of macrophages and nanostring of FFPE brain samples in order to evaluate the differences of the cell populations present in the tumoral microenvironment and their functional studies is currently on going. These experiments are being also conducted in GL261-5.

CONCLUSION
Our data suggest that the combination of the Delta-24-ACT with the capacity of activate the immune system and a drug that downregulates the immunosupression results in a survival benefit in model of gliomas and warrants further investigation.
P13.05 Chemical Biopsy as an Alternative Sampling Method in Neurooncology
Authors: Bogusiewicz J , Goryńska P Z , Jaroch K , Goryński K , Paczkowski D , Furtak J , Harat M , Bojko B 
Published: September 2019

Abstract

BACKGROUND
Histopathology is a gold standard for diagnostics of brain tumors but it is time consuming, demands removal of the part of the tissue what makes it highly invasive. That is why it seems to be relevant to develop new diagnostic methods addressing the abovementioned drawbacks. Ideal tool should be easy to use, as low invasive as possible and of high clinical value.
The aim of the study was to assess the usefulness of chemical biopsy based on solid phase microextraction as a sampling method for lipidomic analysis of brain tumors.

MATERIAL AND METHODS
The experiment was carried out on 38 brain tumors. Sampling was performed ex vivo, directly after removal of brain tumors. SPME fibers (coated with biocompatible extraction phase, length and diameter of the coating 7mm and 200um, respectively) were inserted into the sample without prior preparation of the tissue. Desorption of lipids was performed in isopropanol-methanol mixture. Analysis of extracts was carried out using liquid chromatography coupled to high resolution mass spectrometry.

RESULTS
Wide range of tentative lipid species was obtained in the studies. Two histologically different types of brain tumors: gliomas and meningiomas were subjected to the chemical biopsy. The results showed very good separation between the tumor types in unsupervised chemometric tests. The lipid species responsible for this separation were previously reported in the literature as cancer biomarkers. With regards to malignancy grading of gliomas the separation was notable but not as clear as between the tumor types, what is probably related to high heterogeneity of this cancerous tissue and subjectivity of histopathological analysis which were a referring point in methods comparison. Very good agreement was noted for changes in lipidome obtained by chemical biopsy and histological subtypes of gliomas. However, the most promising results showed impact of IDH1 R132H mutation on lipidome of gliomas.

CONCLUSION
Chemical biopsy seems to be useful method in lipidomics studies and for differentiation of brain tumors according their histological origin and malignancy. It also enables to find a relation between IDH1 mutation and lipidomic profile.

ACKNOWLEDGMENTS
The work was supported by the grant 2015/18/M/ST4/00059 funded by National Science Centre, Poland. The authors want to acknowledge Supelco/MilliporeSigma for the SPME probes, Thermo Fisher Scientific for the access to Q-Exactive Focus mass spectrometer, Anchem for the technical support and Shim-Pol for the access to LCMS-8060 mass spectrometer and technical support.
P14.03 Adult medulloblastoma: Influence of risk stratification and molecular subtypes on chemotherapy efficacy
Authors: Absalyamova O , Kobiakov G , Agabekyan G , Ryzhova M , Kobiakov N , Lodygina K , Poddubsky A , Korshunov A 
Published: September 2019

Abstract

BACKGROUND
Incidence of medulloblastoma (MB) in adults is about 1%. Optimal treatment for adult medulloblastoma has not been defined. Published datasets were acquired over a long period of time, during which there were changes in surgical technique, radiotherapy, chemotherapy regimens; often disease stage was not considered in the analyses. Recently discovered molecular subgroups are not taken into account in studies concerning treatment of medulloblastoma in adults.

MATERIAL AND METHODS
Study includes 64 patients with medulloblastoma (median age 26.5 years (15–62)), who were first admitted to Burdenko Neurosurgery Institute for surgery from 2000 to 2017. 100 % patients included in the study received radiotherapy - craniospinal irradiation, 36 Gy (20 x 1.8 Gy) with boost to primary site (2 cm around tumor bed) up to 55 Gy total dose. 41 patients (64%) received chemotherapy (ChT). Chemotherapy was started 4–6 weeks after finishing craniospinal irradiation, the regimen included cisplatin 25 mg/m2 days 1–4+etoposide 100 mg/m2 days 1–4+cyclophosphamide 600 mg/m2 days 1–4; the cycles repeating every 28 days, 6 cycles in total. Treatment volume didn’t correspond with risk group and/or molecular genetic subgroup (these parameters were determined retrospectively). Median follow-up time is 4.45 years.

RESULTS
53% patients had classic histology MB, 27% - desmoplastic, 20% - large cell/anaplastic. High risk (HR), standard risk (SR) and unspecified risk (UR) groups included 23, 16 and 25 patients respectively. Molecular subgroup testing was performed in 39 cases: SHH-activated - 59%, WNT-activated - 18%, GROUP4 - 23%. Median time to tumor progression (MTTP) in patients who received radio-chemotherapy versus radiotherapy alone was 4.3 and 2.64 years, respectively (p=0.264). The differences in MTTP were the most pronounced in SR and UR patients who received radio-chemotherapy (5.5 and 6.0 months, respectively) versus radiotherapy alone (1.5 and 2.0 months, respectively). HR patients showed the least difference in MTTP for radiotherapy (2.0 years) versus radio-chemotherapy (2.5 years), p=0.093. The SHH-subgroup patients had MTTP of 3.1 years (3.1 and 3.0 years for ChT+ and ChT-, respectively). GROUP4 patients had MTTP of 4.3 years (4.3 and 1.5 years for ChT+ and ChT-, respectively). All WNT-subgroup patients received chemotherapy, MTTP was 9.0 years. Median overall survival cannot be defined in any of the subgroups.

CONCLUSION
Chemotherapy in adult medulloblastoma patients increases MTTP in SR and UR patients. Low efficacy of chemotherapy for high risk medulloblastoma urges search for more efficacious treatment protocols. WNT-activated adult medulloblastoma has the highest MTTP among other molecular subgroups.
P14.04 10 years of weekly web conference for brain tumor of Adolescent/Young Adult (AYA) on behalf of ANOCEF, GO-AJA and SFCE societies
Authors: Frappaz D , Bronnimann C , Faure Conter C , Vauleon E , Meyronnet D , Sunyach M , Leblond P , Tanguy R , Laurence V , Bonneville-Levard A 
Published: September 2019

Abstract

BACKGROUND
The skills of adult versus pediatric neuro-oncologists are not completely similar though additive. Because the tumors and their protocols are different and the tolerance and expected sequelae are specific. Multidisciplinary meetings including adult and pediatric neuro oncologists are warranted to share expertise.

MATERIAL AND METHODS
Since 2008, on behalf of ANOCEF, GO-AJA and SFCE societies, a weekly national web based conference was held in France. Any patient with the following criteria could be discussed: Adolescent and Young Adults aged between 15 and 25 years, and any adult with a pediatric type pathology, including medulloblastoma, germ cell tumors, embryonic tumors, ependymoma, pilocytic astrocytoma.

RESULTS
Number of cases discussed increased from 8 to 202/year, with a mean number of 3 cases (1 to 7) discussed at each meeting. In 2018, 36 meetings were held, with a mean of 8 participants (2 to 14) issued from various French centers. 168 cases were discussed in 2018. Mean age was 30 years old (7 to 67). 45% were discussed at diagnosis; The patients had mostly medulloblastomas (n=47), ependymomas (n=24), low (n=21) or high grade gliomas (n=11), pineal tumors (n=20), germ cell tumors (n=9) and embryonal tumors (n=6). The rate of inclusion in protocols was increased since the opening of this web conference, especially for the germ cell tumor GCT SIOP protocol that is opened without age restriction, and in RSMA standard risk or MEVITEM relapse adult medulloblastoma protocols.

CONCLUSION
Multidisciplinary Web conference for AYAs is feasible and fruitful. It shares knowledge and increases the inclusion rate in protocols. It should be developped further.
P14.08 Bevacizumab treatment for the lesion emerging after the radiotherapy for malignant glioma
Authors: Miwa K , Ito T , Yokoyama K , Shinoda J 
Published: September 2019

Abstract

BACKGROUND
Because blocking vascular endothelial growth factor from reaching leaky capillaries is a logical strategy for the treatment, we reasoned that bevacizumab might be an eﬀective treatment on recurrent malignant glioma and radiation necrosis (RN). In this study, the authors examined to diﬀerentiate RN from recurrent malignant glioma, and evaluated the results of bevacizumab treatment in each diagnosis.

MATERIAL AND METHODS
Four patients of malignant glioma (2 glioblastomas and 2 anaplastic astrocytomas), which demonstrated symptomatic lesion after radiotherapy, were involved in this study. All four patients were treated with bevacizumab on a 10 mg/kg biweekly (one cycle), for a total dose of 30 mg/kg (3 cycles) or furthermore. RN was diﬀerentiated from local recurrence in all four patients on the basis of 11C-methionine positron emission tomography and/or clinical course. Clinical evaluation and MRI studies were obtained after bevacizumab treatment in all cases repeatedly as possible.

RESULTS
Two patients were diagnosed as RN, and another two patients as tumor recurrence. Of the two patients with RN, neurological dysfunction was distinctly alleviated after bevacizumab treatment. Other two patients with tumor recurrence demonstrated no remarkable improvement in neurological dysfunction after bevacizumab treatment. Of all the two patients with RN, post-treatment MRI performed after the bevacizumab therapy showed a significant reduction of the massive lesion.

CONCLUSION
We concluded that bevacizumab could control the symptomatic massive lesion occurring after radiotherapy, and it might be more eﬀective with the patients of RN, than with those of recurrent tumor.
P14.09 INITIAL GLOBAL SYMPTOMS IN GLIOBLASTOMA ARE OFTEN MISINTERPRETED AND ASSOCIATED WITH SHORTER SURVIVAL
Authors: Bruhn H , Dahle C , Vrethem M , Henriksson R , Lindh J 
Published: September 2019

Abstract

BACKGROUND
A seizure as the only symptom before diagnosing glioblastoma improves survival rate. Apart from seizures, the main presenting symptom of glioma in adults is cognitive dysfunction. The effect of generalized symptoms or loss of function on lead times and survival of glioblastoma has not been studied. Generalized symptoms include cognitive dysfunction, headache, dizziness and fatigue. Loss of function comprise paresis, sensory deficit and speech aberrations. The objective of this study was to evaluate the influence of different presenting symptoms regarding health care level, lead times and survival.

MATERIAL AND METHOD
Medical case notes regarding 189 consecutive patients with histopathologically verified glioblastoma, were reviewed for information about the date and level of care of the first medical appointment, presenting symptom/s, and date of the diagnostic radiology. The extent of surgery was noted. Data on oncologic treatment was retrieved. Summary statistics were provided for patient demographics and treatment factors. The estimates of overall survival were calculated using the Kaplan-Meier method. Survival time was calculated from the date of radiological diagnosis.

RESULTS
The majority of patients (66%) presented with generalized symptoms, which significantly reduced survival compared to not having generalized symptoms (mean survival 10.5 months vs 19.9 months, p=0.001). The most common generalized symptom was cognitive dysfunction which further reduced survival (mean survival 9.0 months, p=0.0001). Among the different cognitive aberrations, personality change and memory impairment were associated with a significantly poorer survival, (mean survival 7.9 months, p=0.015 and 8.0 months p=0.010, respectively). Disorientation also significantly reduced survival (mean survival 8.2 months p=0.001). Presenting with loss of function (58%) did not influence survival (mean survival 12.3 months). 32% of patients with an epileptic seizure as initial symptom had significantly prolonged survival compared to those not having an epileptic seizure (mean 18.9 months vs 11.0 months p=0.002). When comparing focal and secondary generalized epileptic seizures, focal epileptic seizures were more favorable. The first medical appointment was evenly distributed between primary health care and the emergency units. 8.4% of patients had multiple contacts in primary health care without being admitted to radiology or specialized care. All but one of them presented with generalized symptoms.

CONCLUSION
Glioblastoma patients presenting with generalized symptoms such as cognitive dysfunction are difficult to identify and have significantly poorer survival than other glioblastoma patients. Patients presenting with an epileptic seizure have shorter leadtime and longer survival.
P14.13 Incidence of pseudoprogression in high-grade IDH-mutant gliomas
Authors: SEYVE A , Cartalat S , Meyronet D , D’hombres A , Barritault M , Jouanneau E , Berhouma M , Guyotat J , Honnorat J , Ducray F 
Published: September 2019

Abstract

BACKGROUND
Pseudoprogression (PsP) is a well-known concern in IDH-wildtype glioblastomas. The aim of the present study was to describe its incidence in high-grade IDH-mutant gliomas.

MATERIAL AND METHODS
We retrospectively analyzed the characteristics of a consecutive series of high-grade IDH-mutant gliomas treated with radiotherapy (RT) with or without chemotherapy between March 2009 and September 2017. PsP was defined as a new enhanced lesion that occurred after RT and subsequently disappeared or remained stable during follow-up for a least 6 months.

RESULTS
The study population consisted of 38 anaplastic IDH-mutant and 1p/19q codeleted oligodendrogliomas, 34 IDH-mutant anaplastic astrocytomas and 18 IDH-mutant glioblastomas. Treatment consisted of radiotherapy alone (n=8, 9%), radiotherapy and PCV chemotherapy (n=63, 70%) and temozolomide radiochemotherapy (n=19, 21%). After a median follow-up of 3.5 years (range 1–8 years), 24 patients (28%) presented a PsP that occurred after a median delay of 10 months after radiotherapy (2 to 32 months). PsP was more frequent in patients treated with RT+PCV than in those treated with RT+TMZ (34% vs 10%, p=0.05). During the first two years after RT completion, 19 patients (21%) presented a PsP and 15 patients (17%) a true progression. At last follow-up, 1 patient (4%) in the PsP group had died compared to 10 patients (16%) in the group of patients without PsP.

CONCLUSION
PsP is a frequent issue in IDH-mutant high-grade gliomas. Its timing of onset is delayed compared to the timing of PsP onset reported in IDH-wildtype glioblastomas. The association between the use of PCV chemotherapy and PsP requires validation in an independent series.
P14.22 Long-term survival of treatment of HGG using PDT
Authors: Rynda A , Olyushin V , Rostovtsev D , Zabrodskaya Y 
Published: September 2019

Abstract

BACKGROUND
As a supplement to the adjuvant treatment of malignant gliomas of the cerebral hemispheres, the substance of the 2nd generation chlorins e6 was investigated. This study reflects the survival and size of the relapse-free period of patients in the Polenov Russian Research Institute of Neurosurgery, using the base of patients who received adjuvant PDT therapy in addition to surgical resection of the tumor.

MATERIAL AND METHODS
The analysis of 160 patients with glial brain tumors of supratentorial localization, of various degrees of malignancy, operated on in the Department Neurooncology, Polenov Russian Research Institute of Neurosurgery from 2004 to 2015. 79 patients (study group) removal of a tumor with intraoperative photodynamic therapy with a drug of the chlorin e6 group of the 2nd generation. 81 patients (control group), tumor removal without photodynamic therapy.

RESULTS
The median survival for patients with Grade III gliomas using PDT was 40.4 ± 7.4 months; in the control group (without PDT) - 23.4 ± 3.9 months (p = 0.0003). The median survival for patients with Grade IV gliomas using PDT was 21.3 ± 5.1 months; in the control group (without PDT) - 13.7 ± 3.7 months (p = 0.0002). The median duration of the disease-free period for patients in the Grade III subgroup was: in the study group, 22.5 ± 3.79 months; in the control group, 16.1 ± 3.22 months (p = 0.0002). The median duration of the disease-free period for patients in the Grade IV subgroup was 11.4 ± 2.49 months in the study group; in the control group - 8.2 ± 2.13 months (p = 0.0001).

CONCLUSION
Photodynamic therapy is a promising and safe technique that allows intraoperative action on the residual volume of tumor cells located in the perifocal zone. The use of PDT in the complex treatment of glial brain tumors allows to increase the median of survival and the recurrence-free period.