bluuebunny/crossref_metadata_2025_split huggingface dataset:
P05.01 the efficacy of donepezil on cognitive function in postoperative brain tumor patients
Authors: Diansari Y , Harun Y , Marisdina S , Felistia Y 
Published: September 2019

Abstract

BACKGROUND
Cognitive impairment is frequently found in brain tumor patients. More than 90% of patients with brain tumor have at least one cognitive domain disturbance. Decline in cognitive function could happen before due to the tumor or after the treatment because of surgery, radiotherapy or chemotherapy. Until now there is no available standard treatment for patients with cognitive impairment due to brain tumor. Moreover, Donepezil is an acetylcholinesterase inhibitor known to be useful for improving cognitive function in patients with dementia. This clinical study aims to determine the cognitive effects of donepezil therapy in patients with brain tumors following surgery.

MATERIAL AND METHODS
This is a pilot study with total of 20 adult brain tumor patients were double blinded randomly assigned to receive a single daily dose (5mg for 12 weeks) of donepezil or placebo. The inclusion criteria were patients with primary brain tumor who had undergone surgery with cognitive impairment at the initial evaluation and age range 18 to 65 years old. Patients with previous cognitive problem, other diseases that can cause cognitive decline e.g. stroke and history of taking donepezil, memantine, methylphenidate, ginkgo biloba, and modafinil were excluded. A cognitive test using Mini Mental State Examination (MMSE) and Montreal Cognitive Assessment Indonesia Version (MoCA-INA) assessing memory, attention, language, visuospatial, verbal fluency, and executive functions were administered before random assignment and at 4, 8 and 12 weeks. A cognitive composite score (primary outcome) and individual cognitive domains were evaluated. Furthermore, side effects and adverse events were also recorded.

RESULTS
Of this mostly middle-age (30–60 years old), female, meningioma as primary brain tumor with frontal and temporal lobe are the most frequent locations. After 12 weeks of treatment, the composite scores did differ significantly between groups (MMSE P=0.027, MoCA-INA P=0.024). Furthermore, the significant differences favouring donepezil were observed for orientation and recall domains using MMSE with p value 0.017 and 0.006 respectively. Visuospatial (P=0.034) and delayed recall domains (P=0.004) were significant through MoCA-INA evaluation. In addition, Mean MMSE score for pre-donepezil administration was 14.60 ± 4.47 and after 3 months was 20.40 ± 4.24 (P=0.000). Mean MoCA-INA score for pre-donepezil administration was 9.30 ± 3.65 and after 3 months was 15.30 ± 4.24 (P=0.000). However, there was no differences in the placebo group (MMSE P= 0.066, MoCA-INA P=0.313).

CONCLUSION
Three months treatment with donepezil significantly improve the cognitive functions among post-operative brain tumor patients with no reported side effect. Moreover, further research is needed for longer duration of follow-up and possibility of increased doses.
P05.08 High-grade gliomas and immunotherapeutic early phase clinical trials: a single-center experience
Authors: Simonelli M , Persico P , Dipasquale A , Lorenzi E , Giordano L , Pessina F , Navarria P , Scorsetti M , Bello L , Santoro A 
Published: September 2019

Abstract

BACKGROUND
Patients with high-grade gliomas (HGGs) have historically been excluded from immunotherapeutic early-phase clinical trials (ieCTs) due to unavailability of serial bioptic sampling, the frequent need of corticosteroids, concerns regarding activity of immunotherapy in central nervous system, and rapid clinical deterioration.

MATERIAL AND METHODS
We retrospectively reviewed data of all recurrent HGG patients enrolled in ieCTs at Humanitas Cancer Center Phase I Unit between 2014 and 2019. Disease control rate (DCR) according to RANO criteria, six-months progression-free and overall survival (PFS-6; OS-6), and treatment-related adverse events (TRAEs), were evaluated. A control-cohort (CC) of patients treated with standard treatments (temozolomide, fotemustine, lomustine and procarbazine, bevacizumab) matched (1:1) for sex, age, line of treatment, MGMT methylation status, and IDH mutational status, was selected for comparison. A series of clinical parameters with an established prognostic value for patients with solid tumors treated into ieCTs were correlated with survivals through an univariate analysis. These include: use of steroids, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, lactate dehydrogenase, albumin, total protein.

RESULTS
Five among the 23 ieCTs conducted at our Phase I Unit allowed inclusion of HGG patients. 25 patients were enrolled in the experimental cohort (EC): 22 (88%) glioblastoma, 3 (12%) anaplastic astrocytoma. Median age was 50 years (range 25–71); 16 patients (64%) were men, 9 (36%) women; 17 pts (68%) required steroid therapy, with a median baseline dexamethasone dose of 2 mg (range 1–6). The median number of prior systemic therapies was 1 (range 1–2). Twelve patients (48%) received monotherapies (anti PD-1, anti CSFR-1, anti TGF-ß, anti cereblon), 13 (52%) combination regimens (anti PD-L1 + anti CD38, anti PD-1 + anti CSFR-1). DCR was 40% (1 CR + 2 PR + 7 SD) and 37% (9 SD), in EC and CC, respectively. Four patients (16%) in EC had grade ≥3 TRAEs (1 neutropenia, 1 pneumonia, 2 hepatitis). With a median follow-up of 14 months PFS-6 were 35% and 16% (p=0.075), in EC and CC respectively, while OS-6 was significantly improved in the EC (82% vs 44%, p=0.004). In our small series, none of clinical factors resulted prognostic.

CONCLUSION
Survival outcomes of ourHGG patients treated into ieCTs compared very favorably with a matched CC. Inclusion of HGGs patients into ieCTs should be strongly encouraged. Identification of clinical factors to select who may benefit from ieCTs still remains crucial.
P07.01 Functional role of N-Myc in SHH type TP53 mutated MB’s metabolism
Authors: Yokogami K 
Published: September 2019

Abstract

BACKGROUND
Medulloblastoma is classified in 4 subgroups. Prognosis and therapeutic option was different from each subgroups. Thus, we need subgroup-specific in vitro models for investigating new therapeutic targets. Little established medulloblastoma cell-lines, which have been subgrouped is available. Especially, commercially available SHH type TP53 mutated cell-line is only DAOY. We established new cell lines 505CSC / 507FBS from the patient with SHH type with TP53 mutated MB. This matched pair cell line showed high expression of N-MYC in serum free conditioned medium. To know the functional role of N-MYC in MB, we used 507CSC and DAOY.

MATERIAL AND METHODS
Using chemical inhibitor of N-Myc in 507CSC and DAOY, proliferation assay, mRNA expression and measurements of ex-vivo metabolic phenotype were performed.

RESULTS
N-MYC inhibition leads to cell death in both cell lines. N-MYC regulated glucose, glutamine and methionine metabolism. Especially the targets were PKM2, GLS2, MAT2A, DNMT1 and 3A.

CONCLUSION
N-MYC is a target of therapy in a patient with SHH type TP53 mutated medulloblastoma.
P08.04 Glioblastoma and Alzheimer pathology: lessons from a single case with practical implications and need for further research
Authors: Gállego Pérez-Larraya J , Esparragosa I , Puigdelloses M , Idoate M , Alonso M 
Published: September 2019

Abstract

BACKGROUND
Glioblastoma (GBM) and Alzheimer’s disease (AD) are frequent among the elderly: about 50% of all GBM patients are 65 years or older, and 5–10% of people above this age threshold suffer from AD.

MATERIAL AND METHODS
We describe the case of an elderly patient with newly diagnosed GBM who developed a rapidly progressive severe dementia immediately following concomitant radio-chemotherapy. A purposed retrospective analysis of the surgical sample revealed Alzheimer pathology.

RESULTS
A 69-year old woman with no relevant past-medical history was diagnosed with a right temporo-parietal GBM on May 2017, with wild-type IDH1R132H gene and methylated MGMTP. After complete resection she received radiotherapy (60 Gy in 30 fractions) and concomitant chemotherapy with Temozolomide 75 mg/m2/day. During the last weeks of concomitant radio-chemotherapy and further on the patient developed a progressive neurological worsening with severe cognitive dysfunction, gait impairment and sphincter incontinence, becoming severely disabled and requiring continuous assistance. Brain MRI exams showed no signs of tumor recurrence, with focal white matter changes consisting on T2/FLAIR hyperintensities within the radiation field, enlarged sulci and ventriculomegaly. Underlying infectious and metabolic disorders, non-convulsive epileptic status and normal-pressure hydrocephalus were ruled out. Facing this situation the patient relatives were purposely asked for previous cognitive symptoms, and described very mild complaints of short-term memory loss during the previous year. Aiming at investigating the possibility of an underlying AD, focused examination of the surgical sample revealed the presence of frequent neuritic plaques, a neuropathological hallmark of AD. The patient developed a severe dementia with akinetic mutism by September 2017. Without evidence of tumor recurrence despite lack of adjuvant chemotherapy, she died of aspiration pneumonia on January 2019.

CONCLUSION
A unique retrospective study including elderly GBM patients treated only with surgery revealed that Alzheimer disease pathology was present in 42% of them. This case illustrates the need for actively addressing the previous cognitive status of elderly patients with GBM. Histopathological assessment of Alzheimer pathology might also be considered in this specific population. In positive cases, particularly in those with methylated MGMTP, radiotherapy should be avoided and treatment alone with Temozolomide might be considered.
P11.08 Defining EGFR amplification status for clinical trial inclusion
Authors: French P , Eoli M , Sepulveda J , de Heer I , Kros J M , Walenkamp A , Frenel J , Franceschi E , Clement P , Weller M , Ansell P , Looman J , Bain E , Morfouace M , Gorlia T , van den Bent M 
Published: September 2019

Abstract

BACKGROUND
Precision medicine trials targeting the epidermal growth factor receptor (EGFR) in glioblastoma patients require selection for EGFR-amplified tumors. However, there is currently no golden standard in determining the amplification status of EGFR or EGFRvIII expression. Here, we aimed to determine which technique and which cut-offs are suitable to determine EGFR amplification status.

MATERIAL AND METHODS
We compared fluorescent in-situ hybridization (FISH) and RT-qPCR data from patients screened for trial inclusion into the Intellance 2 clinical trial, with data from a panel-based next generation sequencing (NGS) platform (both DNA and RNA).

RESULTS
By using data from >1000 samples, we show which cut-offs are optimal to determine EGFR gene amplification by FISH. Our data also show that gene amplification (as determined by FISH) correlates with EGFR expression levels (as determined by RT-qPCR) with ROC analysis showing an under the curve area of up to 0.902. EGFR expression as assessed by RT-qPCR therefore may function as a surrogate marker for EGFR amplification. Our NGS data shows that EGFR copy numbers can strongly vary between tumors with levels ranging from 2 to more than 100 copies per cell. Levels exceeding 5 gene copies can be used to define EGFR-amplification by NGS; below this level FISH detects very few (if any) EGFR amplified nuclei and none of the samples express EGFRvIII.

CONCLUSION
Our data from central laboratories and diagnostic sequencing facilities, using material from patients eligible for clinical trial inclusion, help defining the optimal cut-off for various techniques to determine EGFR amplification for diagnostic purposes.
P11.09 Pan-RTK inhibition of sLRIG1 mediates AXL downregulation in Glioblastoma
Authors: Neirinckx V , Hau A , Schuster A , Fritah S , Chevigné A , Schmidt M H H , Niclou S P 
Published: September 2019

Abstract

INTRODUCTION
Aberrant regulation of receptor tyrosine kinase (RTK) activity is characteristic of Glioblastoma (GBM). However, RTK-based targeted therapies have been largely unsuccessful in GBM patients, partially due to the complexity and redundance of RTK signaling. LRIG1 (Leucine-rich Repeats and ImmunoGlobulindomains protein 1) is known as an endogenous inhibitor of epidermal growth factor receptor (EGFR) during health and disease, however its mechanism of action is poorly understood. We previously showed that the soluble form of LRIG1 potently inhibits of GBM growth in vivo, irrespective of EGFR expression level and status, suggesting the involvement of other RTKs. Here, we aimed to shed light on the molecular mechanisms underlying its anti-cancer activity.

MATERIAL AND METHODS
We generated a recombinant human soluble LRIG1 protein by expressing LRIG1 ectodomain in insect cells via baculovirus infection and subsequent His-tag purification. rh-sLRIG1 was applied in the medium of classical GBM cell lines, patient-derived GBM stem-like cells and patient-derived 3D tumor organoids. Using different cell-based assays, cell proliferation, invasion, cell morphology, as well as protein expression and protein-protein interactions were investigated.

RESULTS
We find that recombinant sLRIG1 efficiently reduces proliferation, invasion and viability of GBM cells and patient-derived organoids, and modulates cytoskeleton proteins and cell shape. In line with previous data, the effect of recombinant sLRIG1 is independent of EGFR expression. Interestingly sLRIG1 regulates several RTKs by direct protein downregulation, including AXL, while EGFR expression is not affected. At the molecular level, we find that sLRIG1 interferes with AXL dimerization, while no protein interaction with EGFR is detected.

CONCLUSION
We identify AXL as a novel LRIG1 target and provide evidence that sLRIG1-mediated RTK downregulation requires direct protein-protein interaction. These data pave the way for a potential therapeutic application of recombinant sLRIG1 in the inhibition of growth factor signaling in GBM.
P11.12 Periostin is expressed by pericytes and is crucial for angiogenesis in glioma
Authors: Huizer K , Kros J M , Zhu C , Chirifi I , Krist B , Cheng C , Mustafa D 
Published: September 2019

Abstract

BACKGROUND
The expression of the matricellular protein periostin has recently been associated with glioma progression and angiogenesis. The aim of the present study was to identify the cellular source of periostin expression in human gliomas and to study the role of periostin in an in vitro model for angiogenesis.

MATERIAL AND METHODS
The expression of periostin in various types and grades of brain tumors was investigated at the genetics level by RT-PCR and at the protein level by immunohistochemistry. In addition, the expression of periostin in glioma samples was studied by double labeling and in situ RNA techniques. Subsequently, by silencing periostin in a 3D in vitro angiogenesis model, its effects on angiogenesis were studied.

RESULTS
Periostin RNA and protein expression was found to be elevated in pilocytic astrocytoma and glioblastoma, but not in grade II/III astrocytomas. The expression of periostin co-localized with PDGFRβ + cells, but not with Olig2+ / Sox2+ glioma stem cells. Silencing of periostin in pericytes resulted in the attenuation of the number and the length of the vessels, and in decrease in the number of vessel junctions formed.

CONCLUSION
The results prove that pericytes are the main source of periostin in human gliomas. We demonstrate that periostin plays an essential role in the growth and branching of blood vessels. Therefore, periostin and / or its molecular interactions should be explored as a novel target for developing a new anti-angiogenic therapy for glioma.
P11.14 The addition of hyperbaric oxygen to the treatment of T98G glioblastoma cell cultures with selected CK2 inhibitor TDB enhances its anti-tumour effect
Authors: Pucko E , Ostrowski R , Zielinska M , Matyja E 
Published: September 2019

Abstract

BACKGROUND
Glioblastoma (GBM) is the most aggressive glial neoplasm characterized by infiltrative cell growth in adults. The current standard of care for high-grade glioma patients includes surgery, radiotherapy and chemotherapy using temozolomide and other alkylating agents. Despite this, median survival of the patients with GBM is less than two years. One of the main factors related to the progression of neoplastic cells is hyperactivity of protein kinases, including CK2 kinase and a high level of tumor hypoxia, both of which also contribute to tumour resistance to treatment. Our previous study indicated that some CK2 inhibitors exhibit anti-proliferative effect on glioma cells. The aim of this study was to examine whether HBO may enhance the anti-tumour efficacy of 1-(β-D-2’-deoxyribofuranosyl)-4,5,6,7-tetrabromo-1H-benzimidazole (TDB) - CK2 inhibitor, under combination HBO/TDB therapy.

MATERIAL AND METHODS
Studies were performed on human glioblastoma T98G cell line (ATCC). Cells were cultured in MEM medium supplemented with 1-(β-D-2’-deoxyribofuranosyl)-4,5,6,7-tetrabromo-1H-benzimidazole in concentrations of 0.1 μM; 1 μM, 25 μM, 50 μM, 75μM, 100 μM. Cultures were sustained in various oxygen conditions: normoxia for 24 and 48 hours or1 hour of hyperbaric oxygen (HBO, 97,5% O2/2,5% CO2, pressure of 2 ATA) followed by 23 hours of normoxia (21% O2/5% CO2/78% N2). Control groups included the cultures sustained in normoxia conditions. The viability of glioma cell lines was established at 24 and 48 hours post TDB treatment by Cell Titer 96®A Queous One Solution Cell Proliferation Assay.

RESULTS
The study evidenced that TDB inhibited the viability of neoplastic cells at a concentration of 75 μM after 24 and 48 hours. Administration of hyperbaric oxygen alone also caused a reduction in viability of glioblastoma cells. The cytotoxic effect of the tested CK2 inhibitor was significantly enhanced when tested compound was combined with HBO. What’s more, under the influence of hyperbaric oxygen, TDB significantly reduced the viability of tumor cells already at a concentration of 25 μM after 24 hours.

CONCLUSIONS
Hyperbaric oxygen administration significantly reduces the viability of T98G line cells and increases their sensitivity to the tested CK2 kinase inhibitor. The beneficial cytotoxic effect of TDB/HBO can be obtained at lower concentrations of the tested compound and after shorter exposure time as compared to its administration without HBO. Acknowledgement: The research was supported by the Foundation for the Development of Diagnostic and Therapy, Warsaw
P11.20 Assessing TTFields-response and associated gene expression in various human cancer cell lines
Authors: Kinzel A , Lavy-Shahaf G , Giladi M , Schneiderman R , Gotlib K , Zeevi E , Porat Y , Munster M , Weinberg U , Kirson E , Palti Y 
Published: September 2019

Abstract

BACKGROUND
Various cancer cell lines were reported to be affected in an inhibitory manner of varying magnitude by tumor treating fields (TTFields). Here, we aimed to detect response markers for TTFields treatment by analyzing specific properties of cell lines according to their response pattern to these alternating electric fields of intermediate frequency and low intensity.

MATERIAL AND METHODS
We treated 45 cell lines of diverse types of human cancer with TTFields at their specific optimal frequency and equal nominal intensity of 1.7 V/cm for 72 h. In addition to investigating cytotoxicity and clonogenic potential, we used the Cancer Cell Line Encyclopedia (CCLE) database for further analysis: First, to functionally examine patterns of differentially expressed genes or mutations associated with response to TTFields; and second, to compare sensitivity to TTFields using pharmacological profiling (CCLE).

RESULTS
TTFields had a cytotoxic effect on tested cell lines of 50 % on average (range: 14–86% reduced cell counts), whereas the clonogenic effect varied between no effect and 88 % reduction in the number of colonies. With regard to differential gene expression and mutation analysis, our analysis detected upregulated pathways associated with migration, DNA damage repair response, oxidative stress, and hypoxia. Further, cells identified as having a better response to TTFields were also more sensitive to lapatinib, PHA-665752 and PLX-4720.

CONCLUSION
In this study, we determined the optimal frequency for maximum response to TTFields in numerous human cancer cell lines. Our results argue strongly for a vast effectiveness of TTFields treatment in cancer cells, and synergistic effects in combination with other therapeutic agents might be revealed in future studies using pharmacological profiling. Beyond that, further research is needed on the role of identified response-associated mutations.
P11.34 Bone Morphogenetic Protein 4 can sensitize glioblastoma cells to temozolomide
Authors: Verploegh I , Conidi A , Lamfers M , Dirven C , Leenstra S , Huylebroeck D 
Published: September 2019

Abstract

BACKGROUND
Glioblastoma (GBM) is the most prevalent and lethal primary brain tumor. Its recurrence and resistance to current therapies, i.e. temozolomide (TMZ), is thought to result from a subpopulation of cells exhibiting stem cell properties, called glioblastoma stem-like cells (GSCs). Bone Morphogenetic Protein 4 (BMP4) induces GSCs differentiation, leading to a less resistant phenotype. In this study we show that co-treatment of BMP4 with TMZ has therapeutic benefit in a subset of GBM cell lines. Furthermore, we looked for patients’ molecular signatures that could predict sensitivity to this combination treatment.

MATERIAL AND METHODS
A panel of 17 primary GBM cultures (passages 5–10) were treated with increasing concentrations of TMZ, BMP4 and TMZ + BMP4 for 5 and 7 days and cell viability has been measured. The Combination Index (CI) of the two drugs was calculated to assess the response of each line to TMZ and BMP4 treatment. DNA was used to determine the MGMT promotor methylation status and for targeted exome sequencing. Expression levels of BMP signaling components and differentiation associated genes were determined by qPCR.

RESULTS
12 cultures of primary GBMs and 5 cultures of recurrent GBMs were included. Overall, 71% of the tested cell lines was resistant to TMZ, while 41% was resistant to BMP4. Strikingly, 53% of primary cultures show synergy between TMZ and BMP4 (CI < 1 at a Fraction Affected of 50% (Fa50)). There was no significant difference in synergy between five or seven days of treatment. However, combination treatment of BMP4 and TMZ was more effective than sequential treatment.

CONCLUSION
Co-treatment of BMP4 and TMZ could be of therapeutic benefit in GBM patients, irrespective of their sensitivity to TMZ. Further research regarding the mechanism behind this synergy is necessary as to identify predictive markers for treatment response.