bluuebunny/crossref_metadata_2025_split huggingface dataset:
OS09.7.A Quality of life outcomes in patients with incidental and operated meningiomas: the QUALMS study
Authors: Keshwara S M , Islim A I , Millward C P , Gillespie C S , Richardson G E , Mustafa M A , George A M , Mills S J , Brodbelt A R , Jenkinson M D 
Published: September 2021

Abstract

BACKGROUND
Long-term Health-Related Quality of Life (HRQoL) is an important measure of patient wellbeing. There is a paucity of studies evaluating HRQoL in meningioma patients.

MATERIAL AND METHODS
Cross-sectional study of adult patients with an incidental or symptomatic intracranial meningioma. Patients with less than 5 years of follow-up, a history of craniospinal radiation or neurofibromatosis type 2 were excluded. HRQoL was evaluated with SF-36, EORTC QLQ-C30 and EORTC QLQ-BN20 questionnaires. Outcome determinants were evaluated using a multi-variable linear regression analysis, adjusted for patient, tumour and treatment characteristics, and duration of follow-up.

RESULTS
699 patients were invited to participate and 246 responded: 118 (48%) had an incidental meningioma. Mean age at diagnosis was 56.8 years (SD=13) and 81% were female. Median time from diagnosis to completion of questionnaire was 8.5 years (IQR 6.8–11.5). During follow-up, 158 patients (64.2%) had at least one operation for their meningioma and 47 patients (19.1%) had radiotherapy. Of those operated, 126 (79.7%) had WHO grade 1 and 24 (15.2%) had grade 2 meningiomas. Compared to normative population values, meningioma patients reported a worse SF-36 general health score (mean 61.9 vs 56.5, P=0.003) but a similar QLQ-C30 global health score (mean 62.3 vs 65.8, P=0.039), worse SF-36 and QLQ-C30 physical functioning scores (mean 74.1 vs 64.6, P&lt;0.001 and mean 81.8 vs 76.5, P=0.007) and similar SF-36 and QLQ-C30 emotional health scores (mean 72.2 vs 70.9, P=0.367 and mean 71.0 vs 71.9, P=0.960). QLQ-C30 cognitive functioning was worse (mean 80.5 vs 71.4, P&lt;0.001). Compared to the meningioma literature, QLQ-BN20 seizure burden was similar (mean 2.0 vs 1.6, P=0.760). A worse performance status at diagnosis was associated with an inferior QLQ-C30 global health score (β-coefficient=-4.9 [95% CI -9.1-(-)0.6] P=0.024). Number of surgeries was significantly associated with a worse QLQ-C30 cognitive functioning score (β-coefficient=-7.0 [95% CI -13.2-(-)0.9], P=0.025). Anti-epileptic drug use was associated with a significantly worse QLQ-C30 emotional health score (β-coefficient=-10.9 [95% CI -21.7-(-)0.01], P=0.050).

CONCLUSION
Meningioma patients have long-term HRQoL impairments affecting their physical and cognitive functions. An understanding that multiple surgeries affects cognitive function, and the need for anti-epileptic drugs equate to poorer emotional health, could help target appropriate therapies and support in the future.
P04.09 Frequent inactivating mutations of PBRM1 in meningioma with papillary features
Authors: Williams E , Brastianos P , Santagata S , Cahill D , Ramkissoon S , Juratli T 
Published: September 2021

Abstract

BACKGROUND
Papillary meningiomas (PM) are rare WHO grade III tumors that are associated with frequent recurrences and metastatic disease in spite of surgery and radiation. Due to their low incidence and scarcity of tumor tissues available for genomic analyses, the genetic alterations associated with PM remain unclear.

MATERIAL AND METHODS
We mined data collected as part of our clinical comprehensive genomic profiling (CGP) initiative which has to date analyzed 8 PM (&gt;50% papillary morphology) and 22 meningiomas with focal papillary features (10–50%) amongst over 500 additional meningiomas of other subtypes. The samples were analyzed in a CAP/CLIA-accredited laboratory (Foundation Medicine, Cambridge, MA). GCP was performed on hybridization-captured, adaptor ligation-based libraries to a mean coverage depth of &gt;650x for 236 or 315 genes plus the introns from 19 or 28 genes frequently involved in cancer.

RESULTS
In our cohort of 8 PMs, we identified three cases with inactivation of PBRM1; two cases with a truncating mutation in PBRM1 and one with homozygous deletion of PBRM1. Of the 22 meningiomas with only focal papillary features, 8 cases were PBRM1-mutant. Thus, 11 of 30 cases (36.7%) with at least focal (&gt;10%) papillary morphology had inactivation of PBRM1.In the entire cohort of 562 meningiomas, we identified five additional cases with inactivating alterations in PBRM1 that did not display overt papillary morphology in the H&E sections available for analysis. Thus, 11 of 16 PBRM1-mutant cases (69%) occurred in meningioma with papillary histologic features as opposed to 19 of 546 wild-type cases (3.5%), supporting a significant association between papillary features and PBRM1 mutation (p&lt;0.0001). The majority of PBRM1-mutant meningiomas occurred in female patients (n=10/16, 62.5%), and median age was 51 years. Most cases were located supratentorially (n=10).

CONCLUSION
We identified the tumor suppressor gene PBRM1 as a recurrently altered gene in meningiomas with papillary histomorphology. Further investigational studies are needed to assess outcomes of PBRM1-mutant meningioma and to determine whether mutation is an independent negative prognostic biomarker.
P04.20 The role of YAP in Glioblastoma cell lines
Authors: Casati G , Giunti L , Iorio A , Marturano A , Sardi I 
Published: September 2021

Abstract

BACKGROUND
Glioblastoma (GBM) is a primary human malignant brain tumor, the most common in adults. Several studies have highlighted the Hippo-pathway as a cancer signalling network. The Hippo pathway is an evolutionarily conserved signal cascade, which is involved in the control of organ growth. Dysregulations among this pathway have been found in lung, ovarian, liver and colorectal cancer. The key downstream effector of the Hippo-pathway is the Yes-associated protein (YAP); in the nucleus, its function as transcription co-activator is to interact with transcription factors, resulting in the expression of target genes involved in pro-proliferating and anti-apoptotic programs.

MATERIAL AND METHODS
Using western blotting analysis, we determined the nuclear expression of YAP on three GBM cell lines (U87MG, T98G and A172). To investigate which inhibitors against the Hippo-pathway were the most efficient, we performed a cytotoxic assay: we treated all the three cell lines with different inhibitors such as Verteporfin (VP), Cytochalasin D (CIT), Latrunculin A (LAT), Dobutamine (DOB) and Y27632. Afterwards, we performed a treatment using Doxorubicin (DOX) combined with the inhibitors, evaluating its cytotoxic effect on our cell lines, through cell viability experiments. More western blotting experiments were performed to investigate the oncogenic role of YAP at nucleus level. Furthermore, preliminary experiments have been conducted in order to investigate the apoptosis, senescence and autophagy modulation due to the Hippo-pathway.

RESULTS
We showed our cell lines express nuclear YAP. We assessed the efficiency of the main inhibitors against Hippo-pathway, proving that VP, LAT A and CIT show a strong cytostatic effect, linked to time increase; plus we saw a cytotoxic effect on T98G. The association of DOX with selected inhibitors is able to reduce cell viability and nuclear YAP expression rate in all three GBM lines. Finally, preliminary experiments were set up to assess how and if the mechanisms of apoptosis, autophagy and senescence were affected by the Hippo-pathway. The combination of DOX with inhibitors promotes resistance to apoptosis.

CONCLUSION
Our results show that nuclear YAP is present in all tumor lines, thus confirming that this molecular pathway is functioning in GBM lines. Nuclear YAP is more highly expressed after DOX administration. Moreover, the combined treatment (DOX with Hippo-pathway inhibitors) reduces both cell proliferation and viability, and increases the rate of apoptosis. Preliminary experiments on senescence and autophagy were used to determine the best Hippo-pathway inhibitor. These data demonstrate that the Hippo-pathway plays a crucial role in GBM proliferation and resistance to apoptosis. Inhibiting this pathway and in particular the transcription factor YAP, in association with DOX, might be an excellent therapeutic target.
P11.02 Long-term impact of primary brain tumour diagnosis on health-related quality of life: a systematic review
Authors: Frances S , Velikova G , Klein M , Short S , Murray L , Wright J , Boele F 
Published: September 2021

Abstract

BACKGROUND
A primary brain tumour (PrBT) diagnosis can be devastating, and results in a wide range of symptoms. Relatively little is known about the long-term challenges these symptoms pose on HRQOL. The aim of this review is to identify the long-term HRQOL issues reported at least two years following diagnosis of a PrBT.

MATERIAL AND METHODS
Systematic literature searches were carried out using Medline, EMBASE, CINAHL, PsycINFO and Web of Science Core Collection. Searches were designed to identify a range of reported HRQOL aspects defined as physical, mental or social issues, in adult WHO grade II or III patients. To capture the full extent of patients’ experience, studies of any design reporting on primary data where patients had at least two years follow-up from diagnosis were included. WHO grade I and grade IV tumours were excluded due to their different prognoses and the expected nature of their disease trajectories. Quality assessment was conducted using the Mixed Methods Appraisal Tool (MMAT). Narrative synthesis was used to collate findings.

RESULTS
The search returned 8438 articles. 477 titles remained after title and abstract screening, with eighteen full text articles included in the final analysis. The majority of studies used quantitative methods, with only two articles reporting qualitative or mixed methodology. Articles were predominantly cross-sectional studies (n = 10), along with cohort studies (n = 3), clinical trials (n = 3) and pilot studies (n = 2). Results indicated that patients reported a variety of issues influencing their HRQOL, with emotional/psychological/cognitive changes being the most commonly reported. Physical complaints included problems with fatigue, seizures and maintaining daily activity. Social challenges included strained social relationships and issues managing finances. Patient coping strategies were found to significantly influence wellbeing and subsequent HRQOL.

CONCLUSION
PrBT patients’ long-term HRQOL and daily functioning can be impacted by their physical, mental and social wellbeing. Findings from this review lay the groundwork for efforts to improve patient HRQOL in long-term survivorship.
P12.01 The effectiveness of antiepileptic drug treatment in glioma patients: lamotrigine versus lacosamide
Authors: van Opijnen M P , van der Meer P B , Dirven L , Fiocco M , Kouwenhoven M C M , van den Bent M J , Taphoorn M J B , Koekkoek J A F 
Published: September 2021

Abstract

BACKGROUND
Optimal treatment with antiepileptic drugs (AEDs) is an important part of care for brain tumor patients with epileptic seizures. Lamotrigine and lacosamide are both examples of frequently used non-enzyme inducing AEDs with limited to no drug-drug interactions, reducing the risk of unfavorable side effects. This study aimed to compare the effectiveness of lamotrigine versus lacosamide.

MATERIAL AND METHODS
In this multicenter study we retrospectively analyzed data of patients with diffuse grade 2–4 glioma with epileptic seizures. All patients received either lamotrigine or lacosamide during the course of their disease after treatment failure of first-line monotherapy with levetiracetam or valproic acid. Primary outcome was the cumulative incidence of treatment failure, from initiation of lamotrigine or lacosamide, with death as competing event, for which a competing risk model was used. Secondary outcomes were uncontrolled seizures after AED initiation and level of toxicity.

RESULTS
We included a total of 139 patients of whom 61 (44%) used lamotrigine and 78 (56%) used lacosamide. At 12 months, there was no statistically significant difference in the cumulative incidence of treatment failure for any reason between lamotrigine and lacosamide: 38% (95%CI: 26–51%) versus 30% (95%CI: 20–41%), respectively. The adjusted hazard ratio for treatment failure of lacosamide compared to lamotrigine was 0.84 (95%CI: 0.46–1.56). The cumulative incidences of treatment failure due to uncontrolled seizures (18% versus 11%) and due to adverse events (17% versus 19%) did not differ significantly between lamotrigine and lacosamide.

CONCLUSION
Lamotrigine and lacosamide show similar effectiveness in diffuse glioma patients with epilepsy.
P12.09 Clinical features and management of normal pressure hydrocephalus associated with non-obstructive vestibular schwannoma
Authors: Redaelli V , Gaviani P , Simonetti G , Botturi A G , Marchetti M , Broggi M A , Silvani A 
Published: September 2021

Abstract

BACKGROUND
Some (elderly) patients present a communicating (normal pressure) hydrocephalus (NPH) in association with or secondary to vestibular schwannoma (VS). We aim to investigate the usefulness ventriculo-peritoneal shunt (VPS) without tumor removal.

MATERIALS AND METHODS
8 patients aged from 50 to 78 years received both diagnosis of VS (mean maximum diameter 21 mm, range 13–28 mm) and NPH. None presented the classical Hakim’s triad. They presented isolated ataxia with gait impairment and loss of equilibrium. It was hard to distinguish if these symptoms were due to NPH or to VIII cranial nerve compression. They underwent TAP test, through a lumbar puncture with a very slow whithdrawal of at least 30 ml of cerebrospinal fluid (CSF).

RESULTS
None of the 8 patients presented improvement after lumbar puncture. Despite this, we decided to proceed with VPS in 4 patients because of a high risk of falls.... All these 4 patients showed clinical improvement after VPS.. The VS were treated as follows: 4 surgery, 2 radiosurgery, 2 observation.

CONCLUSIONS
Although some authors indicate VS removal as the best option to improve also NPH symptoms, some patients present high risk of falls in the presence of a small VS. These clinical features are more likely to be relayed related to NPH instead of VS.. VPS carries lower postoperative risks compared to VS removal. For this reason, VPS has to be considered, even without a positive response to a TAP test, as a good alternative to improve quality of life in patient affected by NPH associated with VS.
P13.01 Neuronal activity drives distinct invasion modes of glioma cells
Authors: Yang Y , Venkataramani V , Schubert M , Beretta C , Botz M , Fankhauser L , Wick W , Kuner T , Winkler F 
Published: September 2021

Abstract

BACKGROUND
Gliomas are incurable brain tumors characterized by their infiltrative growth which makes them a whole-brain disease. Previously we described membrane protrusions called tumor microtubes (TMs), and glutamatergic synapses between neurons and glioma cells, as mechanisms contributing to glioma cell invasion and tumor progression. However, the interrelation of the two, and the exact mechanisms of glioma cell dynamics over time was unknown. Therefore, we investigate neuronal synaptic input on TM-associated glioma cell motility.

MATERIAL AND METHODS
Here we established a novel workflow for analyzing single glioma cell dynamics over several hours with in-vivo two-photon microscopy. First, a membranous fluorescent marking of patient-derived glioma cells was established to reliably track membrane changes. Secondly, augmented microscopy based on deep- and machine-learning algorithms was used to track glioma cells. Neuronal activity was manipulated with different doses of isoflurane anesthesia, and used to study its effects on glioma cell dynamics.

RESULTS
This novel method revealed that motility of glioma cells can be described by the displacement of whole glioma cell somata (somatokinesis) and TM dynamics. TM motility in turn could be sub-categorized into protrusion, retraction and branching. Next, we describe three different invasion modes, all with similarities to different cell types involved in CNS development. Lastly, the effects of neuronal activity on glioma cell invasion were investigated. With the application of high anesthesia and subsequently reduced neuronal activity, TM turnover, branching events and as a result glioma cell invasion were inhibited, but in a heterogeneous manner.

CONCLUSION
The novel workflow allowed to comprehensively characterize glioma cell invasion over several hours. Its application demonstrates novel, hitherto unknown cellular mechanisms of glioma cell invasion, and provides a link between TM biology and neuron-glioma communication. Finally, neuronal input drives distinct subtypes of glioma cell motility patterns.All in all, this work presents an important first step in understanding mechanisms that lead to the whole- brain colonization of glioma cells making these brain tumors incurable. A further characterization of the exact molecular mechanisms that drive neuronal activity-dependent glioma cell motility is warranted.
P13.10 Chemoattraction of glioma cells in a local hydrogel trap and immune control associated with improved survival and cognitive functions in a mouse model of glioblastoma resection
Authors: Castel H , Laillet De Montulle E , Dubois M , Ferracci F , Mutel A , Dembele K , Desrues L , Derrey S , Langlois O , Chever O , Gandolfo P , Morin F 
Published: September 2021

Abstract

BACKGROUND
Glioblastoma (GB) is the most aggressive brain primary tumor. The prognosis remains poor mainly due to the invasiveness of glioma cells, radio and/or chemoresistance and GB-induced immunosuppressive environment. Here, we propose to use a local delivery system based on a biocompatible hydrogel containing the chemopeptide urotensin II (hUII) or a biased synthetic analog DAB8-hUII, to “trap” GB cells, and/or to control immune cells expressing its G protein-coupled receptor UT, leading to tumor regression and neurological benefit, in a mouse model of GB resection.

MATERIAL AND METHODS
In vitro, invasion towards UII/analog across different hydrogels or glue of human or murine GB-GFP cell lines was evaluated in Boyden chamber and cloning ring assays. In vivo GB cells were intrastriatally xenografted, then resected while hydrogel- or glue-containing UII/analog was injected in the cavity resection. Behavioral tests, brain immunohistochemical analyses and mouse survival were then investigated.

RESULTS
In vitro, invasive capacity of human U87 and 42MG or murine GL261 and CT2A GB cells was stimulated by UII loaded into hydrogel-based hyaluronic acid supplemented with collagen or other chemicals, PNIPAAm-PEG, or thrombin-fibrin glue. In vivo, injection of UII- or DAB8-hUII-loaded glue into the cavity resection of GL261 and CT2A GB in C57BL/6 mice significantly improved survival compared with tumor and resected experimental conditions. Neurological status was also tested before and after GB resection. We found that GL261 and CT2A cell-bearing mice expressed altered spontaneous activity, emotion and cognitive functions. Intracavity injection of the glue improved resignation and anxiety and increased motor activity and cognition with a best cognitive recovery with hUII and DAB-8-hUII-loaded glue groups. Ex vivo brain analyses revealed high expression of UT and UII in some GB GFP-positive cells and macrophages within GB core and at the interface with the normal brain, GB cells expressing UT migrating along tortuous podocalyxin+ vascular components. In brains bearing hydrogel/hUII glue, vascularization appears modified and GFAP+ astrocytes and F4/80+ macrophages were highly recruited in the border of the cavity, compared with the other conditions.

CONCLUSION
A local glue containing UII may trap GB cells and remodel the tumor microenvironment responsible for survival and cognitive improvements, providing new option in the therapeutic arsenal of GB.
P13.21 PET-based dose painting radiation therapy strategy in a glioblastoma rat model using the small animal radiation research platform
Authors: Donche S , Verhoeven J , Bouckaert C , Descamps B , Raedt R , Vanhove C , Goethals I 
Published: September 2021

Abstract

BACKGROUND
Previously, a rat glioblastoma model to mimic chemo-radiation treatment of human glioblastoma in the clinic was established. Similarly to the clinic, CT and MRI were combined during the treatment planning process. PET imaging was subsequently added which allowed us to implement sub-volume boosting using a micro-irradiation system. However, combining three imaging modalities (CT, MRI and PET) using a micro-irradiation system, proved to be labour intensive because multimodal imaging, treatment planning and dose delivery have to be completed sequentially in the preclinical setting.

MATERIAL AND METHODS
Two different methodologies were compared in silico for performing preclinical [18F]FET PET based radiation therapy (20 Gy based on MRI, 8 Gy boost based on PET) based on three different cases. Method 1 is based on the previously published methods1,2. However, the process is automated using an in-house developed MATLAB code. Method 2 consists of a more sophisticated method where a series of isocenters and jaw dimensions for the motorised variable collimator were determined based on the [18F]FET PET uptake. Both methods were evaluated by means of the dose volume histograms (DVH) and Q-volume histograms.

RESULTS
The setup parameters for both methods were calculated. The DVHs for method 2 are systematically closer to the ideal dose distribution compared to method 1. These findings are confirmed by the D90 and D50 values which are considerably lower for method 1. When observing the Q-factor, method 2 always results in dose distributions that are closer to the dose objectives (method 1: 0.141±0.046; method 2: 0.064±0.011).

CONCLUSION
The described novel method to optimize the preclinical treatment planning process has many advantages in terms of dose delivery, time efficiency and variability, when compared to the previously used methods1,2. These improvements are important to narrow the gap between clinical and preclinical radiation research and for the development of new therapeutics and/or radiation therapy procedures for glioblastoma.
1. Bolcaen, J., Descamps, B., Boterberg, T., Vanhove, C. & Goethals, I. PET and MRI Guided Irradiation of a Glioblastoma Rat Model Using a Micro-irradiator. J. Vis. Exp. 1–10 (2017) doi:10.3791/56601.
2. Verhoeven, J. et al. Technical feasibility of [18F]FET and [18F]FAZA PET guided radiotherapy in a F98 glioblastoma rat model. Radiat. Oncol. 14, (2019).