bluuebunny/crossref_metadata_2025 huggingface dataset:
P04.20 The role of YAP in Glioblastoma cell lines
Authors: Casati G , Giunti L , Iorio A , Marturano A , Sardi I
Published: September 2021

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

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

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

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

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

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.
P13.11 Transcriptional CDK inhibitors, CYC065 and THZ1 promote apoptosis in preclinical models of primary and recurrent GBM tumour cells and glioma stem cells
Authors: Juric V , Duessmann H , Jahns H , Verreault M , Idbaih A , Lamfers M L , Hopkins A M , Prehn J H , Rehm M , Murphy B M
Published: September 2021

BACKGROUND

Activation of cyclin-dependent kinases (CDKs) contributes to the uncontrolled proliferation of tumour cells. Genomic alterations that lead to the constitutive activation of CDKs are a feature of many tumours including glioblastoma (GBM), the most common and aggressive primary brain tumour. Patient resistance to the current standard of care, temozolomide and radiotherapy, is common and highlights the need to discover more effective treatment strategies. Additionally, glioma stem cells (GSCs), tumour initiating cells contribute to treatment resistance in GBM. Targeting GBM tumour cells and GSCs using transcriptional CDK inhibitors, CYC065 and THZ1 is a potential novel treatment to prevent relapse of the tumour.

MATERIAL AND METHODS

The therapeutic efficacy of two CDK inhibitors (CKIs) was tested in a panel of ten low-passage GBM patient-derived gliomasphere cultures and semi-in vivo chick embryo xenograft models. Specifically, transcriptional inhibitors targeting CDK9/2 (CYC065) and CDK7 (THZ1) were used. Mechanism of cell death was examined following CKI treatment. Additionally, dependence on anti-apoptotic proteins was studied using genetic depletion and BH3 profiling. Fluorescence activated cell sorting (FACS) and light-sheet fluorescence microscopy (LSFM) were employed to study stem cell populations in recurrent GBM and evaluation of CKI efficacy against GSCs.

RESULTS

We here demonstrate that CYC065 and THZ1 treatments cause loss of cell viability and induce caspase-dependent apoptosis in primary and recurrent patient-derived gliomaspheres while sparing primary cortical neurons. Importantly, apoptosis responses manifested across a range of time points that significantly correlated with the cell doubling time. Mechanistically, CYC065 and THZ1 downregulate the anti-apoptotic protein Mcl-1, which suffices to sensitise gliomasphere cultures to treatment-induced apoptosis in a Bim-dependent manner. Additionally, high expression levels of chemo- and radio-resistant GSCs were found in recurrent gliomaspheres. CKIs induced apoptosis in isolated CD133 and CD44 biomarker-positive cells while TMZ was ineffective, highlighting the potential of these drugs to overcome resistance to conventional chemotherapy. Additionally, using LSFM we shown that CD133, CD44 GSC biomarker-negative cells convert into GSC biomarker-positive cells and contribute to the enrichment in GSCs in recurrent GBM which could potentially explain the TMZ ineffectiveness. Finally, CKIs reduced proliferation and promoted apoptosis in chick embryo xenograft models of primary and recurrent GBM.

CONCLUSION

Collectively, these data demonstrate that CYC065 and THZ1 display high anti-cancer activity in primary and recurrent GBM and provide scientific rationale for the further development of CDK inhibitors to potentiate their clinical utilization in the future.
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

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).
P14.03 Shifting trends and entity-specific aspects in patients with brain metastasis: real-life analysis from 6031 individuals over an observation period of 30 years
Authors: Steindl A , Brunner T J , Heimbach K , Schweighart K , Moser G M , Niziolek H M , Moor E , Kreminger J , Starzer A M , Dieckmann K , Gatterbauer B , Widhalm G , Preusser M , Berghoff A S
Published: September 2021

BACKGROUND

We aimed to investigate the changing clinical characteristics of patients with brain metastases (BM) over the last three decades as the foundation for modern BM specific clinical trial planning.

MATERIAL AND METHODS

6031 patients with newly diagnosed BM from different solid tumors treated between 1986–2020 were identified from the Vienna Brain Metastasis Registry.

RESULTS

The fraction of BM originating from the most common BM causing primary tumors (lung cancer, breast cancer and melanoma) was stable over the observation period from 1986–2020. BM from renal cell carcinoma, colorectal cancer and cancer of unknown primary (CUP) decreased over time (p<0.001). Synchronous diagnosis of BM and primary tumor was more frequently observed in lung cancer and CUP patients compared to breast cancer patients (p<0.001). An increasing fraction of patients presented with asymptomatic BM (1986–1999: 20.2% vs. 2010–2020: 30.4%; p<0.001), specifically in lung cancer (p<0.001), melanoma (p<0.001) and renal cell cancer (p=0.004). A decrease of neurosurgical procedures (1986–1999: 39.3% vs. 2010–2020: 20.4%) and an increase of radiation treatments (1986–1999: 56.5% vs. 2010–2020: 73.0%) and systemic therapies (1986–1999: 0.6% vs. 2010–2020: 2.4%; p<0.001) was observed. Furthermore, median overall survival significantly increased across entities (1986–1999: 5 months vs. 2010–2020: 7 months; p=0.001). Intracranial progression as the cause of death increased across entities (p< 0.001). The prognostic DS-GPA (Hazard ratio [HR] 1.42; p< 0.001) and the Lung-molGPA (HR 1.67; p<0.001) could be validated.

CONCLUSION

We observed changes of BM presentation and clinical parameters during the observation period depending on primary tumor origins. Future BM studies should follow an entity-specific approach and address the characteristics of modern BM cohorts.
P14.18 Patient and Public Involvement to define patient-centred outcomes from National Cancer Datasets
Authors: Pakzad-Shahabi L , Cherrington C , Brassil N , Even P , Gardner D , Fulcher W , Le Calvez K , Mauricaite R , Williams M
Published: September 2021

BACKGROUND

GlioCova uses linked national cancer data on all 51 000 adult patients with a primary brain tumour in England (2013 - 2018) to understand patterns of care, treatment, and outcomes in patients with glioma (http://wwwf.imperial.ac.uk/blog/gliocova/). A key aim is the use of patient and carer input in defining patient-centered outcomes. We have held multiple Patient & Public Involvement (PPI) sessions with patients and carergivers and data analysts to understand what patient and caregivers want to know about brain tumours.

MATERIAL AND METHOD

We used a modified Delphi method. The online PPI sessions (Zoom) consisted of two presentations, open discussions, and Q&As. We made the sessions as interactive as possible by using Mentimeter and an interactive online white board (Explain Everything). Pre-reading material was circulated via email. Attendees (6–14 per session) covered a wide range of ages (30–75), diagnoses (GBM, recurrent gliomas, low grade gliomas, ependymoma); patients, caregivers, neuro-oncology staff, data analysts and basic scientists. Work was conducted in line with the INVOLVE PPI guidance.

RESULTS

We identified four questions that were of interest to patients and had correlates in the data:

Patients and caregivers were also interested in the impact of diet, quality of life, social life, and exercise. However, these data cannot be answered using the current national data.

CONCLUSION

Our PPI work has helped us to identify and prioritise questions to ask of the data. Ongoing PPI work will provide a wider perspective and identify knowledge gaps for future research. Patients and caregivers report feeling empowered, being part of a team, feeling like they had given something back and done something meaningful for the research community and other patients. Patients and caregivers also felt that they had an enriched understanding of the data that is collected. As this process is an iterative process, we will hold more PPI sessions to identify and prioritise topics to analyse.
P14.23 Relation between neurological deficits and location of postsurgical ischemia in glioma resection
Authors: van der Boog A T J , David S , Steennis A M M , Dankbaar J W , Snijders T J , Verhoeff J J C , Robe P A
Published: September 2021

BACKGROUND

Postoperative ischemia is a known complications of glioma resection and can lead to neurological deficits. New or worsened postoperative deficits are often transient, but some patients experience persisting effects after surgery. Neuroanatomical location of ischemia is suspected to play an important role in the development as well as persistence of neurological deficits. Therefore, the aim of this study was to investigate the spatial relation between postoperative ischemia and short-term and long-term neurological deficits.

MATERIAL AND METHODS

Postoperative ischemia was defined as new confluent areas of diffusion restriction on DWI in a retrospective database of 144 adult WHO grade II-IV supratentorial glioma patients, who received MRI within 3 days after resection in 2012–2014. New or worsened neurological deficits of any grade at discharge and after 3 months was assessed in relation to postoperative ischemia by an experienced neuro-oncologist. We manually delineated ischemic lesions and spatially normalized these to stereotaxic MNI space. Next, we performed voxel-based analysis (VBA) to identify locations of ischemia associated with new or worsened neurological deficits and corrected for multiple comparisons using family-wise error correction to eliminate false positive results. Delineations were labeled using the Harvard-Oxford cortical and subcortical atlases and a white matter atlas (XTRACT).

RESULTS

Any new or worsened neurological deficits were present in 44 (30.5%) cases at discharge and in 27 (20.9%) cases after 3 months, of which respectively 26 (18%) and 21 (16.3%) were related to ischemia. Volume of ischemia was significantly associated with deficits at discharge (P = 0.003) and after 3 months (P = 0.039). No areas of ischemia were associated with a lack of new or worsened deficits. A statistically significant cluster of 42.96cc was associated with deficits at discharge and encompassed the right frontal, insular and tempo-occipital regions. Voxels associated only with deficits at discharge included lateral occipital cortices and supramarginal gyri. A cluster of 17.68cc in the right frontal and insular lobes was significantly associated with deficits after 3 months. Overlapping areas included the right thalamus, caudate nucleus, putamen, globus pallidum, insular cortex, middle and inferior temporal gyri, corticospinal tract and superior thalamic radiation.

CONCLUSION

Transient and persisting new or worsened deficits after glioma resection were significantly associated with volume of postoperative ischemia. Ischemic lesions in right frontal and insular regions, including the basal nuclei, corticospinal tract and superior thalamic radiation were significantly associated with persisting neurological deficits after 3 months, while temporo-occipital lesions were associated with transient deficits only found at discharge.
P14.65 Survival in a consecutive series of 467 glioblastoma patients: impact of prognostic factors and recurrent treatment at two independent institutions
Authors: Blakstad H , Brekke J , Rahman M A , Arnesen V S , Brandal P , Lie S A , Chekenya M , Goplen D
Published: September 2021

BACKGROUND

Glioblastoma (GBM) is an aggressive primary brain tumor with median overall survival (OS) of less than one year in unselected adult patients. There is no standard therapy at recurrence. We aimed to evaluate OS in a consecutive series of GBM patients from Norway’s two largest regional health authorities, compare the effect of physicians’ choice of antineoplastic treatment upon recurrence and identify prognostic and predictive factors.

MATERIAL AND METHODS

Clinicopathological data from n=467 patients with histologically confirmed GBM diagnosed and treated at Haukeland and Oslo university hospitals from January 2015 to December 2017 was retrospectively collected. Data included tumor location, methylation status of the methylguanine-DNA methyltransferase (MGMT) promoter and mutation of the isocitrate dehydrogenase (IDH) genes, patient age and sex, extent of tumor resection at primary diagnosis, and treatment at first, second and third tumor recurrences. Cox-proportional hazards regression with pairwise analyses adjusted for multiple testing with Scheffé’s post-hoc test were used to adjust effect of multiple risk factors on mortality.

RESULTS

Median OS was 12.1 months and 21.4 % and 6.8 % of patients were alive at 2 and 5 years, respectively. Treatment at recurrence varied between institutions but did not impact OS (p=0.201). Median time to progression was 8.2 months. Age, MGMT promoter methylation, tumor location and extent of tumor resection were all independent prognostic factors for OS. Patients receiving radiotherapy to 60 Gray with concomitant and adjuvant temozolomide at primary diagnosis had best outcome with median OS of 16.1 months and 9.3% were alive at 5 years. At first recurrence patients eligible for gammaknife/stereotactic radiosurgery (GK/SRS) or surgery, alone or combined with chemotherapy, had superior survival compared to chemotherapy alone (p<0.0001 and p=0.014, respectively). On Scheffé’s post-hoc analyses only GK/SRS was superior to chemotherapy (p=0.01). At second and third recurrence none of the antineoplastic strategies came across as superior or inferior to each other using Cox. On Scheffé’s post-hoc analyses chemotherapy alone and combined with bevacizumab were superior at second recurrence (p=0.008 and p=0.042, respectively) and chemotherapy combined with bevacizumab was superior at third recurrence (p=0.043), compared to no antineoplastic treatment. Our retrospective study is limited by small sample sizes and heterogeneous treatment groups, especially at second and third recurrences, as well as patient selection.

CONCLUSION

Recurrence treatment differed between the two institutions but there was no difference in OS. Our findings underline the lack of standard therapy upon GBM recurrence and the urgent need for novel therapeutic strategies.
P14.69 Trends in postoperative chemoradiotherapy for Glioblastoma patients: a Danish cohort study
Authors: Trip A K , Veluppillai V K , Dahlrot R H , Guldberg T L , Muhic A , Høyer M , Lukacova S
Published: September 2021

BACKGROUND

Postoperative chemoradiotherapy (CRT), using conventional radiotherapy (convRT), has a key role in the treatment of glioblastoma (GBM) supported by level 1A evidence. In the past decade, evidence supporting hypofractionated radiotherapy (HFRT) has emerged. However, GBM patients in clinical trials are highly selected. Consequently, real-world patients may not be able to undergo evidence-based treatments. The aim of this retrospective Danish cohort study was to evaluate the utilisation of and compliance with postoperative CRT in real-world GBM patients over time.

MATERIAL AND METHODS

All adults (≥18 years) with newly diagnosed GBM (histology confirmed) between 2011 and 2018 were identified via the Danish Neuro-Oncology Registry, which was furthermore used to extract all data. Radiotherapy (RT) was classified as convRT (≤2 Gy/fr, planned dose 44–66 Gy) or HFRT (>2 Gy/fr, planned dose 34 or 40 Gy). The utilisation of and compliance with CRT (only concomitant treatment assessed) was measured by intended and administered treatment, respectively. To assess trends, patients were grouped per year of diagnosis. Multivariable logistic regression was used to analyse the association of age (</≥70), sex, performance status (PS) before surgery and RT, tumour focality, extent of surgery, concomitant chemotherapy (CT), hospital (4 University Hospitals), and year of diagnosis, with convRT or HFRT.

RESULTS

The cohort consisted of 2153 patients. For the entire period, postoperative RT was planned in 1743 patients: utilisation of 81%, over time fluctuating between 77 and 84%. ConvRT was planned in 1428 patients (66%), with a steadily decreasing utilisation from 73% in 2011 to 52% in 2018. Of those, 1346 (94%) could complete RT as planned (over time fluctuating between 88–97%). In this group, the utilisation of and compliance with concomitant CT was 86% (fluctuating between 80–93%) and 73% (fluctuating between 47–84%), respectively. HFRT was planned in 315 patients (15%), with a utilisation of up to 26% in 2018, after a more pronounced increase since 2014. The compliance with HFRT was 93%, fluctuating between 85–100%. In this group, the utilisation of and compliance with concomitant CT was 33% (fluctuating between 0–47%) and 78% (fluctuating between 33–100%), respectively. The utilisation of HFRT compared to convRT was significantly associated with higher age, poorer PS before RT, multifocal tumour, less extensive surgery, less frequent concomitant CT, one hospital of RT treatment, and more recent diagnosis years.

CONCLUSION

The increased utilisation of HFRT is in line with emerging evidence during the cohort period. However, while HFRT was developed as a more convenient schedule for those with a poorer PS and older age, the overall utilisation of postoperative RT did not increase. Nor did the compliance with CRT increase in real-world Danish GBM patients.
P16.06 Immunophenotyping of tumor-infiltrating T cells in primary CNS lymphoma
Authors: Schliffke S , Maire C , Holz M , Bokemeyer C , Westphal M , Lamszus K , Mohme M
Published: September 2021

BACKGROUND

Primary CNS lymphoma represents a malignant disease with dismal prognosis. Standard of care is high dose chemotherapy and radiation. However, this combination cannot be applied to the elderly and fragile population. Immunotherapy holds great promise to be effective in these patients. This study therefore aims to explore the phenotype of tumor-infiltrating lymphocytes (TIL) in order to analyze the potential for immune checkpoint inhibition.

MATERIAL AND METHODS

We performed ex vivo multicolor flow-cytometry on surgical specimens of nine patients with intracerebral lymphoma, including seven with primary CNS lymphoma after isolation of TILs following standard protocols. Data was analyzed using a Fortessa LSR flow cytometer and Diva software. The study was approved by the local ethics committee (PV4904).

RESULTS

Our ex vivo phenotyping demonstrated a predominant infiltration of CD8+ T cells, which outnumber CD4+ T cells by a ratio of 2:1 (p<0.01). Regulatory T cells (Tregs) were not increased in the tumor microenvironment and the NK cell frequency was reduced compared to the peripheral blood. While CD4+ T helper cells displayed significantly increased surface expression of multiple activation and checkpoint markers, including TIGIT, PD-1, Tim3 and CD57, cytotoxic CD8+ T cells predominantly expressed only TIGIT and PD-1. On average 70% and 80% of CD8+ T cells expressed PD-1 and TIGIT, respectively, compared to 35% and 60% of PD-1 and TIGIT on CD4+ T cells (p<0.05). CD8+ T cells furthermore showed an increased expression of CD39 and a simultaneous downregulation of CD73, both ectoenzyms involved in the modulation of intratumoral ATP, thereby indicating a metabolic immune modulation by the tumor.

CONCLUSION

Taken together, our study demonstrates a strong infiltration of cytotoxic CD8+ T cells into cerebral lymphoma, which potentially can be disinhibited using checkpoint immunotherapy. Our profiling suggests that PD-1 and TIGIT present appealing targets for such kind of immune disinhibition.
Genomic diversity and post-admixture adaptation in the Uyghurs
Authors: Pan Yuwen , Zhang Chao , Lu Yan , Ning Zhilin , Lu Dongsheng , Gao Yang , Zhao Xiaohan , Yang Yajun , Guan Yaqun , Mamatyusupu Dolikun , Xu Shuhua
Published: September 2021

Population admixture results in genome-wide combinations of genetic variants derived from different ancestral populations of distinct ancestry, thus providing a unique opportunity for understanding the genetic determinants of phenotypic variation in humans. Here, we used whole-genome sequencing of 92 individuals with high coverage (30–60×) to systematically investigate genomic diversity in the Uyghurs living in Xinjiang, China (XJU), an admixed population of both European-like and East-Asian-like ancestry. The XJU population shows greater genetic diversity, especially a higher proportion of rare variants, compared with their ancestral source populations, corresponding to greater phenotypic diversity of XJU. Admixture-induced functional variants in EDAR were associated with the diversity of facial morphology in XJU. Interestingly, the interaction of functional variants between SLC24A5 and OCA2 likely influences the diversity of skin pigmentation. Notably, selection has seemingly been relaxed or canceled in several genes with significantly biased ancestry, such as HERC2–OCA2. Moreover, signatures of post-admixture adaptation in XJU were identified, including genes related to metabolism (e.g. CYP2D6), digestion (e.g. COL11A1), olfactory perception (e.g. ANO2) and immunity (e.g. HLA). Our results demonstrated population admixture as a driving force, locally or globally, in shaping human genetic and phenotypic diversity as well as in adaptive evolution.
Impact of Changes of the 2020 Consensus Definitions of Invasive Aspergillosis on Clinical Trial Design: Unintended Consequences for Prevention Trials?
Authors: Wingard John R , Alexander Barbara D , Baden Lindsey R , Chen Min , Sugrue Michele W , Leather Helen L , Caliendo Angela M , Clancy Cornelius J , Denning David W , Marty Francisco M , Nguyen M Hong , Wheat L Joseph , Logan Brent R , Horowitz Mary M , Marr Kieren A
Published: September 2021

Background

Consensus definitions for the diagnosis of invasive fungal diseases (IFDs) were updated in 2020 to increase the certainty of IFD for inclusion in clinical trials, for instance by increasing biomarker cutoff limits to define positivity. To date, there is a paucity of data as to the impact of the revised definitions on clinical trials.

Methods

In this study, we sought to determine the impact of the new definitions on classifying invasive aspergillosis (IA), the most common invasive mold disease in immunocompromised patients. We reclassified 226 proven and probable IA cases plus 139 possible IFD cases in the Aspergillus Technology Consortium (AsTeC) and in an antifungal prophylaxis trial (BMT CTN 0101) using the new criteria.

Results

Fewer cases met the more stringent diagnostic 2020 criteria after applying the reclassification criteria to define probable IA. Of 188 evaluable probable cases, 41 (22%) were reclassified to 40 possible IA and 1 probable IFD. Reclassification to possible IFD occurred in 22% of hematologic malignancy (HM) patients, 29% of hematopoietic cell transplant (HCT) patients, and in no lung transplant (LT) patients. Date of diagnosis was established a median (range) of 3 (1–105) days later in 15% of probable IA cases using the new criteria. Applying the new definitions to the BMT CTN 0101 trial, the power to detect the same odds ratio decreased substantially.

Conclusions

The updated IA consensus definitions may impact future trial designs, especially for antifungal prophylaxis studies.
Conquering COVID: How Global Vaccine Inequality Risks Prolonging the Pandemic
Authors: Oehler Richard L , Vega Vivian R
Published: September 2021

The development of effective vaccines during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has been deemed a towering achievement in modern science. Since the end of 2020, the vaccine rollout has offered the promise of vanquishing the pandemic in the United States and other developed countries. Even as the United States and other wealthier nations encounter both setbacks and successes in their coronavirus disease 2019 (COVID-19) eradication efforts, developing countries around the world are likely to face far less fortunate fates. With much of the world’s vaccine production and distribution capacity reserved by wealthier nations, impoverished countries stand to face devastating financial, social, and health-related impacts. The consequences of this disparity will resonate deeply into the collective fabric of these countries, ensuring that the economic and geopolitical imbalance between developed and developing nations will widen even more substantially. Wealthier countries must do more to eliminate the inequality that exists in widespread SARS-CoV-2 vaccine availability in less-developed nations. Like HIV, tuberculosis, malaria, and other global epidemics, COVID-19 cannot be forgotten just because the pandemic is eventually contained from the shores of wealthier nations. For as long as the pandemic rages in any corner of the globe, the world will never be truly rid of COVID-19. And all nations, rich or poor, will suffer the consequences.
Grand Strategy
Authors: Freedman Lawrence
Published: September 2021

A concept of “grand strategy” only emerged during the first decades of the twentieth century. Through the nineteenth century, strategy had a very narrow meaning, largely concerned with getting troops into the best position for battle. Tactics was concerned with the conduct of battle. For a number of reasons, including the importance of peacetime preparation for war, the separation between military strategy and the wider political and economic context came to be recognized as untenable. The contemporary strategy of grand strategy was developed in the UK first by the naval theorist Corbett and then by Fuller and Liddell Hart after the First World War. It referred to the nonmilitary aspects of prosecuting a war. After the Second World War, grand strategy tended to be used to refer to the higher conduct of war where the political, social, and economic came together with the military. Most use was made by historians who found it helpful as a way of discussing past politico-military conduct, even going back to the Romans. It came back into prescriptive use as the Cold War drew to a close. This encouraged the contemporary concept, which refers to the bringing together of all elements of a state power in pursuit of long-term objectives, which has been criticized for being too ambitious.
Culture, Identity, and Grand Strategy
Authors: McCourt David M.
Published: September 2021

What do culture and identity have to do with grand strategy—the task of matching broad national security aims to capabilities? Is grand strategy not the preserve of politics and power, and the timeless wisdom of realpolitik? This chapter argues that culture and identity are essential components of any realistic account of grand strategy, since grand strategies tell a story of who or what a country is, and should be, in world politics. Grand strategies are performative, making the world at the same time as speaking of it, and fashioning an identity for an international actor. The centrality of culture and identity in international politics are key insights from the constructivist approach to IR theory. The chapter outlines the constructivist challenge to mainstream approaches that emphasize material conceptions of power and interests. It then illustrates the ubiquity of culture and identity in the formulation of UK and US grand strategy. It explores recent developments in culturalist theorizing that caution against taking culture and identity as stable entities rather than often contradictory processes. This serves to connect the insights from this chapter to others in the volume on practice, discourse, legitimation, power, and expertise.
The Challenge of Evaluating Grand Strategy
Authors: Wohlforth William C.
Published: September 2021

This chapter demonstrates that evaluating grand strategy is central to the study of international relations, establishes just how big a challenge it is, and proposes principles for meeting that challenge in a rigorous manner. A grand strategy is a sustained, major intervention in a mind-bogglingly complex social world that aims to advance an actor’s interests over the long term. Evaluating such a strategy requires ruthless discipline in defining the actor’s interests, assessing its strategic environment, identifying plausible alternative strategies, and deploying theory and evidence to run grand counterfactual experiments to determine whether those strategies would better realize the actor’s interests. The chapter takes the reader through these steps, illustrating each with examples of best and worst practices from historical and contemporary grand strategy debates.
Teachers conceptualizing and developing assessment for skill development: Trialing a maker assessment framework
Authors: Lock Jennifer , Becker Sandra , Redmond Petrea
Published: September 2021

A makerspace is a place where people create artifacts while sharing ideas, equipment, and knowledge. In so doing, makers develop a range of knowledge and skills, such as creativity, problem-solving, collaboration, and self-regulation, to help them achieve their goals. These skills are broadly touted as key for learning and transferable across disciplines and making contexts. This article will first review the state of play in the literature to assess skill development. Secondly, itreports on the trial of an assessment framework developed through a literature review and implemented in a maker learning environment with an elementary school context. Finally, the article concludes with implications for practice.