bluuebunny/crossref_metadata_2025 huggingface dataset:
Global burden for dengue and the evolving pattern in the past 30 years
Authors: Yang Xiaorong , Quam Mikkel B M , Zhang Tongchao , Sang Shaowei
Published: September 2021

Background

Dengue is the most prevalent and rapidly spreading mosquito-borne viral disease. We present the global, regional and national burden of dengue from 1990 to 2019 based on the findings from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019 (GBD 2019).

Methods

Based upon GBD 2019 dengue data on age-standardized incidence rate (ASIR), age-standardized death rate (ASDR) and age-standardized disability-adjusted life years (DALYs) rate, this study estimates and presents annual percentage change (EAPC) to quantify trends over time to assess potential correlates of increased dengue activity, such as global travel and warming.

Results

Globally from 1990 to 2019, dengue incident cases, deaths and DALYs gradually increased. Those under 5 years of age, once accounting for the largest portion of deaths and DALYs in 1990, were eclipsed by those who were 15–49 years old in 2019. Age standardized incidence [ASIR: EAPC: 3.16, 95% confidence interval (CI): 2.90–3.43], death (ASDR: EAPC: 5.42, 95% CI: 2.64–8.28) and DALY rates (EAPC: 2.31, 95% CI: 2.00–2.62) accelerated most among high-middle and high sociodemographic index (SDI) regions. South-East Asia and South Asia had most of the dengue incident cases, deaths and DALYs, but East Asia had the fastest rise in ASIR (EAPC: 4.57, 95% CI: 4.31, 4.82), while Tropical Latin America led in ASDR (EAPC: 11.32, 95% CI: 9.11, 13.58) and age-standardized DALYs rate (EAPC: 4.13, 95% CI: 2.98, 5.29). SDI showed consistent bell-shaped relationship with ASIR, ASDR and age-standardized DALYs rate. Global land–ocean temperature index and air passenger travel metrics were found to be remarkably positively correlated with dengue burden.

Conclusions

The burden of dengue has become heavier from 1990 to 2019, amidst the three decades of urbanization, warming climates and increased human mobility in much of the world. South-East Asia and South Asia remain as regions of concern, especially in conjunction with the Americas’ swift rise in dengue burden.
Illuminated Caxtons and the Trade in Printed Books
Authors: James-Maddocks Holly
Published: September 2021

This article suggests that the illuminated initials and borderwork added to ten early printed books in England are attributable to a single illuminator, the ‘Incunables Limner’, an individual for whom there is circumstantial evidence that he specialized in the illumination of printed books. Five of these books are copies of William Caxton’s Golden Legend (Westminster, 1483–84), while the other five are Continental imprints (two from Strasbourg, and one from each of Basel, Verona, and Parma) printed between 1476 and 1484. In addition, a second illuminator can be identified in a sixth copy of Caxton’s Golden Legend, working to the same design as that employed within the five copies decorated by the Incunables Limner. The possibility is considered that books illuminated by the Incunables Limner were products of Caxton’s overseas trade, and that it was through acting in this capacity that the artist’s specialization was viable. The Continental books are explored for what they might imply about Caxton’s wider book-selling strategies, and three with evidence for early English ownership are selected for particular attention.
PL02.5.A The clinical significance of telomerase reverse transcriptase (TERT) promoter mutations, telomere length and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status in newly diagnosed and recurrent IDHwildtype glioblastoma (GBM) patients (PTS): A large mono-institutional study
Authors: Lombardi G , Giunco S , Cavallin F , Angelini C , Caccese M , Cerretti G , De Bonis P , De Rossi A , Zagonel V
Published: September 2021

BACKGROUND

the clinical significance of TERT promoter mutations, telomere length and their interactions with MGMT promoter methylation status in patients with IDH-wildtype GBM patients remain unclear. We performed a large monoinstitutional study to better investigate their impact and their interaction on clinical outcomes

MATERIAL AND METHODS

TERT promoter mutations (C228T and C250T), relative telomere length (RTL) and MGMT methylation status were assessed in 278 newly diagnosed and in 65 recurrent IDH-wildtype GBM PTS which were treated at Veneto Institute of Oncology (Padua, Italy) from Dec 2016 to Jan 2020. We have retrospectively explored association between gene characteristics and neuroradiological response (RANO criteria), progression-free survival (PFS), overall survival (OS). Telomere length was measured by monochrome multiplex PCR and RTL values were calculated as a telomere/single-copy gene ratio

RESULTS

characteristics of newly diagnosed GBM PTS were: median age 63 ys, ECOG PS 0–1 in 71% of PTS, radical surgery in 38%, 78% received radiation therapy plus TMZ, MGMT was methylated in 53%, TERT promoter was mutated in 80% (75% C228T, 25% C250T), median RTL was 1.57 (range 0.4–11.37). Objective response rate was reported in 15% of PTS, median OS was 15ms (95% CI 13-18ms), median PFS was 8ms (95% CI 7-9ms). At multivariable analysis, TERT promoter mutations and RTL were not associated with clinical outcomes; about OS, TERT promoter mutations and RTL reported a HR of 1.05 (95% CI 0.64–1.64) and 0.99 (95% CI 0.89–1.10), respectively; MGMT methylated tumors showed significant improved PFS and OS with a HR of 0.54 (95% CI 0.40–0.71) and 0.47 (95% CI 0.34–0.64), respectively. All interactions among MGMT status, TERT mutation status and RTL were not statistically significant. Characteristics of recurrent GBM PTS were: median age 55 ys, ECOG PS 0–1 in 60% of PTS, MGMTmet in 37%, TERT promoter mutations in 75% (75% C228T, 25% C250T), RTL was 1.67 (range 0.68–8.87). At multivariable analysis, only MGMT methylated tumors resulted significantly associated to prolonged OS (HR 0.16; 95% CI 0.07–0.40). No gene interaction was significant

CONCLUSION

for the first time worldwide, we analyzed the impact of TERT promoter mutations, RTL and MGMT methylation status in both newly diagnosed and recurrent IDH-wildtype GBM PTS. TERT promoter status and RTL were not associated with clinical outcomes at both diagnosis and relapse. MGMT promoter methylation status was the only prognostic factor in both cases. No significant interaction was demonstrated between TERT promoter mutations, RTL and MGMT methylation status
JS01.3.A Oncogenic chaperoning of Hsp90 in glioma with FGFR3-TACC3
Authors: Li T , Mehraein-Ghomi F , Forbes M , Namjoshi S , Ballard E , Song Q , Chou P , Wang X , Yang X , Zhang W
Published: September 2021

BACKGROUND

Fusion genes are chromosomal aberrations in malignancies that can be used as prognostic markers as well as therapeutic targets. The FGFR3-TACC3 (F3-T3) was initially discovered as an oncogenic molecule in glioblastoma and bladder cancer and subsequently found in many other cancer types. Based on clinical evidence, F3-T3 was found in glioblastoma patients before and after TMZ and radiotherapy treatment, suggesting that targeting F3-T3 is a valid strategy for glioblastoma treatment.

MATERIAL AND METHODS

We profiled the proteins that interacted with F3-T3 fusion protein in U-251 MG cells with F3-T3 through 2-D liquid chromatography-tandem mass spectrometry. To validate the result of proteomic analysis, we performed reverse immunoprecipitation by pulling down Hsp90 or Cdc37 in U-251 MG cells stably expressing F3-T3. To inhibit the association between F3-T3 and the Hsp90-Cdc37 complex, we treated U-251 MG and LN-229 cells stably expressing F3-T3 with Hsp90 inhibitors or siRNA of Cdc37. We applied the CCK8 assay to evaluate the sensitivity of glioblastoma cells stably expressing F3-T3, wild-type FGFR3, kinase-dead F3-T3 (K508R), and empty vectors to TMZ. Immunoblot and immunofluorescence staining were used to detect DNA damage marker pH2AX. The drug combination effect index was analyzed using software CalcuSyn. U-251 MG cells stably expressing F3-T3 infected with luciferase virus were intracranially injected in nude mice. The experimental group was administered with temozolomide (5mg/kg/day) by oral gavage, Hsp90 inhibitor Onalespib (30mg/kg/day) by tail vein injection or the combination of the two for indicated days.

RESULTS

We identified the proteins that showed increased binding ratios to F3-T3 over full-length FGFR3, the molecular chaperone proteins encoded by the genes HSP90AB1, HSP90AA1, and CDC37 emerged as 5th, 6th, and 7th on the top ten list, showing an approximately 4-fold increase in normalized spectral counts. Using Hsp90 inhibitors or Cdc37 siRNA disrupted the formation of the F3-T3/Hsp90/Cdc37 complex. Disruption of Hsp90-Cdc37 chaperoning caused a ubiquitination-mediated degradation of the glycosylated form of F3-T3 and abrogated the maturation of nascent F3-T3, resulting in suppression of F3-T3 signaling pathways. Additionally, our results provide evidence that the F3-T3 signaling pathway confers drug resistance to TMZ induced DNA damage. However, the resistance of TMZ was disrupted in glioblastoma cells harboring kinase-dead F3-T3 (K508R). We also demonstrated Hsp90 inhibitor significantly sensitized glioblastoma cells harboring the F3-T3 fusion gene to TMZ treatment and improved survival of xenograft model bearing F3-T3 tumor in vivo.

CONCLUSION

F3-T3 is a strong Hsp90 client that shows strong addiction to the Hsp90-Cdc37 chaperone system. Combination therapy with Hsp90 inhibitor overcomes the TMZ resistance conferred by F3-T3.
OS06.4A Identification of T cell receptors targeting ZFTA-RELA fusion-positive ependymoma
Authors: Kehl N , Friedrich M , Kilian M , Zheng T , Pajtler K , Bunse L , Platten M
Published: September 2021

BACKGROUND

The oncogenic gene fusion between ZFTA (formerly C11orf95) and RELA has in recent years been highlighted as oncogenic driver event ultimately leading to malignant transformation and progression of ependymoma. Representing a genetic hallmark in 17.6% of ependymomas, ZFTA-RELA fusion-positive tumors qualified as separate diagnostic entity in the 2016 revision of the WHO classification of CNS tumors. This tumor entity mainly occurs in pediatric patients and is characterized by poor prognosis and the lack of biology-driven therapy.

RESULTS

De novo prediction of putative gene fusion-derived neoepitopes in malignant CNS diseases yielded several potential candidates suitable for screening. Of these, vaccination of A2.DR1-transgenic major histocompatibility complex (MHC)-humanized mice with in silico compiled peptide vaccines encompassing the ZFTA-RELA fusion sequence elicited robust antigen-specific CD4+-restricted immune responses. We identified ZFTA-RELA-reactive T cell clones by multiplexed Interferon-γ / Interleukin-2 recall response. Single-cell VDJ-sequencing of reactive T cells demonstrated a highly clonal T cell receptor (TCR) repertoire and shared clonotypes among all vaccinated animals. Matching TCRα/β chains have been assembled from single-cell sequencing data and cloned for functional testing of neoepitope-reactive TCR-transgenic T cells in vitro as well as in vivo using a transposon system-based immunocompetent, MHC-humanized ZFTA-RELA fusion-positive ependymoma model.

CONCLUSION

Here we identify the oncogenic ZFTA-RELA gene fusion product as a novel tumor-specific neoepitope that is recognized by MHC class II-restricted TCRs. Therapeutic efficacy of TCR-transgenic cell therapy can be further investigated using an immunocompetent MHC-humanized mouse model of ZFTA-RELA fusion-positive ependymoma. Our findings provide initial evidence for neoepitope-specific immunotherapy in pediatric CNS tumors.
OS07.5A Diagnostic Instrument for Mild Aphasia (DIMA): sensitive and valuable addition to standard language assessment in glioma patients
Authors: Mooijman S , Vincent A , De Witte E , Visch-Brink E , Satoer D
Published: September 2021

BACKGROUND

Low-grade glioma (LGG) patients typically suffer from mild aphasia that often cannot be detected with standard aphasia tests. The Diagnostic Instrument for Mild Aphasia (DIMA) is the first standardized test-battery to assess mild language disorders. We investigate pre- and postoperative linguistic abilities of LGG and high-grade glioma (HGG) patients with the DIMA.

METHODS

The DIMA consists of subtests that tap phonology (word, compound, non-word, sentence repetition), semantics (odd-picture-out), and syntax (sentence completion). Additionally, we administered the Boston Naming Test, Category- and Letter Fluency, and the Token Test. Patients were assessed before awake surgery (T1, N=98), three-months (T2, N=69), and one-year (T3, N=30) postoperatively. DIMA performance was compared to healthy controls (N=214). Group differences were examined with parametric (t-test) and nonparametric (Mann-Whitney-U, Wilcoxon) tests.

RESULTS

DIMA: Preoperatively, patients deviated on sentence repetition and sentence completion (p<0.05). HGG patients performed worse than LGG on word, non-word, and sentence repetition (p<0.05). There was no effect of hemispheric tumor localization. At T2, compound repetition and odd-picture-out also became impaired (p<0.05) and there was a decline compared to T1 on all repetition tasks (p<0.05). At T3, only sentence completion remained impaired (p<0.01) with a deterioration compared to T1 (p<0.01).

Standard tests: At T1, patients were impaired on BNT, Category- and Letter Fluency (p<0.01). HGG patients performed worse than LGG patients on BNT and TT (p<0.01). Patients with left-hemispheric tumors performed worse on BNT and Letter Fluency compared to right-hemispheric tumors (p<0.05). At T2, TT also became impaired (p<0.05) and patients declined compared to T1 on Verbal Fluency tests (p<0.01). At T3, only BNT and Category Fluency remained impaired (p<0.05), with no significant declines compared to T1.

CONCLUSION

The DIMA is the first test-battery to detect peri-operative impairments at different linguistic levels (phonology, semantics, syntax) in patients with left- or right-hemispheric gliomas. It even appeared more sensitive to detect surgical effects than standard tests: all phonological DIMA subtests captured short-term decline (T1-T2), in line with earlier evidence for the value of (non-)word repetition. DIMA sentence completion detected long-term decline (T1-T3), reflecting earlier spontaneous speech analyses. As expected, Verbal Fluency was also sensitive to short-term postoperative decline. Left-hemispheric tumor localization only affected standard test performance. HGG patients had more severe impairments than LGG on DIMA repetition and standard tests (BNT and TT). We advise adding the DIMA to standard language evaluation of glioma patients, as it allows for more detailed counseling about language outcome.
OS09.3.A Caregiver burden of glioma patients: the impact of informal care
Authors: van den Borg R , Weerdesteijn-Prinsen A , Nijboer C M , Postma T J , Kouwenhoven M C M , Schuur M
Published: September 2021

BACKGROUND

Each year 1.300 new patients are diagnosed with a glioma in the Netherlands. Patients experience a substantial physical and cognitive decline during the course of the disease. The impact of neurological deterioration on social and family life is substantial. Caregivers give high demanding care to their partners for long periods of time, while they combine this care with many other tasks, as: care for children, administrative household tasks and securing the families financial situation through work. As a consequence caregivers experience a high burden.In this study, we evaluated the degree of caregiver burden, its impact on daily life and the preferred support needed. With better insight in caregivers needs, support for the caregivers can be optimized.

MATERIAL AND METHODS

The study was conducted at the Brain Tumor Center Amsterdam, the Netherlands, between March and June 2019. We prospectively collected information using two Dutch questionnaires: the “Experienced Burden of Care” (EDIZ) and the “Features of Caregiver Care” questionnaire. The questionnaires were handed out to 93 caregivers of glioma patients at the outpatient clinic. The data were analysed using descriptive statistics.

RESULTS

In the studied population, 36,6% of caregivers experienced a high burden (score 7–9 on EDIZ questionnaire). The features of caregiver care questionnaire showed that 11,2% was overloaded (score >31), and 57,3% nearly overloaded (score 22–30). Caregivers indicated that the continuous care for the patient and lack of time for their own needs were a major cause for the high burden they experienced. One third of the caregivers reported a substantial change in physical, mental and behavioural functioning of the patient during the study. Caregivers experienced a lack of support and information; they felt a need for more psychological support (34,9%) and advice how to deal with the cognitive and behavioural decline of the patient (33,3%). The need for information of caregivers varied, ranging from information on the course of the disease (28,6%) to information on the social support act (23,8%). The question when to receive additional information was answered by most caregivers to a ‘self-chosen point in time’ instead of set time points by the medical team.

CONCLUSION

The burden of caregivers of glioma patients is high; nearly 70% of caregivers are even (nearly) overloaded. Caregivers need information and support on different aspects of the disease. As these aspects vary between different caregivers and possibly during the disease course, support to caregivers should be structurally assessed. A better understanding of the caregivers needs in combination with active support could prevent dropout of caregivers and improve the quality of life of both caregivers and patients.
OS10.3.A Predicting delirium after craniotomy in neuro-oncology
Authors: Kappen P R , Kappen H J , Dirven C , Klimek M , Osse R , Vincent A
Published: September 2021

BACKGROUND

Post-operative delirium (POD) is a frequent and severe complication after neurosurgical operations. Good prediction of POD after craniotomy in neuro-oncologic patients is important to install prophylactic measures, increase recognition and apply early treatment. Hence, we compared logistic regression with machine learning to build an accurate predictive model in a large dataset.

MATERIAL AND METHODS

POD was defined in case of a Delirium Observation Scale (DOS) ≥ 3 or start of antipsychotic treatment for delirium within 10 days after surgery. Adult patients undergoing a craniotomy for a neuro-oncologic disease in the Erasmus Medical Centre in Rotterdam were retrospectively included. The cohort was split into a training (75%), after three-fold cross validation, and test set (25%). Logistic regression and Lasso Elastic-Net Regularized Generalized Linear Models (GLMNet) were trained based on 19 pre- and intra-operative features and risk factors were identified based on the superior model.

RESULTS

We included 1025 neuro-oncologic craniotomies between June 2017 and September 2020. Overall incidence of POD was 18.6% (95%CI 17.4–19.8). Compared to logistic regression, Lasso GLMNet performed superior (AUC 0.73 vs. 0.76) based on the optimal tuning parameters (α=1, λ=0.014). Several non-modifiable risk factors such as age (OR1.01), prior delirium (OR1.04), memory problems (OR1.12), surgery duration (OR1.01) and modifiable risk factors, such as low potassium (OR0.97) levels and opioid administration (OR1.03), were identified.

CONCLUSION

POD is a frequent complication after craniotomy in neuro-oncologic patients. Lasso GLMNet was useful in predicting POD in this cohort. Validation in a prospective cohort of this model should be applied to further evaluate its value in diminishing POD.
OS12.4.A MHC class II-restricted transgenic T cell receptor therapy targeting mutant capicua transcriptional repressor in experimental gliomas
Authors: Kilian M , Friedrich M , Sanghvi K , Green E , Pusch S , von Deimling A , Wick W , Sahm F , Platten M , Bunse L
Published: September 2021

BACKGROUND

Glioma subtypes are classified according to their characteristic mutations and show a high degree of resistance to standard therapeutic interventions such as radiotherapy and alkylating chemotherapy. Some of these characteristic mutations have shown to generate immunogenic neoepitopes that can be targeted with immunotherapy. 70% of oligodendrogliomas carry capicua transcriptional repressor (CIC) inactivating mutations.

RESULTS

In a screen for potential immunogenic glioma neoepitopes we identified recurrent CIC hotspot mutations at position 215 (CICR215W/Q) expressed in a subset of oligodendrogliomas as an immunogenic major histocompatibility complex (MHC) class II-restricted neoepitopes. Peptide-based vaccination of MHC-humanized mice resulted in the generation of robust mutation-specific T cell responses against CICR215W/Q, restricted to MHC class II. Droplet-based single cell T cell receptor (TCR) sequencing from CICR215W-specific T cell lines enabled retrieval of MHC class II-restricted CICR215W-reactive TCRs. By retroviral transduction of T cells, we established a flow cytometry-based testing platform of retrieved TCRs and were able to show the top reactive TCR against CICR215W to be shared between individual mice. Using a newly developed glioma model in MHC-humanized mice induced by CRISPR-based delivery of tumor suppressor targeting guide RNAs, we show that adoptive intraventricular transfer of CICR215W-specific TCR-transgenic T cells exert anti-tumor responses against CICR215W-expressing syngeneic gliomas.

CONCLUSION

The integration of immunocompetent MHC-humanized orthotopic glioma models in the discovery of shared immunogenic glioma neoepitopes facilitates the identification and preclinical testing of HLA-restricted neoepitope-specific TCRs for locoregional TCR-transgenic T cell adoptive therapy.
P03.05 The use of subcortical intraoperative electrical stimulation mapping for assessment of executive functions: A summary of the evidence so far
Authors: Landers M J F , Sitskoorn M M , Rutten G J M , Mandonnet E , De Baene W
Published: September 2021

BACKGROUND

Over the past years, the functional subcortical architecture of the brain has been increasingly acknowledged in neurosurgical planning. A method to study anatomo-functional correlations is direct electrical stimulation (DES). DES is widely used by neurosurgeons and considered as a reliable tool to minimize the occurrence of permanent postoperative motor, language and visual deficits. In recent years, DES has also been used for mapping of other cognitive functions, such as executive functions.

MATERIAL AND METHODS

We systematically summarized the evidence so far from DES studies on subcortical pathways that are involved in the following three executive functions: (1) inhibitory control, (2) working memory and (3) cognitive flexibility.

RESULTS

We only found twelve articles that reported on intraoperative electrical stimulation of white matter pathways to map executive functions and explicitly clarified which subcortical tract was stimulated. The results indicate that the second branch of the right superior longitudinal fasciculus (SLF-II) is involved in inhibitory control, the first branch of the right superior longitudinal fasciculus (SLF-I) and the third branch of the left superior longitudinal fasciculus (SLF-III) are involved in working memory and the cingulum is involved in cognitive flexibility.

CONCLUSION

We were unable to draw any specific conclusions, nor unequivocally established the pathways involved in executive functions due to heterogenous study characteristics, methods and tasks, and the limited number of studies that assessed these relationships. Clearly, neurosurgical groups are exploring novel methods to assess cognition during awake neurosurgery, but are far from consensus on indications and protocols, which complicated the comparison and summarization of findings. We will discuss possible approaches for future research to obtain converging and more definite evidence for the involvement of subcortical pathways in specific executive functions.
P04.23 Multinodular and vacuolating neuronal tumor - advanced MRI features
Authors: Ivan R , Mitrică M , Sîrbu O M , Sîrbu C A
Published: September 2021

BACKGROUND

A rare pathology, multinodular and vacuolating neuronal tumors (MVNT) have been first described in 2013 and included in the 2016 World Health Organization Classification of Tumors of the Central Nervous System as having a distinctive radiological and cytoarchitectural appearance.

This study aims to evaluate the imaging features of MVNT, it’s differential diagnosis, and possible involvement in adult-onset epilepsy.

MATERIAL AND METHODS

We present the case of a 29-year-old male, smoker, and drug abuser, who developed a seizure after 25 hours’ sleep deprivation, alcohol, energy drinks, cigarettes, and cocaine consumption. Cerebral CT, MRI, electroencephalogram, MR spectroscopy, and tractography was performed.

RESULTS

The MRI performed revealed a right, cortico-subcortical pseudo-nodular temporal lesion, non-enhancing, with a slight thickening of the adjacent cortex and right hippocampal involvement. The neurological examination was normal, but the electroencephalogram showed a right temporal irritative pattern. MR- Spectroscopy described a slight increase of choline (Cho), reduction of N-acetylaspartate (NAA), and also increased myo-inositol peak, ruling out a high-grade tumoral substrate. A tractography was also performed, excluding the other alternative diagnosis of focal cortical dysplasia, thus leaving MVNT to be the most probable explanation for the lesion.

CONCLUSION

Advanced MRI features were useful to increase the diagnosis accuracy. The future management consisted of image surveillance, anticonvulsant treatment, and lifestyle improvement. Adult-onset seizures are among the most frequent discovery possibilities for MVNT. In our case, it is to be seen whether the lifestyle changes and medication will prevent future seizures.
P06.02 Efficacy of Arc based Radiation in children & young adults with Medulloblastoma
Authors: Mathew S M , U A S , V C V , Lokesh V
Published: September 2021

BACKGROUND

To compare doses to Organs At Risk and assess low dose radiation bath by Cranio Spinal Irradiation in children and young adults with Medulloblastoma between different Techniques.

MATERIAL AND METHODS

30 Patients [Median Age: 8(5–23), M: F= 2:1] with Medulloblastoma, planned for Craniospinal Irradiation by Arc based Radiotherapy (VMAT- Elekta) also had an alternative Radiotherapy Plan (IMRT/ 3DCRT) to compare radiation doses to critical OARs (Cochlea, Thyroid, Heart) and low dose radiation bath to Vertebral Body and Supratentorial normal brain). Mean doses of Organs in parallel, Maximum doses of organs in series and Integral Dose was compared. Pre radiation Vertebral Body CT Density (HU) and the absorbed dose to it at various levels was estimated for each patient on the TPS. With the PTV coverage being 95% to the volume, dosimetrically superior plan was chosen for therapy.

RESULTS

The cohort had a risk stratum in the ratio 4:1 (Standard: High). IHC based molecular subtyping showed WNT, SHH and Non WNT/ Non SHH sub type (3:1:2). For ease of Analysis, the sample was divided among age groups into <8 years, 8–12 years and >12 years. Among the various Age groups, children < 8 years received the lowest dose of 21 Gy to Thyroid via Arc Therapy [(27Gy±4Gy) vs (31Gy± 3Gy)]. Children at 8–12 years received the lowest mean dose of 35 Gy with Arc plan to B/L Cochlea. [(36Gy± 4Gy) vs 41Gy± 4 Gy)]. Significant reduction of Mean dose to the heart was noted in >12 years with Arc [(8 Gy± 1Gy) vs(10 Gy± 2 Gy)]. The Mean CT density by HU of Vertebral Body (Thoraco-Lumbar) estimated were 145 HU, 195 HU and 315 HU in three age groups. Mean Doses to the Vertebrae was significantly lower with VMAT in kids < 8 years. ([3211 cGy ± 80 cGy] vs [3397 cGy ± 70cGy]). Supratentorial brain (basi frontal) received an additional [373.9 cGy ± 0.2Gy] vs[425 cGy ±0.3 Gy]) during PF Boost.

CONCLUSION

Arc Therapy in Medulloblastoma reduces in field normal tissue radiation dose (Thyroid, Cochlea and heart) at respective ages of <8 years, 8–12 years and > 12 years as well as the low dose radiation bath to structures (Vertebral body and Supratentorial brain) beyond the target volume which may reduce long term complications in children and young adults.
P11.06 Health-related quality of life and emotional wellbeing connected to glioblastoma; a longitudinal follow-up of patients and relatives
Authors: Ståhl P , Henoch I , Smits A , Rydenhag B , Ozanne A
Published: September 2021

BACKGROUND

Glioblastoma is the most common malignant brain tumor in adults and also the most aggressive one. At present, there is only palliative treatment available. The aim of this study is to investigate the HRQoL and emotional well-being of patients with glioblastoma by surveying them and their relatives from a time point before surgery until 2 years later.

MATERIAL AND METHODS

Patients and their relatives answered the validated questionnaires SF-36 and HADS at several time points: preoperatively, at 3 weeks postoperatively, at 12 weeks postoperatively, at 6 months postoperatively, at 1 year postoperatively, at 1.5 years postoperatively, and at 2 years postoperatively. At baseline, the paired patients and their relatives came to consist of 63 patients and 63 relatives. Descriptive statistics and the Wilcoxon signed-rank test were used.

RESULTS

Relatives scored more symptoms of anxiety than patients on all occasions except at 1.5 years postoperatively, with the largest significance preoperatively with p<0.001 and at 3 weeks postoperatively with p<0.001. 50% or more of the relatives reported the presence of symptoms of anxiety on all measured occasions. Furthermore, relatives scored worse for the SF-36 mental component summary (MCS) on all occasions except at 1.5 years postoperatively. Patients scored the SF-36 physical component summary (PCS) worse than the relatives on all measured occasions e.g., preoperatively p<0.001, at 3 weeks postoperatively p<0.001, at 12 weeks postoperatively p<0.001 and at 6 months postoperatively p<0.001. A comparison was also made between patients’ PCS and MCS with an age and gender matched population, patients scored MCS significantly worse than the general population preoperatively p<0.001 with effect size r=0.5, at 3 weeks postoperatively p<0.001with effect size r=0.5 and at 1.5 years postoperatively p=0.013 with effect size r=0.6.

CONCLUSION

The comparison between the HRQoL and emotional well-being of patients with glioblastoma and their relatives from presurgery to one and a half years postsurgery shows that patients on most occasions scored worse physical HRQoL and that relatives mostly scored worse mental HRQoL and emotional well-being. When comparing the patients in the present study with an age and gender matched reference population, it was found that the patients with glioblastoma scored worse HRQoL than the reference population.
P13.17 CD95 gene silencing affects growth and invasiveness of glioma-initiating cells in a CD95L-independent manner
Authors: Quijano-Rubio C , Weller M
Published: September 2021

BACKGROUND

CD95 (Fas/APO-1) holds a dual role of potential relevance in tumor development. CD95-CD95 ligand (CD95L) signaling regulates apoptotic cell death in CD95-expressing cells, but non-apoptotic, tumor-promoting CD95-CD95L signaling has been likewise described. Therapeutic stimulation of apoptotic CD95 signaling is associated with major clinical side effects. However, inhibition of tumor-promoting CD95 signaling may represent a promising treatment strategy for human cancers where potential tumor-promoting CD95 functions include invasiveness and cancer cell stemness, including glioblastoma.

MATERIAL AND METHODS

In this study, CD95 and CD95L expression was characterized in human glioma-initiating cells (GIC) in vitro and in vivo. CD95 and CD95L gene knockout (KO) GIC were generated by means of CRISPR-Cas9 and the effects of gene silencing were evaluated by assessing growth, clonogenicity, invasiveness and tumorigenicity in nude mice.

RESULTS

CD95 expression and sensitivity to exogenous CD95L-induced apoptosis were confirmed in selected GIC in vitro. CD95L expression was not detected. Upon CD95 KO, all GIC acquired resistance to CD95L-induced apoptosis. Furthermore, despite the confirmed absence of CD95L expression in vitro, CD95 KO S-24 GIC revealed decreased cell growth, inferior sphere forming capacity and decreased invasiveness. These data suggested a CD95L-independent tumor-promoting role of CD95 in S-24 GIC. In vivo, however, CD95 KO did not prolong the survival of glioma-bearing mice. Analyses of further GIC models are ongoing.

CONCLUSION

These data demonstrate that, unlike CD95, CD95L is not expressed in cultured human GIC and that CD95-CD95L interactions are not required for tumor-promoting CD95 signaling. Although CD95 KO is detrimental for S-24 GIC in vitro, CD95 KO alone does not affect survival in S-24 human GIC xenograft-bearing mice.
P13.19 Bi-modular G-quadruplex DNA-crypto-aptamers diminish viability of glioma primary cell cultures of patients
Authors: Kopylov A M , Samoylenkova N , Bizayeva A , Arutyunyan A , Tashlitsky V , Golbin D , Usachev D , Pavlova G
Published: September 2021

BACKGROUND

G-quadruplex oligonucleotides (GQs) exhibit specific anti-survival activity in human cancer cell lines; they can selectively inhibit the viability/proliferation. The most studied, AS1411, had been in clinical trials. This anti-proliferative ability of GQs could be translated into glioma, which currently has poor prognosis and low-efficiency therapeutic treatments for glioblastoma multiform (GBM). Set of GQs have been designed, synthesized, and tested: they have different amount of Q-quartets, they have dimers of different GQ modules: either covalent dimers or non-covalent ones; all of them could be coined as ‘twins’.

MATERIAL AND METHODS

Folding of synthetic DNA oligonucleotides into GQs and thermal stability have been studied by circular dichroism, melting with unfolding-folding regimes, oligomerization was followed by original SE-HPLC. Conventional human cell lines U87 and fibroblasts from human embryo (HEF) were provided from the collection of the Centre of Neurosurgery (Moscow, Russia). GBM primary cell cultures N1, G11, Sus/fP2, G22, G23, and G01 were developed in Burdenko National Medical Research Centre of Neurosurgery (NMRCN) from the surgery samples of patients (PCC_SSP). All samples had WT IDH1. This study was approved by the Ethics Committee of Burdenko NMRCN, Russian Academy of Medical Sciences (№_12/2020, 15.12.2020). All subjects gave written informed consent in accordance with the guidelines of Declaration of Helsinki. Cell viability was tested by conventional MTT-test.

RESULTS

Novel bi-modular GQ, bi-(AID-1-T), twin of three-quartet AID-1-T, was designed by covalent conjugation of two AID-1-Ts via three thymidine link, TTT; and linking did not interfere with its GQ structure. Comparison of bi-(AID-1-T) with mono-modular AID-1-T, mono-modular two-quartet HD1, bi-modular bi-HD1, and two-quartet AS1411, was made. Among five GQs, bi-(AID-1-T) had the highest anti-survival activity for U87, while not affecting the control, HEF. GQs, for the first time, were tested on several PCC_SSP. Sensitivity of PCC_SSP toward GQs varied, with apparent IC50 of less than 1 μM for bi-(AID-1-T) toward the most sensitive G11 (glioma, Grade III).

CONCLUSION

GQs as anti-proliferative crypto-aptamers with moderate activity due to restricted functioning of apparent GQ-binding proteins could be applied toward real glioma PCC_SSP. Variety of effects reflects glioma inter-tumor heterogeneity.Research was funded by Ministry of Education and Science of Russia, grant number № 075-15-2020-809 (13.1902.21.0030) and by Russian Foundation for Basic Research, grants number №18-29-01047
P14.01 Incidence and impact of venous thromboembolism and major bleeding in patients with glioblastoma
Authors: Kaptein F H J , Stals M A M , Klaase E , Kapteijn M Y , Cannegieter S C , Taphoorn M J B , Dirven L , Huisman M V , Koekkoek J A F , Klok F A
Published: September 2021

BACKGROUND

Patients with glioblastoma are considered to be at high risk of venous thromboembolism (VTE) and major bleeding (MB), although reliable incidence estimates are lacking. The aim of this study was to assess the cumulative incidence, risk factors and prognostic impact of VTE and MB in a large cohort of glioblastoma patients.

MATERIAL AND METHODS

Patients diagnosed with glioblastoma between 2004–2020 from the Leiden University Medical Center and Haaglanden Medical Center were included and followed from 6 months before date of histopathological glioblastoma diagnosis up to two years after, or until an outcome of interest (VTE and MB) or death occurred. Cumulative incidences were estimated using Kaplan-Meier and cumulative incidence competing risk methods. Outcome predictors were determined with multivariable (time-dependent) Cox models.

RESULTS

Of the 967 included patients, 631 died, 101 were diagnosed with VTE and 130 with MB during a median follow-up of 15 months (IQR 9–22). The majority of MBs were intracranially (94%), of which half was within 4 weeks post-surgery (51%). Ambulant patients did not routinely receive pharmacological thromboprophylaxis. The adjusted 2.5-year-cumulative incidence of VTE was 12% (95%CI 10–14) and of MB 16% (95%CI 13–18). One year increase in age (HR 1.03, 95%CI 1.01–1.05), tumor resection (vs. biopsy: HR 0.56, 95%CI 0.35–0.89) and performance status (ECOG >1 vs ≤1: HR 1.8, 95%CI 1.2–2.7) were independent predictors of VTE (a biopsy rather than resection was performed in patients with the worst prognosis). MB and VTE predicted all-cause mortality (adjusted HR 1.7, 95%CI 1.3–2.1 and 1.3, 95%CI 0.99–1.6 respectively).

CONCLUSION

The incidences of VTE and MB in patients with glioblastoma are high, with both complications associated with a poor prognosis. Our observations emphasize the need for prospective studies to determine optimal thromboprophylaxis and VTE treatment strategy in these patients.
P14.04 Detection of circulating tumor cells in cerebrospinal fluid for patients with suspected breast cancer leptomeningeal metastases. A prospective study
Authors: Darlix A , Pouderoux S , Thezenas S , Bievelez A , Jacot W , Cayrefourcq L , Leaha C , Alix-Panabières C
Published: September 2021

BACKGROUND

Breast cancer (BC) is the most frequent cause of leptomeningeal metastases (LM). LM diagnosis is confirmed by the detection of tumor cells in the cerebrospinal fluid (CSF) using conventional cytology (gold standard). However, even with optimal CSF sample volume and time to the analysis, the sensitivity of this technique is low, demanding repeated samples. Here, we aimed to evaluate the value of circulating tumor cell (CTC) detection in CSF using the CellSearch® system for LM diagnosis.

MATERIAL AND METHODS

This prospective, monocentric study included adult BC patients with suspected LM (clinical and/or radiological signs). CSF samples from 1–3 lumbar puncture(s) were analyzed: protein level, conventional cytology (60 drops), and CTC detection with the CellSearch® system (60 drops, first lumbar puncture only). Sensitivity (Se) and specificity (Sp) were calculated, using the results of the conventional cytology as the gold-standard.

RESULTS

Forty-nine eligible patients were included (Jan 2017-Jan 2020): median age 51.8, 95.9% women, 20.4% HER2+ BC, 93.8% previously diagnosed with metastatic BC, 89.8% with clinical symptoms. Among them, 40 were evaluable (CTC detection failure: n=8, eligibility criteria failure: n=1). Median sample volume was 3.0 mL for conventional cytology samples (median time to analysis: 22min) and 3.3 mL for CTC samples. Of the 40 evaluable patients, 18 had a positive cytology (on CSF sample n=°1/n°2: n=16/n=2) and were therefore diagnosed with LM using the gold-standard method. Protein level was elevated in 88.2% of these patients, compared with 45.1% of patients with negative CSF cytology (p=0.005). CTCs were detected in these 18 patients (median 5824 CTCs, range 93-45052). CTCs were also detected in 5/22 patients with a negative cytology (median 2 CTCs, range 1–44). Among them, one patient (44 CTCs) was diagnosed with a cytologically-proven LM 9 months later, while there was no further argument for LM in the other 4 patients’ history (1–3 CTC), who died of the extra-cerebral disease after a median time of 5.2 months (range 0.9–25.9). The detection of at least one CTC in CSF was associated with a Se of 100.0% (IC95% 82.4–100) and a Spe of 77.3% (IC95% 64.3–90.3) for the diagnosis of LM.

CONCLUSION

CTCs were detected with the CellSearch® system in all patients diagnosed with a cytologically-proven LM, as well as in a few patients without a cytological confirmation of LM. The prognosis of these patients with CSF cytology-/CTCs+ needs to be further investigated in a larger cohort.
P14.06 Radiomics for the non-invasive determination of the BRAF mutational status in patients with melanoma brain metastases
Authors: Meissner A , Gutsche R , Galldiks N , Kocher M , Juenger S T , Wendl C , Mauch C , Proescholdt M , Grau S , Lohmann P
Published: September 2021

BACKGROUND

The BRAF V600E mutation is present in approximately 50% of patients with melanoma and is an important prerequisite for a response to targeted therapies such as BRAF inhibitors. In the majority of patients, the BRAF mutational status is based on the analysis of tissue samples from the extracranial primary tumor only. Since the extracranial and intracranial BRAF mutational status may be discrepant, the additional information on the BRAF mutational status of melanoma brain metastases would be of clinical value, e.g., for the prediction of response to targeted therapies. Here, we evaluated the potential of structural MRI radiomics for the determination of the intracranial BRAF mutational status in patients with melanoma brain metastases.

MATERIAL AND METHODS

Fifty-nine patients with melanoma brain metastases from two university hospitals (group 1, 45 patients; group 2, 14 patients) underwent surgery with subsequent genetic analysis of the brain metastases tissue to determine the BRAF mutational status. All patients underwent structural MRI preoperatively. Areas of contrast enhancement were manually segmented and analyzed. Group 1 was used for model training and validation, group 2 for model testing. After image preprocessing, 1,316 radiomics features were extracted using the open-source PyRadiomics package. A test-retest analysis was performed to identify robust features prior to feature selection. Finally, the best performing radiomics model was applied to the test data (group 2). Diagnostic performances were evaluated using receiver operating characteristic (ROC) analyses.

RESULTS

Twenty-two patients (49%) in group 1, and 6 patients (43%) in group 2 had an intrametastatic BRAF V600E mutation. Using a six parameter radiomics signature, a linear support vector machine classifier yielded an average area under the ROC curve (AUC) of 0.87 (accuracy, 85%; sensitivity, 78%; specificity, 91%) for prediction of the BRAF mutational status in the training data (group 1). Finally, the classifier achieved an AUC of 0.85 (accuracy, 86%; sensitivity, 83%; specificity, 88%) in the test data (group 2).

CONCLUSION

The developed radiomics classifier allows a non-invasive prediction of the intracranial BRAF V600E mutational status in patients with melanoma brain metastases and may be of value for treatment decisions.
P14.31 Between hospital variation in timings to multidisciplinary glioblastoma care in the Dutch Brain Tumor Registry
Authors: De Swart M E , Ho V K Y , Lagerwaard F J , Brandsma D , Broen M P , French P , Gijtenbeek A , Geurts M , Hanse M C J , Idema B , Klein M , Koekkoek J A F , Polman S K , Samuels C W , Seute T , Sijben A E J , Smits M , Vos M J , Walenkamp A M E , Wesseling P , Kouwenhoven M C M , De Witt Hamer P C
Published: September 2021

BACKGROUND

Delay in cancer care may adversely affect emotional distress, treatment outcome and survival. Optimal timings in multidisciplinary glioblastoma care are a matter of debate and clear national guidelines only exist for time to neurosurgery. We evaluated the between-hospital variation in timings to neurosurgery and adjuvant radiotherapy and chemotherapy in newly diagnosed glioblastoma patients in the Netherlands.

MATERIAL AND METHODS

Data were obtained from the nation-wide Dutch Brain Tumor Registry between 2014 and 2018. All adult patients with glioblastoma were included, covering all 18 neurosurgical hospitals, 28 radiotherapy hospitals, and 33 oncology hospitals. Long time-to-surgery (TTS) was defined as >3 weeks from the date of first brain tumor diagnosis to surgery, long time-to-radiotherapy (TTR) as either >4 or >6 weeks after surgery, and long time-to-chemotherapy (TTC) as either >4 or >6 weeks after completion of radiotherapy. Between-hospital variation in standardized rate of long timings was analyzed in funnel plots after case-mix correction.

RESULTS

A total of 4203 patients were included. Median TTS was 20 days and 52.4% of patients underwent surgery within 3 weeks. Median TTR was 20 days and 24.6% of patients started radiotherapy within 4 weeks and 84.2% within 6 weeks after surgery. Median TTC was 28 days and 62.6% of patients received chemotherapy within 4 weeks and 91.8% within 6 weeks after radiotherapy. After case-mix correction, three (16.7%) neurosurgical hospitals had significantly more patients with longer than expected TTS. Three (10.7%) and one (3.6%) radiotherapy hospitals had significantly more patients with longer than expected TTR for >4 and >6 weeks, respectively. In seven (21.2%) chemotherapy hospitals, significantly less patients with TTC >4 weeks were observed than expected. In four (12.1%) chemotherapy hospitals, significantly more patients with TTC >4 weeks were observed than expected.

CONCLUSION

Between-hospital variation in timings to multidisciplinary treatment was observed in glioblastoma care in the Netherlands. A substantial percentage of patients experienced timings longer than anticipated.
P14.49 Prescription preferences of antiepileptic drugs in brain tumor patients: an international survey
Authors: van der Meer P B , Dirven L , van den Bent M J , Preusser M , Taphoorn M J B , Ruda R , Koekkoek J A F
Published: September 2021

BACKGROUND

This study aimed at investigating antiepileptic drug (AED) prescription preferences in patients with brain tumor-related epilepsy (BTRE) among the European neuro-oncology community, the considerations that play a role when initiating AED treatment, the organization of care, and practices with regard to AED withdrawal.

MATERIAL AND METHODS

A digital survey containing 31 questions about prescription preferences of AEDs was set out among members of the European Association of Neuro-Oncology (EANO).

RESULTS

A total of 198 respondents treating patients with BTRE participated of whom 179 completed the entire survey. Levetiracetam was the first choice in patients with BTRE for almost all respondents (90% [162/181]). Levetiracetam was considered the most effective AED in reducing seizure frequency (72% [131/181]) and having the least adverse effects (48% [87/181]). Common alternatives for levetiracetam as equivalent first choice included lacosamide (33% [59/181]), lamotrigine (22% [40/181]), and valproic acid (21% [38/181]). Most crucial factors to choose a specific AED were potential adverse effects (82% [148/181]) and interactions with other antitumor treatments (76% [137/181]). In the majority of patients neuro-oncologists were involved in the treatment of seizures (73% [132/181])). Other relevant findings were that a minority of respondents ever prescribe AEDs in brain tumor patients without epilepsy solely as prophylaxis (29% [53/181]), but a majority routinely consider complete AED withdrawal in seizure free BTRE patients after antitumor treatment (79% [141/179]).

CONCLUSION

Our results show that among European professionals treating patients with BTRE levetiracetam is considered the first choice AED, with the presumed highest efficacy and least adverse effects.