bluuebunny/crossref_metadata_2025 huggingface dataset:
P17.11.A DEVELOPMENT AND CHARACTERISATION OF THE QCELL-R RECURRENT GLIOBLASTOMA PRIMARY CELL LINE RESOURCE: MODELS TO DRIVE BREAKTHROUGH DISCOVERIES IN BRAIN CANCER
Authors: Bradbrook K A , Baumgartner U , Smith F M , Johnston R , Harris L , Hoyte S , Lwin Z , Alexander H , Jeffree R , Day B W
Published: September 2023

BACKGROUND

Glioblastoma (GBM) is the most aggressive brain tumour in adults, with a median survival of only 15 months. Despite aggressive treatment with chemotherapy using temozolomide and radiotherapy, GBM has a high prevalence of recurrence with almost all cases recurring within the first year. This highlights a clear need to develop a deeper understanding of GBM recurrence and to develop effective models to test novel therapies. The vast inter- and intra-tumoural heterogeneity and tumour cell plasticity are complicating the development of effective therapies for brain cancer patients. Large-scale genomic analyses of primary and recurrent human GBM tumour samples have revealed a complex genomic architecture. However, the majority of GBM discovery science has been conducted in treatment naïve tumour models, which fail to capture therapy resistance and tumour evolution. Hence, these changes have been difficult to link to GBM growth and functional cell properties upon recurrence.

MATERIAL AND METHODS

To address this, we have developed the QCell-R resource, a collection of functional models of recurrent GBM. In collaboration with the Royal Brisbane and Women’s Hospital (RBWH), pair-matched patient tumour samples from the initial resection and at recurrence post-therapy have been collected. From these tissue specimens, in vitro cell lines in both 2D and 3D cultures and in vivo orthotopic xenograft models have been developed. Response to standard of care therapy (temozolomide and radiotherapy) were assessed using IncuCyte proliferation assays. Bulk mRNA, scRNA and exome sequencing were also performed.

RESULTS

QCell-R consists of 11 patient-derived recurrent GBM models, with the time between resections varying from 5-13 months. There are four pair-matched QCell-R models, as well as three standalone recurrent models. Response to standard of care therapy varied between models, with one model exhibiting a four fold higher growth rate-50 (GR50) after temozolomide treatment and a 2.7 fold increase in radiation resistance compared to the matched treatment naïve counterpart. The mRNA and scRNA sequencing has been compared to publicly available datasets to identify genes of interest that may be targetable in recurrence to test in these models.

CONCLUSION

QCell-R represents a valuable resource to define novel therapies for recurrent GBM. Elucidation of tumour heterogeneity and tumour evolution will identify targetable genes contributing to therapy resistance in these models. Identifying these targetable genes from QCell-R allows the development of novel treatments, creating strategies that may reduce the rate of recurrence by limiting therapy resistance and inhibiting recurrence-initiating cells.
P17.14.B PHASE I TRIAL OF DNX-2401 ONCOLYTIC ADENOVIRUS COMBINED WITH A SHORT COURSE OF DOSE-DENSE TEMOZOLOMIDE FOR RECURRENT GLIOBLASTOMA
Authors: Gallego Perez-Larraya J , García-Moure M , González-Huárriz M , Zalacaín M , Marrodán L , Puigdelloses M , Labiano S , de la Nava D , Laspidea V , Ausejo I , Hervás I , Esparragosa I , Giráldez M , Domínguez P , Martínez-Simón A , Idoate M , Fueyo J , Gomez-Manzano C , Patiño A , Díez-Valle R , Tejada S , Alonso M
Published: September 2023

BACKGROUND

Oncolytic virotherapy is emerging as a novel therapeutic strategy for glioblastoma (GBM). DNX-2401, an oncolytic adenovirus with selective replication and enhanced infectivity in tumor cells, showed anti-tumor effect in a previous clinical trial for recurrent GBM. The combination of DNX-2401 and Temozolomide (TMZ) has shown a synergistic anti-glioma effect in preclinical models.

MATERIAL AND METHODS

We conducted a phase I open-label single-center study to investigate the safety and efficacy of this therapeutic combination in patients with first recurrence of GBM. Following tumor biopsy or resection, 3x10e10 viral particles of DNX-2401 were injected intratumorally or into the post-resection cavity, respectively. Approximately 2 weeks after DNX-2401 injection, patients were treated with up to two 28-day cycles of oral 150 mg/m2/day TMZ in a 7 days on/7 days off schedule.

RESULTS

Thirty-one patients (13 [42%] female, 18 [58%] male) with confirmed recurrent GBM were enrolled and treated with DNX-2401 followed by a median of 1.5 cycles of TMZ (range, 0-2). Median age was 54 years (range, 25-78) and median KPS was 70 (range 70-90). Surgery consisted of biopsy in 14, partial resection in 15 and complete resection in 2 patients. IDH1/2 mutation was confirmed in 1 patient. MGMTP was methylated in 9 and unmethylated in 21 patients (1 patient, unknown). Best response according to RANO criteria was partial response in 1 patient, stable disease in 21 subjects and progressive disease in the remainder. Median PFS was 51 days (95% CI, 43-81). Median OS was 282 days (95% CI 202-344) with 6-month and 12-month OS rates of 72.5 (95% CI 52.4-85.2) and 27.5 % (95% CI 12.4-45.0), respectively. Four patients survived more than 18 months with 2 long-term survivors exceeding 4.5 years. Treatment was generally well tolerated. The safety profile was as expected for subjects treated with TMZ alone. Except one subject who experienced grade 2 brain edema possibly related to DNX-2401, no additional toxicity was considered attributable to DNX-2401. The most frequent reported adverse events were lymphopenia (54.8%), asthenia (48.4%), constipation (41.9%), headache (29%) and pyrexia (22.6%). Ongoing correlative analyses evaluating immune response are ongoing.

CONCLUSION

Our data suggest that treatment with DNX-2401 followed by a short-course of dose-dense TMZ is feasible, can be safely administered with expected adverse events related to chemotherapy, and appears to render a clinical benefit in a subset of patients with recurrent GBM. Further assessment of this therapeutic approach is warranted.
P18.04.B SINGLE CELL TRANSCRIPTOMIC ANALYSIS IDENTIFIES DISTINCT INTRATUMORAL SUBCLONES IN MENINGIOMA
Authors: Blume C , Tang Y , Dogan H , Ritter M , Dentro S , von Deimling A , Gerstung M , Schlesner M , Sahm F , Maas S L N
Published: September 2023

BACKGROUND

Meningiomas arise from the leptomeninges of the brain and spinal cord. Despite being the most common intracranial tumor in adults, risk stratification remains challenging. Currently, tumors are graded based on histology as well as molecular markers. In recent years, several epigenomic classification systems with a correlation to patient outcome have been proposed for meningiomas. However, these classification systems do not discriminate between effects of the tumor microenvironment and the tumor itself or consider distinct intratumoral subpopulations with different phenotypes. To address this, we set out to investigate intratumoral differences and correlated them with gene expression differences.

MATERIAL AND METHODS

We applied single nuclei RNA sequencing (10X Genomics 3’) to 30 meningioma samples to obtain transcriptomic profiles on single cell level. Copy number variations were estimated for single cells based on the transcriptomic profiles to identify clonal differences within a given tumor.

RESULTS

Based on aberrations in the copy number profile, we were able to identify distinct subclones within the same tumor, which could in many cases be connected to a change in the transcriptomic profile of the respective subclone. Different patterns of subclonal diversity were observed between tumor grades. Further insight into the subpopulations was used to infer a novel model for prognostication which was validated by methylation data.

CONCLUSION

Altogether, these results demonstrate that diverse subclones co-exist within meningioma, especially within higher-grade tumors. Effects of meningioma subclones on tumor growth and their relevance for clinical risk prediction remain to be elucidated.
P18.06.B EVALUATION OF P16 AND MTAP IMMUNOHISTOCHEMICAL EXPRESSION AS SURROGATE MARKERS OF CDKN2A/B DELETION IN MENINGIOMAS
Authors: Ricci A A , Tampieri C , Nozzoli F , Buccoliero A M , Mangherini L , Verdun di Cantogno L , Osella-Abate S , Pellerino A , Bruno F , Rudà R , Garbossa D , Massi D , Cassoni P , Bertero L
Published: September 2023

BACKGROUND

Homozygous deletion (HD) of CDKN2A/B genes (chr. 9p21) is a molecular hallmark for meningiomas grading. However, testing is expensive and time-consuming. Immunohistochemical (IHC) evaluation of the CDKN2A (p16) and adjacent MTAP gene products has been proposed as a diagnostic surrogate of CDKN2A HD, with unsatisfactory or inconclusive results.

MATERIAL AND METHODS

CDKN2A status was assessed by FISH with the Zytolight SPEC CDKN2A/CEN 9 Dual Color probe (Zytovision©) in 68 meningiomas from 56 patients. A 15% cut-off of HD cells was used to define a sample as deleted. Negative (<10% positive cells) p16 (Ventana) and MTAP (Clone 2G4; Abnova) IHC were considered as a surrogate for CDKN2A HD. Since CDKN2A/B deletion in meningiomas is characterized by spatial and longitudinal heterogeneity, the same area selected for FISH analysis was assessed by IHC. Pearson Chi-square test for categorical variables and survival analysis with log-rank test and the Kaplan-Meier method were performed using the Stata/MP 17.0 software.

RESULTS

In our series, 29/56 (51.7%) patients were male, and median age at diagnosis was 69 years. Median overall survival (OS) from diagnosis was 37.9 months (27 months for HD cases and 39.3 months for non-HD). 51 (75%) samples were diagnosed as WHO grade 3 meningiomas, 11 (16.2%) as grade 2 and 6 (8.8%) as grade 1. 11 cases (16.2%) were CDKN2A-deleted by FISH. p16 IHC was negative in 25 (36.8%) cases, while MTAP IHC was negative in 24 (35.3%) cases. No correlation between these markers was observed (Cohen’s κ=-0.0202, p=0.7158). 5/11 (45.4%) deleted samples were negative for p16 staining, while 37/57 (64.9%) non-deleted samples displayed p16 positivity (sensitivity: 20%; specificity: 86.1%). MTAP IHC was negative in 8/11 (72.7%) deleted samples, whereas 41/57 (71.9%) non-deleted samples retained MTAP expression (sensitivity: 33.3%; specificity: 93.2%). Unlike p16 IHC, MTAP loss correlated with CDKN2A HD (p=0.005). To address intratumoral heterogeneity, FISH analysis was repeated on 2 samples with markedly variable p16 and MTAP stainings. For each sample, one positive and one negative area were analyzed, observing a correlation between IHC and HD FISH status.

CONCLUSION

MTAP IHC showed a higher correlation with CDKN2A HD compared to p16 IHC in meningiomas, even though the low sensitivity hinders its use in routine diagnostics. Nevertheless, the use of p16/MTAP IHC to select areas for FISH analysis could be considered to address intratumoral heterogeneity of CDKN2A status.
P18.08.B COMPARISON OF DOSE CALCULATION PLANNING SYSTEMS FOR RECCURENT MENENGIOMA TREATED WITH FRACTIONATED RE-IRRIDATION
Authors: Hıdımoğlu Ç , Delikaya M , Hoca S , Anacak Y , Kamer S
Published: September 2023

PURPOSE

Meningioma is among the most common tumors of the central nervous system, accounting for approximately one-third of all brain tumors. Surgery is mainstay treatment and Radiotherapy (RT) provides long-term control in many patients, however recurrences following RT may occur and the safety and efficacy of a second course of RT is not well defined, technical and planning features are yet to be clarified. In this study, we compared various treatment planning systems (TPS) used in RT in a patient who had progressed meningioma after three applications of Gammaknife radiosurgery (GK-SRS). Case Presentation: 55-year-old male patient was diagnosed with grade-1 meningioma of the sphenoid wing in 2014 and subtotal excision was performed, with no further treatment. Progression was detected in 2016, and 11 Gy single fraction GK-SRS was applied in two sessions (inferior and superior parts of the tumor was irradiated in separate GK-SRS applications with 2 months apart) to the recurrent lesion in the right spheno-orbital region in a GK center. Patient was well until June 2022 when progression was detected in the right infratemporal region. Another GK-SRS application of 11 Gy was performed to the patient at the same institute.In April 2023 progression of the tumor was detected, tumor was irresectable and patient referred to our department for fractionated radiotherapy. Recurrent tumor was originating from right sfenoid wing and extending to right infratemporal fossa. We obtained the radiation dose distributions from the previous GK-SRS plans. Due to dose limits on the right optic nerve due to previous radiation dose disturbution , the conventional fractionated radiotherapy was planned . The PTV dose was planned to be 45 Gy/25 fx. Eclipse and Brainlab systems were compared for treatment planning. Right optic nerve dose of EQD2 was already above the limits, thus conventional fractionation (45 Gyin 25 fractions) was prescribed. Two separate plans were generated using Varian-Eclipse and Brainlab-Elements TPS, and the dose distribution of those plans were compared. Plan optimization was performed in both planning systems to provide PTV D%95. While the PTV Dmax was 57.24 Gy in BrainLAB, it was 48.7 Gy in Eclipse. Dmax doses for Brainlab and Eclipse were: right optic nerve 10.11 Gy vs. 26.9 Gy, chiasm 6.68 Gy vs. 20.5 Gy respectively. In Eclipse plan optimization, the collimator and table angles were optimized manually, while in Brainlab planning system, they were automatically handled, therefore normal tissues can be better preserved with increase of hot spots inside the PTV. This situation is observed clearly in this case.

CONCLUSION

Using different table and collimator angles in plan optimization can yield better results in providing normal tissue dose tolerance, especially in the irradiation of central nervous system.
P18.09.A PROTON THERAPY FOR PATIENTS WITH MENINGIOMA - WHAT ABOUT FINANCIAL TOXICITY AND OCCUPATIONAL STATUS?
Authors: Flechl B , Achtaewa M , Konrath L , Hug E , Fossati P , Pelak M , Georg P , Lütgendorf-Caucig C
Published: September 2023

BACKGROUND

Patients (pts) with meningioma are commonly treated with proton therapy (PT) in order to minimize integral dose to normal brain parenchyma. Considering the high local control probability, preservation of Quality of Life (QoL) is gaining increasing importance.Potential loss of employment, inability to work or need to reduce working hours may lead to financial worries negatively affecting QoL. We investigated the subjective QoL and disease burden in pts with meningioma treated with PT with regards to income, financial toxicity, inability to resume work before and after PT.

MATERIAL AND METHODS

Data from prospectively assessed questionnaires (EORTC QLQ-C30) including an item for subjective financial difficulties, scaled from 1-4 (1=“not at all” to 4=”very much”), was collected from pts treated with PT for meningioma. Observed time points were prior to start of treatment (t1) and incrementally thereafter (completion of treatment, at 3months (ms),6ms,12ms,24ms,36ms and 48ms;t2-t8). Employment status was collected and net household income was assessed and ranked into 5 groups ranging from <1300€ to >5000€.

RESULTS: RESULTS

171pts (39m/131f) aged 20-88yrs (mean 55.1) with meningioma were included. At a mean observation time of 29.6ms, 991 data sets were collected. 37pts (35.9%) reported health-related inability to work before PT. Over follow up (FU), it decreased to 33.8% at 12ms, 27.3% at 24ms, 15.4% at 36ms, 13.6% at 48ms. 34pts (33%) were employed prior to their diagnosis (14part-time, 18full-time). While rates of full-time employment initially decreased, it steadily increased from 1yr FU (t3-t8: 28.7%-59.1%), rates of part-time remained stable (t3-t8:27.2%-27.3%), see figure 1. Subjective financial burden correlated significantly with occupational situation (Spearman;p<0.001) indicating a reduction in patient-reported financial difficulties after commencement of work / increase in working hours. There were no relevant changes in pts´ income (Friedman:p=0.610); however, pts with lower income prior to PT reported subsequently higher levels of financial difficulties (Spearman:p<0.001). Before PT, 69 pts (40%) reported various levels of financial difficulties. Although rates decreased initially at the end of PT (30.2%), they consistently decreased at all subsequent FUs. This reflects the lower burden of financial toxicity over time.

CONCLUSION

At a mean observation time of >2 years, this study prospectively analyzed the potential impact of proton therapy in patients treated for meningioma. Patients reported an overall increase in employment rate, significant improvement in their financial situation and preservation and gain in their quality of life over time.
P19.04.B EXAMINATION OF THE ROLES OF KDM6A AND KDM6B HISTONE DEMETHYLASES IN ISOCITRATE DEHYDROGENASE (IDH) MUTANT GLIOMA
Authors: Sarac S , Yilmaz E , Kayabolen A , Bagci Onder T
Published: September 2023

Glioma, comprising 80% percent of all malignant brain tumors, is one of the most aggressive and difficult to treat tumors. Isocitrate dehydrogenase (IDH) is an enzyme that catalyzes the oxidative decarboxylation of isocitrate, producing α-ketoglutarate. Most IDH-mutant gliomas have a heterozygous point mutation in IDH1 that causes an arginine-to-histidine substitution at amino acid 132. Mutant IDH enzyme leads to 2-hydroxyglutarate accumulation in cells, inhibiting DNA and histone demethylases and ultimately generating a hypermethylated epigenetic phenotype. Considering that the mutant IDH enzyme generates a discrete epigenetic profile, we aimed to develop an epigenetic-based therapy approach for IDH mutant glioma. To this end, we performed chemical library screens consisting of inhibitors of important epigenetic enzymes and identified GSK-J4 as a chemical selectively targeting IDH1 mutant cells.GSK-J4 is a well-known inhibitor for histone demethylases KDM6A and KDM6B; therefore, we aimed to phenocopy the effects of the chemical approach with the genetic approach by depleting KDM6A and/or KDM6B using CRISPR/Cas9. We successfully established IDH-mutant primary glioma cell lines deficient in KDM6A and/or KDM6B expression, as revealed by qRT-PCR and Western Blots. Cells with double knockout were markedly slower in growth compared to controls which had received nontargeting gRNA or single gRNAs targeting each enzyme. In the future, we will examine changes in cell cycle and apoptosis pathways upon KDM6A and KDM6B knockouts and test the response of these cells to mutant IDH inhibitors, TMZ, or irradiation. In parallel, genome-wide changes in gene expression and cellular pathways, histone modifications, and chromatin accessibility will be analyzed, via RNA-seq, ChIP-seq, and ATAC-seq techniques, respectively.Even though KDM6A and KDM6B have been shown to have important but sometimes conflicting roles in various tumor types, no study showed their roles in IDH mutant glioma. Therefore, revealing the functional mechanisms of KDM6A and KDM6B in IDH-mutant gliomas will serve as an important step that leads to the development of novel epigenetic-based therapeutic approaches for IDH-mutant gliomas.This project is supported by TUBITAK with the given grant number: 219S882.
P19.06.B T2/FLAIR MISMATCH, SPECIFIC RADIOGENOMIC MARKER FOR A DIFFUSE LOW GRADE ASTROCYTOMA
Authors: Kwikima U M , Rutabasibwa N , Fezeu F , Gousias K , Minja F , Filippi C
Published: September 2023

A 36-year-old woman presented with recurring episodes of generalized tonic clonic seizures. An MRI from an outside institution demonstrated an intra-axial brain mass suspicious for a primary brain tumor. Repeat conventional and advanced MRI imaging revealed a primary brain mass centred on the left postcentral gyrus involving cortex and subcortical white matter. The lesion was homogenously hyperintense on T2-weighted imaging, and centrally iso-to hypointense on FLAIR with a rim of hyperintense signal on the FLAIR sequence. There was no significant peritumoral edema or minimal effacement of the central sulcus. No abnormal enhancement was seen post-contrast. The lesion demonstrated no reduced diffusivity on diffusion-weighted imaging. MR perfusion showed no elevation in regional cerebral blood volume or flow. Findings are most compatible with a low grade glioma. Patient underwent total surgical resection and biopsy for histopathology. Genetic sequencing revealed an IDH mutant, non 1P,19q codeleted grade II astrocytoma. The diagnosis of adult infiltrating gliomas is predicted using imaging, and confirmed by histopathology, and molecular diagnostic methods. Regardless of grade the 1st phase in glioma diagnosis and management is IDH status. A multidisciplinary approach to the diagnosis of low grade and high grade glioma including genetic and molecular analysis is essential, as different genetic and molecular subtypes have different management and prognostic implications. Conventional MRI still represents a mandatory and extremely important step in the diagnostic workflow of neuro oncological patients for preoperative diagnosis, treatment planning, and subsequent follow up. The T2/FLAIR mismatch sign describes the MRI appearance of an IDH-mutant astrocytoma that is non 1p19q codeleted, and it is considered a preoperative novel specific MRI marker for this type of diffuse astrocytoma. In this case, the MRI findings were used preoperatively as a noninvasive tool to diagnose the patient`s low grade glioma which was confirmed by subsequent histological and genetic analysis. TEACHING POINTS1. T2/FLAIR mismatch allows for pre-operative diagnosis of IDH-mutant astrocytomas with a high level of specificity.2. It is particularly helpful in distinguishing diffuse astrocytoma from an oligodendroglioma3. Conventional MR sequences can suggest the diagnosis of IDH mutant gliomas which can assist neurosurgeons in presurgical planning and can help neuro-oncologists with treatment planning including potential clinical trials.
P20.07.A IDENTIFYING SELF-EFFICACY DIFFERENCES IN ADULT RARE CNS PATIENTS PARTICIPATING IN A NOVEL WEB-BASED NATURAL HISTORY
Authors: Acquaye-Mallory A , Vera E , Choi A , Wall K , Kunst T , Gilbert M R , Armstrong T S
Published: September 2023

BACKGROUND

A cancer diagnosis can diminish self-efficacy (sense of control and confidence), which can be essential for self-management. Perceived control in coping effectively with the adverse effects of a diagnosis has been correlated with improved mood, self-regulation, and decreased symptom distress. Using data collected in our global web-based NCI-CONNECT Natural History study (https://www.cancer.gov/rare-brain-spine-tumor/ ), we explored the relationship between self-efficacy levels in managing social interactions (SEMSI), sample characteristics, and mood-related inference (REM) in adult patients with rare CNS tumors.

MATERIAL AND METHODS

Interested adult patients completed a study enrollment confirming a rare diagnosis. Eligibility and consent forms were reviewed with the study coordinator before consent was signed. A unique link to complete the online survey was sent to enrolled patients. This web-based survey captured current demographic/clinical data, symptom burden, and REM (mood, relations with others, enjoyment of life, scores ≥ 2=moderate-severe (M-S)) from the MDASI-BT & MDASI-SP and the PROMIS SEMSI (t-scores: Low=<40 (lower confidence), Average=50 (US general population), High= >60 (greater confidence)).

RESULTS

Evaluated patients (n=166) were predominantly female (72%), the median age was 45 (19-75, and 15% were on active treatment. An ependymoma diagnosis (66%), no recurrence (80%), and tumor location in the brain (53%) were common. Median time since diagnosis was 14 months (0-402 months). Most patients reported average SEMSI, none reported high, and 28% of brain vs. 7% of spine reported low SEMSI. Among demographic/clinical factors, low SEMSI correlated with lower education (r=0.22) and a prolonged time between symptoms and surgery (r= -0.29) among brain patients. Additionally, married (42%) brain patients had a higher chance of endorsing low SEMSI. No associations were identified for spine patients. Brain patients, reporting low (92%) and average (48%) SEMSI, also endorsed M-S REM (p<0.001, OR=12.1, n=87). Additionally, all M-S REM symptoms (fatigue, disturbed sleep, distress, sadness, irritability) were associated with low SEMSI. As REM worsened, SEMSI decreased in brain patients (r= -0.54), with no relationship found in spine patients.

CONCLUSION

We found that brain tumor patients reported less confidence in managing social interactions with low self-efficacy levels linked to marital status, education, a longer time between symptoms and surgery, and worsened mood-related interference, but surprisingly no association in those with spine tumors. Identifying patient characteristics associated with self-efficacy within tumor locations can lead to targeted cognitive and behavioral interventions motivating patients to mitigate distress that can help with adjustment to one’s disease.
P20.12.B DNA METHYLATION PROFILING OF ADULT SPINAL GLIAL TUMOURS; RESULTS FROM A LARGE SINGLE CENTRE STUDY
Authors: Clarke M T , Pereira R , Mackay A , Grabovska Y , Cruickshank R , Dutt M , Mariathasan P , Kumar A , Casey A , Merve A , Jaunmuktane Z , Jones C , Brandner S
Published: September 2023

BACKGROUND

Glial tumours can occur in any central nervous system location, including the spinal cord. Although rare, spinal gliomas can represent a significant diagnostic challenge and are recognised as separate tumour types in the WHO classification.

MATERIAL AND METHODS

This study used DNA methylation profiling to characterise adult spinal glial tumours from a large neurosurgical centre, exploring relative frequencies, and the value of this technique in diagnostic workflows. A search in our laboratory information management system (2006-2021) identified 116 tumours, from patients aged 17.2-79.2 years. Diagnoses included ependymomas (all grades/subtypes) and other high- or low-grade gliomas (HGG/LGG). Extrinsic tumours (metastases, meningiomas, schwannomas) were excluded. DNA underwent methylation profiling (Illumina EPIC BeadArrays, n=116). iDat files were processed using the brain tumour classifier (MNP v12.5 R package), classifying cases against a reference cohort (n=2,800). Longitudinal (n=8) and poor QC cases (n=3) were excluded.

RESULTS

83% (n=87) classified as an ependymoma (myxopapillary ependymoma (EPN_MPE, n=44), spinal ependymoma (n=43), spinal subependymoma (n=1)). We identified HGGs that were not diagnosed histologically (diffuse midline glioma, H3 K27-altered (n=2), high-grade astrocytoma with piloid features (n=1)) and 41% of cases (n=18/44) diagnosed histologically as an ependymoma, CNS WHO grade 2, classified as EPN_MPE. LGGs were less frequent (pilocytic astrocytoma (n=3), pleomorphic xanthoastrocytoma (n=1), rosette-forming glioneuronal tumour (n=1)). 9% (n=9) did not classify with existing methylation classes. Copy number analysis revealed subtype-specific changes, including prognostic alterations.

CONCLUSION

In conclusion, this single-centre study highlights the crucial role of DNA methylation profiling as part of diagnostic workflows for spinal glial tumours.
P20.15.A DESCRIPTIVE ANALYSIS OF A SERIES OF H3 K27-ALTERED DIFFUSE MIDLINE GLIOMAS IN CHILDREN AND ADULT POPULATION
Authors: Salva de Torres C , Lopez Valbuena D , Gonzalez M , Vieito M
Published: September 2023

BACKGROUND

Molecular biomarkers have gained importance in providing diagnostic information for brain and spinal cord tumors. Diffuse midline gliomas (DMG) are now defined as H3 K27-altered. H3 K27M mutations were first described in pediatric diffuse pontine gliomas but can also be encountered in adult gliomas. The H3 K27M mutation often co-occurs with mutations in TP53, PDGFR, or ACVR1 and is mutually exclusive to IDH1/2 mutations and 1p/19q co-deletion. Surgical resection is often not feasible for its localization and the benefit of temozolomide (TMZ) is not clear as they are MGMT unmethylated; all of it conferring a poor prognosis. It has been suggested that pediatric patients (pts) have worse outcomes. Our aim was to describe pts with H3 K27-altered gliomas to better understand the characteristics of this population.

MATERIAL AND METHODS

We analyzed clinical, histological and molecular features of 6 adults and 10 pediatric pts diagnosed with H3 K27M-mutant gliomas between May 2016 and January 2021 in a tertiary hospital in Barcelona.

RESULTS

For adults, mean age at diagnosis was 34.6 years (range = 20 - 55 years). For children, mean age was 11.2 years (range = 4 - 17 years). Male-to-female ratio was 1:1. Tumors involved thalamus (adult = 3; pediatric = 3), pons (adult = 1; pediatric = 6), and pineal region (n = 1). Ki67 range was 2-60% (pediatric mean 32%, adult mean 20%). A molecular panel was analyzed in 8 pediatric pts and 1 adult. No EGFR amplifications were detected.Three of them had TP53 mutations and 2 had PDGFRA amplification. Only 2 pediatric pts had MGMT methylation. Regarding treatment, 9 pediatric and 4 adult pts underwent radiotherapy and TMZ as first-line, with a mean time to intervention of 5.6 months. One child went through palliative care. As a second-line treatment, re-irradiation was used in 3 pediatric pts and irinotecan-bevacizumab was used in 2 adults. One adult received up to 4 different treatments (TMZ chemoradiotherapy followed by adjuvant TMZ, irinotecan-bevacizumab, lomustine and metronomic TMZ).All 9 pediatric pts died, with a mean OS of 12.0 months. Among adults, 2 pts died, 10.5 and 31.2 months after diagnosis, 1 has progressed to first-line and is receiving PCV as second-line treatment, and 1 has completed Stupp regimen with stable disease as best response.

CONCLUSION

Although the sample size is limited, our cohort data resembles what has been previously reported in terms of clinical and molecular characteristics: diagnosed in young adults and pediatric pts, characterized by a midline location, a low rate of MGMT promoter methylation, frequent TP53 and PDGFR alterations, and poor prognosis. There is currently no consensus on optimal treatment sequence or best treatment for these pts. Collaborative effort and participation in clinical trials are needed to keep advancing in this poor prognosis disease.
P21.02.B THE EFFECT OF SOCIODEMOGRAPHIC FACTORS ON GLIOMA PROGNOSIS
Authors: Söderlund M , Sandström M , Almqvist C , Sjöström O , M Dahlin A , Sjöström S , Numan Hellquist B , Melin B
Published: September 2023

BACKGROUND

Sociodemographic factors are well known to contribute to health disparities for different cancer diagnoses, but they are not extensively studied for glioma patients. In this study socioeconomic status (SES), travel time to health care, cohabitation status, and region (northern Sweden compared to three regions in southern Sweden) were investigated in relation to prognosis for patients with glioma WHO grade I-IV.

MATERIAL AND METHODS

The Swedish National Quality Registry for Brain Tumors was used to identify 1276 patients with glioma WHO grade I-IV, diagnosed 2009-2013. The Swedish population-based database RISK North combines data from several health care and demographic registries through the unique personal identity number. The RISK North was used to study survival in relation to SES, cohabitation status (living alone vs living with another adult person), travel time to the closest regional hospital (i.e. the closest hospital with a neurosurgical unit), and region. Educational level was used as a proxy for SES.

RESULTS

In univariable survival analysis, patients with glioma WHO grade III-IV and high SES had a longer survival compared to patients with low SES (middle school (ref) HR:1, high school HR:0.67 CI[0.56-0.81], university/college HR:0.65 CI[0.53-0.79], p<0.0001). In the multivariable model for the same group, survival was longer for patients with higher SES (middle school (ref) HR:1, high school HR:0.81 CI[0.67-0.98], p=0.033; university/college HR:0.81 CI[0.66-1.00], p=0.048). For patients with glioma WHO grade I-IV, there were no significant differences in survival in relation to travel time, cohabitation status, or region in multivariable survival analysis.

CONCLUSION

Survival was significantly worse in patients with lower SES compared to higher SES for patients with glioma WHO grade III-IV. No significant differences were found in survival in relation to cohabitation status (between those living alone and those living with another adult person), travel time to regional hospital, or between the northern Sweden and three regions in southern Sweden.
P21.03.A CDKN2A/B VERSUS MORPHOLOGY IN DIAGNOSING WHO GRADE 4 IDH MUTATED ASTROCYTOMAS: WHAT IS THE CLINICAL RELEVANCE?
Authors: Lipatnikova A E , Denés A , Olsson Bontell T , Carén H , Ferreyra Vega S , Kling T , Jakola A S
Published: September 2023

BACKGROUND

In the 2021 WHO classification system, the glioma subgroup IDH-mutated astrocytomas grade 4 was introduced, and diagnosis can be based upon molecular or histopathological morphological criteria. We here explore if the reason for a diagnosis of WHO grade 4 IDH mutated astrocytoma influences survival.

MATERIAL AND METHODS

Twenty-five patients with a revised diagnosis of IDH-mutated astrocytoma grade 4 were included. Patients were divided in three groups based upon the; (i) Morphological high grade (necrosis and/or microproliferation in microscopy); (ii) Molecular high grade (homozygous CDKN2A/B homodelation); (iii) Both morphological and molecular high grade. Inclusion period was 2007-2018 for molecular high grade and 2012-2018 for morphological high grade. All patients had potential for at least 5 year follow-up.

RESULTS

The median survival following surgery was 5.2 years (Q1-Q3 2.9-7.0 years). The median age was 42 years (Q1-Q3 33-59). As expected the tumors had the frontal lobe predominance (72%). Seizures were the most common debut symptom, occurring in 48% of patients. There were 12 patients in group (i), nine patients in group (ii), and four patients in group (iii). Group (iii) with both morphological and molecular WHO grade 4 criteria was characterized by a significantly worse prognosis with a median estimated survival of 2.8 years (p = 0.002). There was no substantial difference in overall survival between groups (i) and (ii) (7.3 years vs 5.2 years, p = 0.237).

CONCLUSION

The median survival of IDH-mutated astrocytoma grade 4 is approximately five years, while prognosis seems to be significantly worse for the minority of patients where the tumor fulfills both molecular and morphological criteria. More research into larger cohorts is encouraged.
P21.04.A IMPROVEMENTS IN SURVIVAL FOR GLIOBLASTOMA IN THE POST-STUPP PROTOCOL ERA
Authors: Neff C , Price M , Chavez G , Proescholdt C , Kruchko C , Cioffi G , Waite K , Barnholtz-Sloan J , Ostrom Q T
Published: September 2023

BACKGROUND

The Stupp protocol was accepted as standard of care for glioblastoma in 2005, and has led to significant increases in overall survival. Prior analyses have identified additional survival gains post-Stupp, though the source of these is unknown. In this analysis, we leveraged two large datasets to identify trends in survival and potential treatment factors associated with these improvements.

MATERIAL AND METHODS

Provider-side commercial claims data were obtained from IQVIA for adults (18+ years) diagnosed with malignant brain tumor (ICD-9/ICD-10:191.0-191.9/C71.0-C71.9) from 2015-2021 who received biopsy/resection and temozolomide within 60 days of diagnosis. Treatment patterns were determined using ICD-9/ICD-10 procedure and HCPCS/CPT codes. Death was determined by CPT codes or last claim followed by ≥30 days of no claims. Elixhauser comorbidity score was generated prior to diagnosis. Population-based survival data were obtained from the National Program of Cancer Registries (NPCR) from 2004-2018 for microscopically-confirmed adult (18+ years) glioblastoma cases receiving surgery and radiation. Median survival was estimated using Kaplan-Meier regression, and cox proportional hazards models were used to assess potential prognostic factors. Survival analyses were censored at 36 months.

RESULTS

The IQVIA dataset had 18,883 individuals and NPCR had 92,540 individuals identified as being diagnosed with glioblastoma and meeting treatment criteria. Median survival among IQVIA cases was 13.9 months (95%CI=13.7-14.1), and 14 months (95%CI=14-14) in NPCR. Median survival in NPCR increased from 11 months in 2004-2006, to 14 months in 2016-2018. Within IQVIA, 19% of individuals had ≥1 claim for Bevacizumab and 15.5% had ≥1 claim for tumor treating fields (TTFields). Use of TTFields and/or Bevacizumab in treatment were associated with significantly improved survival after adjustment for age, sex, and comorbidities.

CONCLUSION

s: Survival in glioblastoma continues to improve over time, which may be due to developments in therapeutic approaches. Assessment of population-level survival patterns is essential for understanding the impact of treatment advancements.
P21.06.A TIME IN ONCOLOGY. GLIOBLASTOMA REAL-WORLD DATA
Authors: Macià i Garau M , Lucas Calduch A , García Expósito N
Published: September 2023

BACKGROUND

Time is a crucial component in all diagnostic and therapeutic processes of cancer. Retard in the treatment can have adverse consequences on outcomes. Total treatment delays could be due to patient interval (from the first perceived symptom to the first medical consultation) and system interval (from the first medical consultation to end of treatment). To minimize delays, it is essential to know the time intervals elapsed between each of the steps in the diagnostic and the treatment phase.The purpose of this pilot study is to holistically analyze the total treatment interval of cancer patients as a part of process-oriented total quality management with the ultimate intention of having more useful information for benchmarking and making decisions to improve time in oncology.

MATERIAL AND METHODS

During 2019 in a context of public health-care system all relevant clinical pathway time data from the patient’s perceived first symptom until the end of oncological treatment were collected in a prospective cohort of newly diagnosed glioblastoma patients. Clinical pathway is defined as a description of the current practice in an homogeneous patient group treated by a multidisciplinary team and an inventory of actions defining a diagnostic and therapeutic sequence. This cohort was compared with a serie of glioblastoma patients treated in 2020 (COVID-19-year). We analyzed the mean, median and quartile data of 16-time intervals represented on a time scale

RESULTS

From January 1 to December 31, 2019, we collected data from 59 patients diagnosed and treated for a glioblastoma. There were 24 women and 35 men with a mean age of 60,9 years. We collected 1062 time-points. This group was compared with a COVID-19-year cohort of 49 patients (14 women and 35 men with a mean age of 61,7 years and 630 time-points). The median patient interval time and the system interval time were 6 days (0-210) vs 5 (0-150) and 240 days (81-363) vs 255 (120-482) respectively. Median time from surgery to the start of adjuvancy was 34 days (19-56) vs 34 (17-108). No differences were found in any of the intervals analyzed, in the overall treatment time of radiotherapy or in the dose intensity of chemotherapy.

CONCLUSION

The routine measurement of the intervals between the different diagnostic and therapeutic actions is essential to monitor the time of clinical processes in terms of quality and benchmarking. It is also essential to standardize in a holistic way the distressing temporality in oncology.
P22.02.B RELATIVE REPRESENTATIVES IN RESEARCH: HOW TO APPLY PATIENT AND PUBLIC INVOLVEMENT IN THE DEVELOPMENT OF AN INTERVENTION FACILITATING RELATIVE’S INVOLVEMENT IN THE PATIENT’S CARE AND DISEASE TRAJECTORY
Authors: Guldager R , Smedegaard P S , Nordentoft S
Published: September 2023

BACKGROUND

The importance of engaging patients and the public in health research is gaining growing recognition. However, robust evidence of the process seems to be lacking. This study aims to apply Patient and Public Involvement as a panel of relatives from the development to implementation of a clinical tool, to systematically involve relatives of patients with acquired brain injury and a malignant brain tumor in the patient’s care and disease trajectory.

MATERIAL AND METHODS

This is a descriptive study in the initial phase of applying Patient and Public Involvement in a current research project. Two national patient associations Brain Injury Association and Brain Tumor Association were contacted to recruit relatives of patients within these populations. An informational text with the aim of the overall project and purpose of the research panel was formulated and posted on the home page of- and by the patient associations on behalf of the research group. To enable a broad representation of the whole country, TEAMS was chosen as a communication platform. Preliminary interviews were conducted individually with the relatives and two researchers to align expectations and examine the motivation to participate in the panel.

RESULTS

Six relatives replied and were considered eligible by the research team, able to express both their own experiences, and representing relatives in general. The relative representatives comprised relatives of patients with acquired brain injury (n=3) and malignant brain tumor (n=3). The relatives were all women between the age of 44 to 66, all partners to the patients, and geographically representing four of the five regions in Denmark. Ethical considerations regarding the relatives were taken into account throughout the process. Two-panel meetings have until now been conducted where the relative representatives have been presented for and discussing findings from two scoping reviews. A pivotal finding is a perceived lack of involvement and systematic support for the children and young adults of the patients.

CONCLUSION

By including the relatives in the early stage of the research process, they can validate and nuance the research findings by applying their lived experiences and ensuring relevance to a national context. The perspectives and knowledge from the panel are an important foundation before the development of an intervention facilitating the relative’s involvement in the patient’s care and disease trajectory.
P22.03.A FEASIBILITY OF AND COMPLIANCE TO ELECTRONIC PATIENT-REPORTED OUTCOME ASSESSMENT IN THE MOLECULAR TUMOR BOARD IN (NEURO-)ONCOLOGICAL PATIENTS UNDER TARGETED THERAPY (TRACE)
Authors: Renovanz M , Stange F , Dörner L , Bombach P , Grosse L , Rieger J , Skardelly M , Rieger D , Hille H , Kurz S , Hippler M , Paulsen F , Öner Ö , Ruhm K , Beha J , Sundberg Malek H , Möller Y , Tatagiba M , Wallwiener M , Escher P , Pfeiffer N , Forschner A , Bauer A , Zips D , Bitzer M , Malek N , Gani C , Tabatabai G
Published: September 2023

BACKGROUND

Comprehensive genomic profiling and biomarker-based therapies are increasingly used in clinical trials and in innovative health care systems including the center for personalized medicine network. Systematic assessments of patient-reported outcomes (PRO) are warranted to gain insight into the perspective of patients during biomarker-based therapies. In the present study, we focused on the feasibility of and compliance to an electronic PRO assessment in patients treated at our center.

MATERIAL AND METHODS

Based on a retrospective evaluation of symptom burden in 265 neurooncology patients in the Molecular Tumor Board (MTB), we developed an app by 14 expert rounds including validated assessments of health-related quality of life (HRQoL), burden of symptoms und psychological stress, and tested it in a pilot study. After informed consent, patients were introduced to the app by study staff and completed subsequently patient-reported outcomes at several time points (weekly, monthly, and quarterly). We conducted a structured interview with health care personnel and the patients as users after 3 months to assess the app’s usability and feasibility. The interview was transcribed and analyzed according to Mayring´s qualitative content analysis regarding handling, feasibility and applicability in daily routine.Furthermore, we assessed compliance and descriptive data of the ePROs.

RESULTS

So far, 14 patients and caregivers have been enrolled, (9 female, 5 male). Median age was 50 years (range 28 -79), 3 out of 14 patients dropped out due to death. A total of 4 study staff members, 9 patients and one caregiver were interviewed regarding usability /feasibility. Both evaluated as good (study staff members in total n=40 quotes, patients/caregivers n=112 quotes). Main advantages were the possibility to complete questionnaires at home and the easy implementation in daily life. Compliance to questionnaires was high, e.g., 91% of weekly distributed NCCN Distress Thermometer were answered in time (range 65-100%, assessment duration 5-56 weeks, 262 answers), we observed a median Distress score of 4 (range 0-9, n=262, weekly assessed) and a median Global health score of 66.7 (range 16.7-100, n=69, EORTC QLQ-C30, question 29 and 30, monthly assessed, compliance 94%).

CONCLUSION

This pilot study proved feasibility and acceptance of the app and might enable PRO assessment during biomarker-guided therapies.
Caenorhabditis elegansLIN‐24, a homolog of bacterial pore‐forming toxin, protects the host from microbial infection
Authors: Zhang Huijie , Zeng Weirong , Zhao Ming‐Ming , Wang Jiali , Wang Qiquan , Chen Ting , Zhang Yuyan , Lee Wenhui , Chen Shenghan , Zhang Yun , Lan Xinqiang , Xiang Yang
Published: September 2023

Aerolysin‐like pore‐forming protein (af‐PFP) superfamily members are double‐edge swords that assist the bacterial infection but shied bacteria from the host by various mechanisms in some species including the toad Bombina maxima and zebrafish. While members of this family are widely expressed in all kingdoms, especially non‐bacteria species, it remains unclear whether their anti‐bacterial function is conserved. LIN‐24 is an af‐PFP that is constitutively expressed throughout the Caenorhabditis elegans lifespan. Here, we observed that LIN‐24 knockdown reduced the maximum lifespan of worms. RNA‐seq analysis identified 323 differentially expressed genes (DEGs) post‐LIN‐24 knockdown that were enriched in “immune response” and “lysosome pathway,” suggesting a possible role for LIN‐24 in resisting microbial infection. In line with this, we found that Pseudomonas aeruginosa 14 (PA14) infection induced LIN‐24 expression, and that survival after PA14 infection was significantly reduced by LIN‐24 knockdown. In contrast, LIN‐24 overexpression (LIN‐24‐OE) conferred protection against PA14 infection, with worms showing longer survival time and reduced bacterial load. Weighted gene co‐expression network analysis of LIN‐24‐OE worms showed that the highest correlation module was enriched in factors related to immunity and the defense response. Finally, by predicting transcription factors from RNA‐seq data and knocking down candidate transcription factors in LIN‐24‐OE worms, we revealed that LIN‐24 may protect worms against bacterial infection by stimulating DAF‐16‐mediated immune responses. These findings agree with our previous studies showing an anti‐microbial role for the amphibian‐derived af‐PFP complex βγ‐CAT, suggesting that af‐PFPs may play a conserved role in combatting microbial infections. Further research is needed to determine the roles this protein family plays in other physio‐pathological processes, such as metabolism, longevity, and aging.