bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract

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

Abstract

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

Abstract

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 (&lt;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

Abstract

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

Abstract

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 &lt;1300€ to &gt;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&lt;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&lt;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 &gt;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

Abstract
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

Abstract
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

Abstract

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=&lt;40 (lower confidence), Average=50 (US general population), High= &gt;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&lt;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.