bluuebunny/crossref_metadata_2025_split huggingface dataset:
P11.09.A SIGNIFICANCE OF MOLECULAR DIAGNOSTICS FOR THERAPEUTIC DECISION MAKING IN RECURRENT GLIOMA
Authors: Blobner J , Dengler L , Blobner S , Eberle C , Weller J , Teske N , Karschnia P , Rühlmann K , Heinrich K , Ziemann F , Greif P A , Jeremias I , Wuerstlein R , Hasselmann K , Dorostkar M , Harter P N , Quach S , Stoecklein V , Albert N L , Niyazi M , Tonn J , Thon N , Westphalen B C , Baumgarten L 
Published: September 2023

Abstract

BACKGROUND
Targeted therapies have substantially improved survival in cancer patients with malignancies outside the brain. Whether in-depth analysis for molecular alterations may also offer therapeutic avenues in primary brain tumors remains unclear. We herein present our institutional experience for glioma patients discussed in our interdisciplinary Molecular Tumor Board (MTB) implemented at the Comprehensive Cancer Center Munich (LMU).

MATERIAL AND METHODS
We retrospectively searched the database of the MTB for all recurrent glioma patients after previous therapy. Recommendations were based uponnext-generation sequencing results of individual patient’s tumor tissue. Clinical and molecular information, previous therapy regimens and outcome parameters were collected.

RESULTS
Overall, 73 consecutive recurrent glioma patients were identified. In the median, advanced molecular testing was initiated with the third tumor recurrence. The median turnaround time between initiation of molecular profiling and MTB case discussion was 48 ± 75 days (range: 32 - 536 days). Targetable mutations were found for 50 recurrent glioma patients (68.5%). IDH1 mutation (27/73; 37%), EGFR amplification (19/73; 26%) and NF1 mutation (8/73; 11%) were the most detected alterations and a molecular-based treatment recommendation could be made for all of them. Therapeutic recommendations were implemented in 12 cases (24%) and one third of these heavily pretreated patients experienced clinical benefit with at least partial response or disease stabilization.

CONCLUSION
In-depth molecular analysis of tumor tissue may guide targeted therapy also in brain tumor patients and considerable anti-tumor effects might be observed in selected cases. However, future studies to corroborate our results are needed.
P11.22.B ANALYSIS OF FACTORS RELATED TO POSTOPERATIVE RECURRENCE AND PROGNOSIS ABOUT HIGH GRADE SPINAL CORD GLIOMAS
Authors: Guihuai W , Chuntian G , Linkai J , Beibei Y 
Published: September 2023

Abstract

BACKGROUND
High grade spinal glioma (HGSG), an extremely rare tumor, accounts for about 7-30% of spinal glioma. Its incidence is only 0.22/100000. The tumor has a rapid clinical progression and a poor prognosis, with a median survival time of 12-24 months. In previous studies on the prognosis of HGSG, the factors related to the prognosis are quite different due to inconsistent tumor classification and diagnosis criteria. It is rarer in the study of postoperative recurrence. Therefore, various factors limit the clinician’s judgment on the factors related to the recurrence and prognosis of HGSG after surgery.

MATERIAL AND METHODS
In this study, the clinical data of 44 patients who were pathologically diagnosed with HGSG and admitted to the Department of Neurosurgery of Beijing Tsinghua Changgung Memorial Hospital from January 1, 2015 to January 1, 2020 were retrospectively analyzed. The postoperative recurrence and death were considered as the research end time, the individual characteristics, imaging characteristics, pathological characteristics, age in treatment, gender, McCormick score, tumor location, WHO grade, tumor volume, degree of resection, radiotherapy, chemotherapy, and H3K27M expression, Ki-67 index, and P53 expression were included in the COX regression model for the univariate and multivariate analysis. The factors related to the recurrence and prognosis of HGSG after surgery were further explored.

RESULTS
The median recurrence-free duration of 44 patients with HGSG was 13.0 months, and the recurrence-free rates of 6 months and 1 year after surgery were 75.0% and 51.9%; the median survival time of the enrolled patients was 21.0 months. The multivariate COX regression analysis on the recurrence of HGSG after surgery showed that the risk of the recurrence was higher in the III-IV group than that the I-II group for the McCormick score ( p=0.001). For WHO grade, the risk of the recurrence was higher in the IV group than that in the III group (p=0.029). The multivariate COX regression analysis on that survival after HGSG surgery showed that the risk of the death was higher in the III-IV group than that in the I-II group for the McCormick score (p=0.006), and the risk of the death was higher for the tumor in the cervical segment than that in the cervical thoracic segment ( p=0.005), thoracic segment ( p=0.003), thoracolumbar segment ( p=0.011). The risk of the death was higher in the H3K27M positive group ( p=0.014) than that in the H3K27M negative group. 0.049).

CONCLUSION
HGSG, as a highly malignant tumour, exhibits rapid progression even after surgical treatment. For future post-operative recurrence and prognosis determination of HGSG, there is a need to focus on assessing the preoperative spinal cord functional status, tumour location, WHO classification and H3K27M mutation status to assist clinicians in giving the best treatment plan.
P11.36.A TUMOR CONTROL AND FUNCTIONAL OUTCOME IN VESTIBULAR SCHWANNOMA - RESULTS FROM A DUAL-CENTER STUDY COMPARING MICROSURGERY AND GAMMA KNIFE RADIOSURGERY
Authors: Wang S , Rick A , Ebner F , van Eck A , Naros G , Horstmann G , Tatagiba M 
Published: September 2023

Abstract

BACKGROUND
The level of evidence to provide treatment recommendations for vestibular schwannoma (VS) is low. Both Stereotactic Radiosurgery (SRS) and microsurgical resection (SURG) are available as treatment options for VS. There are very few direct comparative studies comparing both treatment modalities in large cohorts allowing detailed subgroup analysis.

MATERIAL AND METHODS
This is a retrospective dual-center cohort study. Data was retrospectively collected from two large centers involved in the treatment of solitary vestibular schwannomas for patients between 2005 und 2011 to enable follow-up of up to 10 years. Tumor size was classified by Koos Classification. Clinical state was reported by House and Brackmann (H&B) and Gardner-Robertson (G&R) scale (with H&B and G&R 1-2 considered as good outcome), and Recurrence-free-survival (RFS) was assessed radiographically by contrast-enhanced MR imaging. VS-associated symptoms like trigeminal affection, tinnitus, and vertigo/imbalance were also collected.

RESULTS
The study population included N=901 patients, who were treated in both centers. N=559 patients were treated by SRS, and 342 patients by SURG.Treatment-related functional deterioration (e.g. hearing and facial deterioration) was significantly more common in patients treated by SURG. The incidence of complications was similar in both groups (14% and 13%). Secondary VS-related symptoms like tinnitus, vertigo, imbalance and trigeminal symptoms were significantly improved by microsurgery, but not by SRS. This study reported an overall incidence of recurrence in SURG of only 4%, and 11% in SRS respectively. Tumor control was comparable in small tumors (Koos I and II) in both SRS and SURG. Patients treated by SRS had significantly smaller tumors (p&lt;0.001). In large VS (Koos III and IV), SURG is superior to SRS considering tumor control with a risk reduction for incidence of recurrence.

CONCLUSION
SRS can achieve similar tumor control compared to SURG in smaller VS (Koos I-II) - with less severe postinterventional morbidities (hearing and facial function loss). In large VS (Koos III-IV), tumor control by SRS is inferior to SURG. Therefore, while SURG is increasing the risk for facial palsy, it reduces the risk for recurrence. Moreover, SURG may improve secondary VS symptoms (e.g. tinnitus, vertigo/imbalance and trigeminal symptoms), even in small VS. Our data on tumor control and tumor size in SRS and SURG suggest that if combination therapy is chosen, the residual tumor for adjuvant SRS should not exceed the size of Koos II.These figures should be considered when deciding on treatment modality.
P11.47.B DNA METHYLATION-BASED SUBCLASS PREDICTS THE EFFECT OF THE EXTENT OF RESECTION ON SURVIVAL IN IDH-WILDTYPE GLIOBLASTOMA
Authors: Dankmeijer L G , Westerink L G , de Witt Hamer P C , Wesseling P , Kouwenhoven M C M , Kooi E , Verburg N 
Published: September 2023

Abstract

BACKGROUND
DNA methylation-based classification of diffuse glioma is increasingly used in daily practice. Yet, little is known regarding the prognostic and predictive value of DNA methylation-based subclasses of IDH-wildtype glioblastoma. A recent study found a predictive value for the effect of extent or resection (EOR) on survival for DNA methylation-based subclasses using the v11.4 classifier. We set out to validate these findings in an independent cohort and to test if these results are similar using the newest v12.5 classifier.

MATERIAL AND METHODS
A single-center retrospective cohort study of all patients with a glioblastoma, IDH-wildtype of whom DNA methylation was obtained. Patient and tumor characteristics, pre-operative Karnofsky performance status, and EOR (complete, subtotal, partial, biopsy) were retrieved. DNA methylation-based classification and MGMT promotor status were obtained using version 11.4 and 12.5 of the Heidelberg classifier. Progression-free survival (PFS) and overall survival (OS) were collected and validated using the national brain tumor registry.

RESULTS
Of 149 patients, the subtype was Mesenchymal in 57 (38.27%), RTK1 in 41 (27.52%), and RTK2 in 51 patients (34.23%). PFS and OS did not differ between the three subclasses, also not after pooling RTK1 and RTK2 into one Classical subclass. Complete or subtotal resection resulted in a longer OS than partial resection or biopsy in the entire cohort. This was similar for the pooled Classical subclass. In the Mesenchymal subclass, however, there was no survival advantage for complete or subtotal resection over partial resection or biopsy. These results were similar with the 11.4 and 12.5 classifier version.

CONCLUSION
In IDH-wildtype glioblastoma of the Mesenchymal subclass complete or subtotal resection does not result in a survival benefit. A less aggressive surgical strategy should be considered in these patients. Also, there is need for pre- or intraoperative assessment of the DNA methylation-based subclass of IDH-wildtype glioblastoma.
P11.50.A STEREOTACTIC RADIOSURGERY FOR RECURRENT MEDULLOBLASTOMA IN PEDIATRIC AND ADULT PATIENTS: A SINGLE-INSTITUTION EXPERIENCE
Authors: Yoo K H , Marianayagam N J , Park D J , Gu X , Pollom E L , Soltys S G , Chang S D , Meola A 
Published: September 2023

Abstract

BACKGROUND
Medulloblastoma is the most common malignant brain tumor in children. In recent decades, the therapeutic landscape has undergone significant changes, with stereotactic radiosurgery (SRS) emerging as a promising modality for the treatment of recurrent medulloblastoma. Our study aims to provide a comprehensive long-term analysis of the efficacy and safety of SRS for both pediatric and adult patients with recurrent medulloblastomas at a single institution.

MATERIAL AND METHODS
In our study, we retrospectively reviewed the clinical and radiological records of patients who underwent CyberKnife SRS for medulloblastoma at our institution between 1998 and 2023. Clinical and radiographic follow-up data were available for a total of 15 medulloblastomas in 10 patients. The study population consisted of 8 pediatric patients (ages 3-18) and 2 adult patients (ages 19-75). The median age at the time of SRS was 13 years and the median tumor volume accounted for 1.88 cc. The median biologically equivalent dose (BED) and single-fraction equivalent dose (SFED) were 126 Gy and 18 Gy, respectively. The SRS was administered at the 75% of the median isodose line.

RESULTS
Following a median follow-up of 39 months (range: 6-78) post-treatment, 8 (53.3%) of the medulloblastomas progressed, 2 (13.3%) showed radiographic regression, and 5 (33.3%) remained stable in volume. The 3-year local tumor control rate for all medulloblastomas was 65.2%, with lower rates observed in the adult cohort (50%) and higher rates in pediatric patients (67.3%). The 3-year overall survival rate was 70%, with significantly higher rates in pediatric patients (75%) compared to adult patients (50%). The 3-year progression-free survival rate was 58.3%, with higher rates in pediatric patients (60%) compared to adult patients (50%). Two pediatric patients developed radiation-induced edema, while two adult patients experienced radiation necrosis at the latest follow-up, with both adult patients passing away.

CONCLUSION
SRS is a safe and effective long-term treatment option for recurrent medulloblastoma in both pediatric and adult patients, resulting in improved patient outcomes. Although rare, radiation-induced edema and necrosis were observed as adverse events but were manageable. Overall, our findings provide optimistic evidence for the use of SRS as a viable treatment modality for medulloblastoma.
P11.67.B A RETROSPECTIVE STUDY OF 222 PATIENTS WITH NEWLY DIAGNOSED PRIMARY CNS LYMPHOMA - OUTCOMES INDICATIVE OF IMPROVED SURVIVAL OVER TIME
Authors: Bairey O , Lebe E , Buxbaum C , Porges T , Taliansky A , Gurion R , Goldschmidt N , Tzuk Shina T , Zektser M , Hofstetter L , Siegal T 
Published: September 2023

Abstract

BACKGROUND
Primary central nervous system lymphoma (PCNSL) is a rare disease with an incidence of 0.4/per 100,000 person-years. As there is a limited number of prospective randomized trials in PCNSL, large retrospective studies on this rare disease may yield information that might prove useful for the future design of randomized clinical trials.

MATERIAL AND METHODS
We retrospectively analyzed the data of 222 newly diagnosed PCNSL patients treated in 5 referral centers in Israel between 2001-2020. During this period, combination therapy became the treatment of choice, rituximab has been added to the induction therapy, and consolidation with irradiation was largely laid off and was mostly replaced by high-dose chemotherapy with or without autologous stem cell transplantation.

RESULTS
Patients older than 60 comprised 67.5% of the study population. First-line treatment included high-dose methotrexate (HD-MTX) in 94% of patients with a median MTX dose of 3.5gr/m2 (range 1.14-6 gr/m2) and a median cycle number of 5 (range 1-16). Rituximab was given to 136 patients (61%) and consolidation treatment to 124 patients (58%). Patients treated after 2012 received significantly more treatment with HD-MTX and rituximab, more consolidation treatments, and autologous stem cell transplantation. The overall response rate was 85% and the complete response (CR)/unconfirmed CR rate was 62.1%. After a median follow-up of 24 months, the median PFS and OS were 21.9 and 43.5 months respectively with a significant improvement since 2012 (PFS:12.5 vs. 34.2 p=0.006 and OS:19.9 vs 77.3 p=0.0003). A multivariate analysis found that the most important factors related to OS were obtaining a CR followed by rituximab treatment and ECOG performance status.

CONCLUSION
The observed improvement in outcomes may be due to multiple components such as an intention to treat all patients regardless of age with HD-MTX- based combination chemotherapy, treatment in dedicated centers, and more aggressive consolidation with the

INTRODUCTION
of HDC-ASCT.
P11.72.A INTRACRANIAL CONTROL OF BRAIN METASTASES IN PATIENTS TREATED WITH RADIOTHERAPY PLUS CHEMOTHERAPY, IMMUNOTHERAPY, TARGETED THERAPY AND IMMUNOCHEMOTHERAPY OR TARGETED THERAPY WITH CHEMOTHERAPY
Authors: Sulejmani A , Rinkel G , Etminan N , Brehmer S 
Published: September 2023

Abstract

BACKGROUND
Brain metastases (BM) are the most common intracranial malignancy. For many years, patients with BM were excluded from clinical trials of systemic cancer therapies based on their presumed bad prognosis, which results in a therapeutic nihilism as soon a BM is diagnosed. With the development of immunotherapies and targeted therapies as systemic cancer therapy, we questioned if there is a difference in intracranial response, regardless of the indicated radiotherapy (RT) for the BM.

MATERIAL AND METHODS
67 patients older than 18 years, with multiple BM treated between December 2016 and October 2021, with in total 237 metastases were analyzed. The volume of each metastasis on MRI was calculated at the time of appearance and every 3 months thereafter. The primary outcome was intracranial control according to RANO-BM at 6 months. Because of missing data (MRI at 6 months), 92 metastases had to be excluded, leaving 145 for the analysis. Patients were divided into groups (RT+chemotherapy - CT-group, RT+immunotherapy/targeted therapy - IT/TT-group, RT+chemo-immunotherapy/targeted therapy - CT+IT/TT-group). The second outcome measure was time to progression of metastases; for this outcome 183 metastases could be analyzed. For statistical analysis chi-square test and Tarone-Ware test were performed.

RESULTS
In the CT-group (n=40)10% (n=4) had a progressive disease (PD), 33% (n=13) had a partial response (PR), 57 % (n=23) complete response (CR), and no one stable disease (SD). In the CT+IT/TT-group (n=28) 14% (n=4) had PD, 11% (n=3) SD, 11% (n=3) PR and 64% (n=18) CR. In the IT/TT-group (n=78) 14% (n=11) had PD, 4% (n=3) SD, 26% (n=20) PR and 56% (n=44) CR. The p values for difference in intracranial control were between CT-group/IT/TT-group 0,81 and between CT-group/CT+IT/TT-group 0,58. Patients in the IT/TT-group had a better outcome if a targetable mutation was present (p=0,005). The median time to progression (days) was 474 ± 30 for the CT-group; 581 ± 50 for the IT/TT- group and 360 ± 35 for the CT+IT/TT-group. Tarone-Ware test showed a trend in the progression distributions between the 3 groups favoring the IT/TT-group p= 0,082.

CONCLUSION
Intracranial response could be achieved in all analyzed subgroups without statistically significant difference. Against the background of this data, the therapeutic nihilism due to the presumed bad prognosis is not justified. A subgroup analysis of the IT /TT group showed a significantly better outcome for patients who had a matching gene. Patients who received immunotherapy or targeted therapies showed a trend towards later progression than chemotherapy or combination therapy. Larger patient cohorts should be investigated to see if this trend could be confirmed.
P12.04.B MGMT-STATUS OF TUMOR INFILTRATING MACROPHAGES IN HUMAN GLIOBLASTOMA
Authors: Zeiler A , Liesche-Starnecker F , Delbridge C , Wagner A , Gempt J , Schlegel J 
Published: September 2023

Abstract

BACKGROUND
Glioblastomas are the most prevalent malignant brain tumors in adults, with a frequency ranging from 0.59 to 3.69 in the western world. They are accompanied by a fatal prognosis and a median survival of 12.2 to 18.2 months. Their significant intratumoral and intertumoral heterogeneity is the reason for this. Tumor associated macrophages including microglia can represent up to 30-40% of the cellular component of the tumor and are thought to have an impact on the tumor's behavior. The MGMT promotor methylation is the most significant clinical prognostic factor. Patients with a methylated promotor have a better prognosis and a better response to Temozolomid treatment. This experimental study should determine if the microglia or the tumor cells are responsible for the MGMT status. Moreover, it should show how the MGMT-protein is distributed intracellularly in both cell-populations.

MATERIAL AND METHODS
Therefore, the MGMT-Status of 13 samples of patients with glioblastoma from the division of neurosurgery of the TU München were analyzed. Using magnetic cell sorting and an anti-CD11b antibody, tumor cells and microglia were separated in each sample. A MGMT-assay was carried out for each cell population to demonstrate the proportion of methylated MGMT promotor regions. 25 histological sections underwent immunofluoresence double staining to get a better look at the MGMT protein's intracellular distribution. Two sections of each sample were stained with anti-MGMT antibody and anti-GFAP antibody or anti-IBA1 antibody, respectively, to determine if the MGMT protein is present either in the nucleus or in the cytoplasm of the tumor cells and microglia. A minimum of 200 cells of every section was analyzed manually. Statistical analysis was performed using Mann-Whitney-U-test and a p-value &lt;0.05 was defined as significant.

RESULTS
The separarte MGMT-assay of microglia and tumor cells showed methylated MGMT promotors in 3 samples in both cell populations. Tumor cells as well as microglia demonstrated intracellular MGMT Protein, with no significant difference (0.122 MGMT+ Microglia vs. 0.152 MGMT+ Tumor Cells; p=0.101). The intracellular distribution of the MGMT protein strengthened this result. Tumor cells demonstrated a significantly higher percentage of nuclear MGMT protein (0.602 nuclear MGMT vs. 0.203 cytoplasmic MGMT; p&lt;0.0001), whereas microglial cells showed a significantly higher expression of cytoplasmic MGMT protein (0.608 cytoplasmic MGMT vs. 0.157 nuclear MGMT; p&lt;0.0001).

CONCLUSION
According to the findings of this experimental study, both the microglia and the tumor cells are responsible for the clinical MGMT status. This might fit into the theory of macrophage polarization in the microenvironment of heterogenous tumors. The MGMT protein distribution pattern implies that tumor cells and microglia express their MGMT protein in different cellular compartments.
P12.05.B THE ROLE OF ONCO-METABOLITE IN THE IDH MUTANT GLIOBLASTOMA MICROENVIRONMENT
Authors: Behringer S , Joseph K , Beck J , Schnell O , Heiland H , Ravi V M 
Published: September 2023

Abstract

BACKGROUND
Recently, we found that the reactive astrocytes in the IDH wild type glioblastoma contribute to anti-tumor immunity and support pro-oncogenic signaling. Here, we characterized the transcriptomic signature of IDH1/2-mutant glioma associated astrocytes and determined a unique inflammatory transformation, profoundly different to astrocytes in IDH wildtype glioma patients due to an onco-metabolite R-2-hydroxyglutarate using Next generation sequencing and human ex-vivo slice model.

MATERIAL AND METHODS
We purified and transcriptionally profiled astrocytes from 9 patients with confirmed IDH1-R132H mutation, by means of RNA-sequencing and the data were analyzed using the established pipelines. We also used spatial transcriptomics to evidently show the spatial distribution of astrocytes in IDH-mutated/wildtype glioma samples. We validated our findings using human organotypic slice model inoculated with IDH-mutant cell line or treated with oncometabolite 2-hydroxy glutarate. Additionally, LC-MS was further used to give us a chart of neurotransmitters due to altered microenvironment.

RESULTS
Our results from RNA sequencing showed a transcriptional transformation of reactive astrocytes within the microenvironment of IDH-mutated tumors compared to wildtype glioma by means of RNA-sequencing of purified astrocytes. And, using our established human neocortical GBM model inoculated with IDH mutant tumor and R-2HG treatment, we showed that we were able to activate inflammatory transcriptional programs in astrocytes, mediated by the presence of microglia. Further, by spatially mapping the transcriptomic profiles of purified microglia, we were able to confirm that microglia also demonstrate inflammatory activation in IDH mutated glioma. This inflammatory astrocyte transformation is associated with a loss of neurotransmitter homeostasis (disrupted levels of glutamate) in the treated sections, as has been previously reported in IDH mutated tumors. Additionally, R-H2G increased neuronal spiking rate in, pointing to potential excitotoxicity.

CONCLUSION
Our work provides a crucial contribution towards understanding the role of R-2HG in the IDH mutant glioma microenvironment and sheds light on the significant microenvironmental differences to IDH wild-type glioma.