bluuebunny/crossref_metadata_2025_split huggingface dataset:
OS03.4.A In vivo dynamics and anti-tumor effects of EpCAM-directed CAR T-cells against brain metastases from lung cancer
Authors: Xu T , Karschnia P , Cadilha B , Dede S , Lorenz M , Seewaldt N , Nikolaishvili E , Müller K , Blobner J , Teske N , Langer S , Obeck H , Lorenzini T , Mulazzani M , Zhang W , Ishikawa-Ankerhold H , Buchholz V R , Subklewe M , Thon N , Straube A , Tonn J , Kobold S , von Baumgarten L 
Published: September 2022

Abstract

Background
Lung cancer patients are at a particularly high risk for brain metastases, and a considerable number of affected patients succumb due to their intracranial disease. Chimeric Antigen Receptor (CAR) T-cells emerged as a powerful class of cell-based immunotherapy for hematological malignancies. However, it remains unclear whether CAR T-cells also represent a safe and effective therapeutic option for brain metastases.

Material and Methods
A fully syngeneic orthotopic cerebral metastasis model in mice was established by combining a chronic cranial window with repetitive intracerebral two-photon laser scanning microscopy. This approach enabled the in vivo characterization of red fluorescent CAR T-cells and tumor cells on a single-cell level over weeks. Intraparenchymal injection of Lewis lung carcinoma cells (expressing the tumor cell-antigen EpCAM) was performed, and CAR T-cells directed against EpCAM (EpCAMCAR T-cells) were injected into the adjacent brain parenchyma after solid brain tumors have formed.

Results
All mice had visible tumor take four days after the intracranial tumor cell injection, and rapid growth of solitary lesions was seen in the following days. No toxicities mediated by intracranially injected EpCAMCAR T-cells were encountered. In mice treated with EpCAMCAR T-cells, we initially observed substantial CAR T-cell accumulation within the tumor compared to controls (median number: 1700 versus 939 cells/mm2; p = 0.007). This was paralleled by lower velocities of EpCAMCAR T-cells, characterizing T-cell receptor (TCR)-mediated antitumor cytotoxicity due to long-lasting contacts between effector immune cells and tumor cells. Consequently, treatment with EpCAMCAR T-cells resulted in reduced tumorous growth as determined per in vivo microscopy (median tumor area on day 10: 1.8 versus 10.8 mm2; p = 0.001) and immunohistochemistry of excised brains (median tumor volume on day 10: 3.6 versus 33.2 mm3; p = 0.001). However, the number of EpCAM-directed CAR T-cells within the tumor markedly decreased during the observation period, pointing towards insufficient persistence of EpCAM-directed CAR T-cells. In line with these findings, survival was prolonged in mice receiving EpCAMCAR T-cells but long-lasting remission was rare (median survival: 15 versus 13 days; p = 0.012).

Conclusion
Our findings indicate that CAR T-cells injected into the cerebral parenchyma may induce relevant anti-tumor effects in brain metastases from lung cancer. Due to the translational nature of our study, prospective clinical cohorts appear warranted. Strategies improving the intratumoral persistence of CAR T-cells in brain metastases may be utilized to further boost the success of such promising therapy.
OS03.7.A Clinical characteristics, treatment and long-term outcome of patients with brain metastases from thyroid cancer - an analysis of the Vienna Brain Metastasis Registry
Authors: Wolff L , Steindl A , Dieckmann K , Gatterbauer B , Widhalm G , Berghoff A , Preusser M , Raderer M , Kiesewetter B 
Published: September 2022

Abstract

Background
The incidence of brain metastases (BM) in patients with thyroid cancer (TC) depends on the histological subtype. About 1% of patients with differentiated (DTC), 3% with medullary (MTC) and up to 10% with anaplastic thyroid cancer (ATC) develop BM. The diagnosis of BM drastically worsens the prognosis of TC. Given the rare incidence, little is known about the presentation and outcome of this cohort.

Material and Methods
Patients with a histologically verified diagnosis of TC and BM were identified from the Vienna Brain Metastasis Registry, a comprehensive database managed by the Division of Oncology, Medical University of Vienna, including patients with cerebral metastasis since 1990. Data were obtained from medical records comprising clinicopathological features, treatment, BM-specific characteristics and outcome.

Results
20/6074 patients included in the registry had a diagnosis of TC and radiologically verified BM. 13/20 (65%) were female and the median age at diagnosis of TC and manifestation of BM was 56 years (range 21-75) and 68 years (range 45-75), respectively. In terms of histology, 18/20 (90%) had DTC, one MTC and one ATC. Interestingly, 10/18 DTC presented with follicular histology which underlines the more aggressive course of this rare subtype. 6/20 (30%) had BM at primary diagnosis (DTC n=5, ATC n=1), while the remaining developed BM during follow-up. The median time to diagnosis of BM was 2.6 years for DTC (range 0-42), 22 years in the MTC patient and 2 months for ATC. Regarding BM-specific characteristics, all but one patient had symptoms due to BM (neurological deficits n=11, increased intracranial pressure n=5, seizures n=3). Most patients (13/20) had a singular BM, commonly located in the left hemisphere (8/13), and only one had more than three BMs. Upfront treatment for BM was local therapy (resection n=9, stereotactic radiosurgery n=7, whole brain radiotherapy n=3); one patient received supportive care only. The median overall survival (mOS) from diagnosis of TC was 6 years for DTC (range 2.5 months-42 years), 33 years for the MTC and 9 months for the ATC. The mOS from diagnosis of BM was 14 months for DTC (1.8 months-16 years), 22 years for the MTC and 3 months for the ATC.

Conclusion
Few patients with TC develop BM, which present commonly as single lesion. While in general BM constitute a poor prognostic factor, individual patients experience long-term survival following local therapy. More information about the optimal management of BM in TC is needed to enable guideline recommendations.
OS05.5.A Glioblastoma-instructed microglia transit to heterogeneous phenotypic states with dendritic cell-like features in patient tumors and patient-derived orthotopic xenografts
Authors: Yabo Y A , Pires-Afonso Y , Moreno-Sanchez P M , Oudin A , Kaoma T , Nazarov P V , Skupin A , Niclou S P , Michelucci A , Golebiewska A 
Published: September 2022

Abstract

Background
A major contributing factor to Glioblastoma (GBM) development and progression is its ability to evade the immune system by creating an immune-suppressive tumor microenvironment (TME). GBM-associated myeloid cells, including resident microglia, macrophages and other peripheral immune cells are generally geared towards tumor-supportive roles. It is however unclear whether such recruited myeloid cells are phenotypically and functionally identical. Here, we aim to understand the heterogeneity of the GBM TME, using an unbiased, marker-free approach to systematically characterize cell type identities at the molecular and functional levels.

Material and Methods
We applied single-cell RNA-sequencing, multicolor flow cytometry, immunohistochemical analyses and functional studies to examine the heterogeneous TME instructed by GBM cells. GBM patient-derived orthotopic xenografts (PDOXs) representing different tumor phenotypes were compared to glioma mouse GL261 model and patient tumors.

Results
We show that PDOX models recapitulate major components of the TME found in human GBM. Human GBM cells reciprocally interact with mouse cells to create a GBM-specific TME. The most prominent transcriptomic adaptations are found in tumor-associated macrophages (TAMs), which are largely of microglial origin. We reveal inter-patient heterogeneity of TAMs and identify key signatures of distinct phenotypic states within the microglia-derived TAMs across distinct GBM landscapes. GBM-educated microglia adapt expression of genes involved in immunosuppression, migration, phagocytosis and antigen presentation, indicating functional cross-talk with GBM cells. We identify novel phenotypic states with astrocytic and endothelial-like features. Identified gene signatures and phenotypic states are confirmed in GBM patient tumor tissue. Finally we show that temozolomide treatment leads to transcriptomic adaptation of not only the GBM tumor cells but also adjacent TME components.

Conclusion
Our data provide insights into the phenotypic adaptation of the heterogeneous TME instructed by GBM tumor. We confirm a crucial role of microglia in supporting the immunosuppressive TME and show that PDOXs allow to monitor the highly plastic GBM ecosystem and its phenotypic adaptations upon treatment. This work further confirms the clinical relevance of PDOX avatars for testing novel therapeutics including modalities designed to target the myeloid compartment.
OS07.1.A A threshold of mitotic activity and post-surgery residual volume are independant prognostic factors in astrocytoma IDH-mutant
Authors: Tran S , Thomas A , Touat M , Karachi C , Lozano F , Mokhtari K , Dehais C , Feuvret L , Carpentier C , Giry M , Doukani H , Lerond J , Marie Y , Sanson M , Idbaih A , Carpentier A , Hoang-Xuan K , Capelle L , Bielle F 
Published: September 2022

Abstract

Background
The distinction between grade 2 and 3 is instrumental to choose between observational follow-up and adjuvant treatment in resected astrocytoma IDH-mutant. However, criteria of grade 2 versus 3 have not been updated since the WHO 2007 classification. There is no consensus on the method of evaluation of the mitotic activity or a cut-off of mitoses separating grade 2 and grade 3 tumors. The objectives were to evaluate the maximal mitotic activity on a series of resected astrocytoma IDH-mutant and assess its prognostic impact on survival.

Material and Methods
Maximal mitotic activity on consecutive high power fields corresponding to 3 mm2 was examined in 118 lower-grade astrocytoma IDH-mutant. The prognostic value for time-to-treatment (TTT) and overall survival (OS) of mitotic activity and other putative prognostic factors (including age, performance status, pre-surgical tumor volume, plurilobar involvement, post-surgical residual tumor volume, midline involvement) was assessed in tumors with (i) ATRX loss, and (ii) without CDKN2A homozygous deletion, lesional enhancement, histological necrosis nor microvascular proliferation.

Results
Among the 75 (64%) of tumors which had gone through observational follow-up after resection, the maximal mitotic activity, the post-surgical residual volume and the plurilobar involvement were independent prognostic factors of TTT (p &lt; 0.0001). A threshold of mitotic activity for grade 2 was fitted on TTT and OS prognosis. Using this threshold, patients with “grade 2 tumors” had a median TTT of 55 months versus 19 months for “grade 3” (p = 0.0057) and a median OS of 102 months versus 73 months respectively (p = 0.001). Residual volume &lt; 1 cm3 was associated with longer OS (113 months versus 88 months, p = 0.0021).

Conclusion
Mitotic activity and post-surgical residual volume can be combined to evaluate prognosis in resected astrocytoma IDH-mutant and could select the best candidates for observational follow-up.
OS07.5.A Report from the pooled analysis of the randomized trials NORDIC, NOA-8 and CE.6 on elderly patients with glioblastoma
Authors: Gorlia T , Oppong F , O′Callaghan C , Wick W , Laperriere N , Weller M , Perry J , Reifenberger G , Tavelin B , Malmström A E 
Published: September 2022

Abstract

Background
The majority of patients diagnosed with glioblastoma are over 60 years old. Three randomized trials addressed the roles of radiotherapy (RT) and temozolomide (TMZ) for these patients. Two, the NORDIC and NOA-08 (N&N) compared RT versus TMZ head-to-head, the third, CE.6, randomized between hypofractionated RT and the combination of RT+TMZ. All showed significant benefit for the TMZ arms, especially for patients with MGMT promoter methylated tumors. An ongoing pooled analysis of these three trials focuses on identifying significant baseline prognostic factors and assess their value for predicting outcome in relation to treatment. The aim is improved selection of elderly patients with glioblastoma for their optimal treament; RT alone, TMZ with or without concomitant RT or palliative care.

Methods
The data of two phase 3 studies (N&N) were pooled to build a large dataset and findings are compared to CE.6 trial data. A re-assessment of the clinically most relevant MGMT cut-off is performed. The prognostic value of baseline clinical factors and quality of life scores, determined by the EORTC QLQ-30 and BN-20 questionnaires, are investigated. Data is also analysed to account for a possible impact of sex.

Results
The N&N dataset includes 715 and the comparative dataset (CE.6) 562 patients. Median age for N&N is 71 years and 73 for CE.6. In N&N and CE.6 respectively, 66.2% versus 70.5% underwent resection and 50.9% and 75.3% were on steroids at the time of study inclusion. In N&N, 401 patients received RT alone and 281 in CE.6, while 314 were randomized to TMZ alone in N&N and 281 to concomitant RT and TMZ in CE.6. For N&N MGMT promoter methylation status was successfully determined for 412 (57.6%) and 354 (63.0%) for CE.6. In a first report, patients with the combination of the comorbidities hypertension, diabetes and/or cerebrovascular insult had poorer prognosis when treated with TMZ.

Conclusion
An ongoing pooled analysis of the trials NORDIC, NOA-08 and CE.6 is expected to identify factors that will improve personalized medicine for elderly patients with glioblastoma. Reanalyzed MGMT promoter methylation data and the role of baseline quality of life for outcome will be reported.
OS07.9.A Gliocova: Impact of surgeon and centre volume on 30-day mortality, readmission and risk of complication after first surgical intervention in brain tumour patients in England diagnosed between 2013-2018
Authors: Mauricaite R , Williams M 
Published: September 2022

Abstract

Background
The Gliocova dataset uses linked English national cancer data on all 51,775 adult primary brain tumour patients diagnosed between 2013-2018. Here we are investigating the effect of surgeon and centre volume on post-surgical outcomes such as 30-day mortality, readmission and risk of complication.

Material and Methods
We selected patients from our dataset that have undergone surgical debulking or biopsy for the first time. We calculated surgeon and centre volume per 6 year period. To exclude non-tumour surgeons who might do occasional tumour cases as an emergency, we removed those that performed less than 12 operations over the 6 year period and to remove newly qualified/ near retirement surgeons we removed those that did not perform at least 1 operation within the 6 first months of 2013 and last 6 months of 2018. We developed univariate regression models to link surgeon and centre volume with 30-day mortality, readmission and risk of complication and are currently working on multivariate models including other predictors such as age, sex, Elixhauer comorbidity index, deprivation status, type of intervention (biopsy vs surgical debulking), and tumour type (i.e., Glioblastoma versus other types of brain tumours).

Results
We identified 29,258 patients (out of 51,775) that have undergone a surgical intervention (28,173 surgical debulking; and 1,207 biopsy). In-hospital mortality was 0.99% (N = 289), 30-day mortality was 2.3% (N = 677) and 30-day readmission was 12.7% (N = 3,725). No surgeons performed less than 1 operation during the first 6 months of 2013 or last 6 months of 2018. In univariate analyses, centre volume predicted the risk of 30-day mortality (p-value&lt;0.01) and risk of complication (p-value&lt;0.001), whereas surgeon volume only significantly predicted risk of complication (p-value&lt;0.001). Neither surgeon volume nor centre volume were statistically significant predictors of 30-day readmission in univariate analysis.

Conclusion
As most surgeon and centre volume studies in brain tumour patients come from the United States, our study is one of a few in Europe to investigate this in a large adult brain tumour population. In our future work we will refine the model to account for patient factors, and assess the cost of complications and variation of these across centres, tumour types and other patient and hospital level characteristics. More information about the Gliocova project can be accessed here: https://blogs.imperial.ac.uk/gliocova/about-gliocova/. GlioCova is supported by the Imperial/NIHR BRC, and the members of the GlioCova EAG. This work uses data provided by patients and collected by the NHS as part of their care and support
OS08.2.A Three layers of neuronal-like mechanisms driving brain tumor invasion
Authors: Venkataramani V , Wick W , Kuner T , Winkler F 
Published: September 2022

Abstract

Background
Glioblastoma are characterized by their infiltration into the whole brain. Membrane protrusions of glioma cells called tumor microtubes are subcellular structures contributing to glioma cell invasion. They are the anatomical building block to build a functional and therapy-resistant tumor cell network interconnected by tumor microtubes (TMs) that characterizes a glioblastoma cell subpopulation, while other subpopulations appear unconnected to other glioma cells. The biological role of glioblastoma cells lacking connections with each other remains unclear. Furthermore, how neurogliomal synapses influence this subpopulation is unclear.

Material and Methods
Time-lapse in vivo two-photon microscopy and single-cell RNA-sequencing are combined to characterize functional different subpopulations of glioblastoma cells. Intravital, augmented microscopy, three-dimensional calcium imaging, electrophysiology and volume electron microscopy are used to investigate the role of neuronal invasion mechanisms and the role of neurogliomal synapses for tumor microtube generation and dynamics.

Results
In-vivo imaging revealed that glioblastoma cells lacking connections to other tumor cells and astrocytes were the main subpopulation driving glioblastoma invasion invasion. These glioblastoma cells were characterised with single-cell RNA-sequencing. This revealed that this subpopulation is enriched for neuronal, neural progenitor-like, and non-mesenchymal-like cell states as previously described. Sparse regions enriched with such tumor-cell and astrocyte-unconnected, invasive glioblastoma cells evolve over time into regions with tumor-cell and astrocyte-connected, glioblastoma cell networks reflected by molecular cell state changes that are reflected in cell state changes in different regions of human glioblastoma. In addition, mechanisms of glioblastoma cell invasion resembled neuronal and neural progenitor patterns during brain development. Lastly, neuronal activity stimulated neurogliomal synapses and subsequently increased glioblastoma cell invasivieness by stimulating generation of new tumor microtubes and enhanced tumor microtube dynamics.

Conclusion
This study uncovers three novel layers of neuronal features driving glioblastoma cell invasion. We are able to connect molecular, cellular heterogeneity and functional glioblastoma cell states interlinking heterogeneity and dissemination of glioblastoma, two important hallmarks of this disease. Lastly, this study delineates a potential roadmap to clinical translation with the multidimensional characterisation of human glioblastoma.
OS08.3.A Distinct systemic and tumor microenvironment immune landscapes discriminate across sellar tumor types and controls through a methylation-based deconvolution method
Authors: Herrgott G , Asmaro K , Thomas B , Nelson K , Cazacu S , Hasselbach L , Transou A , deCarvalho A , Mukherjee A , Robin A , Lee I , Kalkanis S , Rock J , Rock J , Noushmehr H , Castro A 
Published: September 2022

Abstract

Background
Systemic (Sys) and tumor microenvironment (TME) immune milieus play a pivotal role in tumor development, outcome and immunotherapy response predictions across a variety of central nervous system tumors. Genome-wide methylation profiling can reliably discriminate and estimate immune cell proportions present in the blood and within the tumor and has not been reported across sellar tumor types (STT).

Material and Methods
We estimated cell composition in liquid biopsy (LB, serum/plasma) and tissue specimens from 42 STT collections (i.e., pituitary neuroendocrine tumors [PitNETs; n=37] and craniopharyngiomas [CP; n=5]), and 26 nontumor controls (LB: 11; Tissue: 15) using MethylCIBERSORT, a methylation-based deconvolution algorithm and established immune cell signatures as reference. LB methylation was profiled with EPIC array. Correlations between estimated cell proportions across sample sources were explored (Spearman). Immune cell proportion hierarchical k-means clustering was performed across tissue and LB specimens. Similarly, mean comparisons between and across sample types and subgroups of interest were performed [Non-parametric Kruskal-Wallis, Wilcoxon rank-sum tests; p&lt;0.05].

Results
We identified three immune-clusters across tissue specimens which distinguished controls (k3-cluster) from sellar tumor specimens (k1- and k2- clusters), primarily attributable to differential B-cell and monocyte proportions. Interestingly, a subset of PitNET and CP, belonging to the k2-cluster, presented a distinct immune profile compared to their K1-sellar tumor counterparts. Analysis of plasma-derived immune clusters revealed that PitNETs were distributed across four distinct immune patterns and CP clustered together with controls and a PitNET subset. One of the PitNET clusters was enriched with patients that died during follow-up and presented an enrichment of CD4-(including the regulatory subtype), CD8 and CD56-T and depletion of natural killer cells. Differences across serum- and tissue-derived clusters were present but less prominent than their plasma counterparts. No correlation between immune cell proportions across other clinicopathological features within each tumor type (sex, age, histotypes, invasion etc) was observed.

Conclusion
Our results suggest that PitNETs are characterized by differential TME and systemic immune subtypes which also distinguish these tumors from CP and controls. Additionally, distinct systemic immune composition between tissue and LB sources, more readily observed in plasma, suggest that the systemic response to the presence of the tumor is distinct from the immune response noted in the TME. Tumor immune subtyping may allow the stratification of STT according to immunotherapy response vulnerabilities.