bluuebunny/crossref_metadata_2025_split huggingface dataset:
JS04.4.A Beyond β-catenin: Genetic alterations ofTP53 andOTX2 and older age indicate increased risk of relapse in WNT medulloblastomas
Authors: Goschzik T , Mynarek M , Doerner E , Spier I , Warmuth-Metz M , Bison B , Obrecht D , Struve N , Kortmann R , Hau P , Aretz S , Rutkowski S , Pietsch T 
Published: September 2022

Abstract

Background
This genetic analysis of WNT-activated medulloblastomas (WNT-MBs) aimed to re-evaluate the prognostic impact of age, TP53 mutations and to identify specific chromosomal aberrations as possible prognostic markers.

Material and Methods
In a cohort of 191 patients with WNT-MBs, mutations in CTNNB1, APC and TP53 were analyzed by Sanger and/or NGS panel sequencing. Chromosomal copy number aberrations were assessed by high-resolution, genome-wide molecular inversion probe technology (MIP), SNP6 array, and/or 850k methylation bead-array hybridization. Association with prognosis was evaluated in 133 patients with follow-up data from the HIT2000 medulloblastoma trial, HIT registries, and the NOA-07 trial.

Results
CTNNB1 mutations were present in 92.2% of the samples. APC mutations were found in 6.8% (13 samples). One CTNNB1 wildtype tumor gained WNT-activation due to a homozygous deletion of FBXW7. Monosomy 6 was present in 78.6%, and more frequent in children compared to adolescents/adults (≥16 years). Adolescents/adults showed worse overall survival (OS; p=0.009) compared to children, but not worse progression-free survival (PFS; p=0.106). With an age cut-off at 18 years, no survival difference was found. Also adolescents alone (16-20 years) had worse OS (p=0.003) compared to children, whereas in patients ≥21 (n=12 adults with PFS/OS data) no tumor progression/relapse occurred. Only one adult died due to therapy-related complications. WNT-MB patients with tumors harboring TP53 mutations (24/133, 18.1%) showed significant worse PFS (p=0.001), which was also found in children and adolescents individually (p=0.004, resp. p=0.017). Gains of the OTX2 locus on chromosome 14q found in 40.2% (35/87) of samples were independent of TP53 mutations and also associated with poor PFS and OS (p=0.034, resp. p=0.016). Individual analyses of OTX2 gains within age groups showed only worse OS in children (p=0.012). Multivariate Cox regression analysis for PFS identified both genetic alterations, but not age, as independent prognostic markers. For OS, multivariate analysis found OTX2 gains and older age as independent prognostic markers.

Conclusion
Our data suggest that adolescent patients with WNT-MB and those patients carrying TP53 mutations or OTX2 gains - independent of age - are at higher risk of relapse. Eligibility of these patients for therapy de-escalation trials needs to be debated.
JS04.5.A Enhancing the activity of anti-CD47 antibody therapy with radiotherapy in preclinical models of medulloblastoma
Authors: Abbas Z , Howlett M , Buck J , Hii H , Kuchibhotla M , Ancliffe M , Whitehouse J , Johns T , Ebert M , Gottardo N , Endersby R 
Published: September 2022

Abstract

Background
Brain cancers are the most common solid cancer in children and the leading cause of cancer-related deaths in children. Medulloblastoma is the most common paediatric brain tumour. Treatment for medulloblastoma involves surgery, craniospinal irradiation (CSI) and chemotherapy. These therapies are extremely damaging to the developing brain and have not changed in decades, resulting in stagnation in the survival outcomes for children with medulloblastoma, and poor quality of life for children who survive their treatment. Immunotherapy has become a focus of novel treatment development. While there are multiple clinical trials aiming to increase immune recognition of medulloblastoma, none have been successful to date. Anti-CD47 is an immune-modulating therapeutic antibody which blocks the anti-phagocytic signal, CD47, expressed by brain cancer cells. Anti-CD47 has shown promising preliminary efficacy in brain cancer models.

Material and Methods
Using a small animal radiotherapy platform, we have developed a preclinical CSI protocol which mimics clinical radiotherapy. Using an orthotopic xenograft model of medulloblastoma, mice were treated with either anti-CD47 antibody therapy, CSI, or the combination of both anti-CD47 and CSI.

Results
CSI was found to deplete adaptive immune cells in the brain, while myeloid cells remained the dominant populations. Anti-CD47 antibody therapy was ineffective as a single agent against a patient derived xenograft model of Group 3 medulloblastoma, and CSI as a monotherapy resulted in temporary tumour regression. We found that the combination of anti-CD47 with CSI resulted in marked and persistent tumour regression.

Conclusion
This preclinical work has shown promising efficacy of anti-CD47 in combination with CSI, which we are currently testing in additional models. Our work is currently employing a range of techniques such as high dimensional flow cytometry and single cell sequencing to elucidate the mechanisms by which radiotherapy enhances the anti-tumour activity of myeloid cells. This work will enable the rational design and translation of optimal combination therapies for medulloblastoma clinical trials.
JS07.4.A Correspondence of glutamine and glycine imaging based on 7T MRSI to amino acid PET
Authors: Hangel G , Rausch I , Furtner J , Roetzer-Pejrimovsky T , Preusser M , Bogner W , Rössler K , Trattnig S , Traub-Weidinger T , Widhalm G 
Published: September 2022

Abstract

Background
New approaches for 7 Tesla magnetic resonance spectroscopic imaging (MRSI) allow the simultaneous imaging of multiple neuro-oncological biomarkers with 3-4 mm resolution in clinically feasible measurement times. Specifically, the amino acids glutamine (Gln) and Glycine (Gly), were previously limited to single voxel detection at lower fields. Both could add to our capabilities to resolve heterogeneous tumour metabolism.

Purpose
To progress the validation of Gln and Gly as neuro-oncological markers by conducting the first comparison to amino acid PET in a cohort of glioma patients.

Material and Methods
In 24 glioma patients (WHO 2021 classification), we quantitatively compared 7T MRSI (3D, 3.4 mm isotropic resolution, 15 min scan time) and routine PET (FET or MET). Within manual tumour segmentations, we defined hotspot volumes of interest (VOI) for the ratios of total choline (tCho, clinical standard reference), Gln, Gly to total N-acetylaspartate (tNAA) and PET tumour-to-brain ratios (TBR), all with a cut-off threshold of 1.6. For these VOIs, we calculated VOI volumes and median ratios as well as Dice similarity coefficients (DSC) and centre of intensity distance (CoI), between MRSI and PET ratios.

Results
We found that Gln and Gly ratios to tNAA had a higher correspondence to PET-based amino acid metabolism than tCho. Our resulting median VOI volumes were 19.08±23.10 cm³ for tCho/tNAA, 33.68±24.60 cm³ for Gln/tNAA, and 22.38±18.49 cm³ for Gly/tNAA compared to 24.33±30.46 cm³ for PET, with correlation coefficients &gt;0.5 for all MRSI hotspot values in relation to PET volumes. Median ratios were 0.52±0.13 for tCho/tNAA, 0.61±0.25 for Gln/tNAA, 0.33±0.15 for Gly/tNAA and 2.11±0.42 for PET. The median DSCs to PET amounted to 0.53±0.36 for tCho/tNAA, 0.66±0.40 for Gln/tNAA, and 0.57±0.36 for Gly/tNAA, while the median CoI distances were 0.56±0.43 cm for tCho/tNAA, 0.39±0.22 cm for Gln/tNAA, and 0.45±0.48 cm for Gly/tNAA.

Conclusion
With this first study that compared high-resolution 3D-MRSI at 7 Tesla to amino acid PET and a quantitative evaluation, we demonstrated that Gln and Gly corresponded better to PET than tCho, which is the main marker used in clinical MR, both within the study and compared to previous literature. Future research is needed to clearly define the benefits of 7T MRSI for neuro-oncology such as the identification of tumour microenvironments or non-invasive determination of molecular-pathologic markers. Gln could be further explored by the application of Gln-based PET tracers to MR-PET. We still see further developments of MRSI methods, such as motion correction or absolute quantification of concentrations instead of ratios, as necessary to obtain such goals.
JS08.6.A A connectivity signature for glioblastoma
Authors: Hoffmann D C , Hai L , Wagener R , Mandelbaum H , Xie R , Hausmann D , Dominguez Azorín D , Weil S , Sievers P , Cebulla G , Ito J , Warnken U , Venkataramani V , Ernst K , Reibold D , Will R , Suvà M L , Herold-Mende C , Sahm F , Winkler F , Schlesner M , Wick W , Kessler T 
Published: September 2022

Abstract

Background
Tumor cell extensions called tumor microtubes (TMs) in glioma resemble neurites during neurodevelopment and connect glioma cells to a network that has considerable relevance for tumor progression and therapy resistance. The determination of interconnectivity in individual tumors has been challenging and the impact of tumor cell connectivity on patient survival remained unresolved so far.

Material and Methods
A connectivity signature was derived by single-cell RNA-sequencing (scRNA-Seq) of highly and lowly connected cells obtained from an SR101 dye transfer xenograft model of primary glioblastoma (GB). The signature was validated in different in vitro models of cell-to-cell connectivity and could be translated to GB clinical specimens.

Results
34 of 40 connectivity genes were related to neurogenesis, neural tube development or glioma progression, including the TM-network-relevant GAP43 gene. Astrocytic-like and mesenchymal-like GB cells had the highest connectivity signature scores in scRNA-Seq data of patient-derived xenografts and patient samples. In 230 human GBs, high connectivity correlated with the mesenchymal expression subtype, TP53 wildtype, and with dismal patient survival. CHI3L1 was identified and validated as a robust molecular marker of connectivity with a functional relevance.

Conclusion
The connectivity signature gives novel insights into brain tumor biology, provides a proof-of-principle that tumor cell connectivity is relevant for patients’ prognosis, and serves as a robust biomarker that can be used for future clinical trials
JS08.7.A Integrative analysis of longitudinal genomic and non-genetic mechanisms of radiotherapy-resistance in glioma
Authors: Kocakavuk E , Varn F S , Johnson K C , Verhaak R G W 
Published: September 2022

Abstract

Background
Radiotherapy (RT) is a mainstay in the treatment of glioma patients, but RT-resistance is common. We have recently identified RT-associated genomic small deletion signatures, marking tumors that have developed resistance. Here, we used longitudinal molecular profiles to explore non-genetic mechanisms of RT-resistance.

Material and Methods
We have analyzed the multi-omic Glioma Longitudinal Analysis (GLASS) dataset, integrating DNA and RNA sequencing datasets from primary and post-treatment gliomas.

Results
We classified tumors as harboring temozolomide-associated hypermutation based on mutational burden increase (HM), and RT-associated signature based on small deletion burden increase (RTscars). By deconvoluting RNA profiles into cell state fractions, we observed an increase of a proliferating stem-like (PSL) cell state in 50% of patients with a RTscars+ signature which was significantly higher than RTscars-/HM- patients (P=8e-04, Fisher’s exact). PSL cell state increase associated with worse overall survival outcomes (P=1.5e-03, log-rank). We observed a significant correlation between the expression change of E2F cell cycle regulator genes (R=0.91, P=6.7e-04, Pearson) and EZH2 (R=0.81, P=8.3e-03) with the increase in the PSL cell state, nominating the E2F/EZH2-pathway as regulator of the PSL cell state. Furthermore, the RTscars signature was associated with an increase in frameshift neoantigens and significantly higher neoantigen burden at recurrence (P=2.4e-02, Kruskal-Wallis). This was accompanied by a significantly higher post-treatment T-cell fraction in RTscars+ tumors (P=8.2e-04, Wilcox), suggesting an increased T-cell infiltration in these patients.

Conclusion
Our analyses revealed a longitudinal increase in the proliferating stem-like cell state associated with RT-resistance and nominates the cell cycle pathway as an actionable target. The RT-associated deletion signature (RTscars) correlated with increased frameshift-neoantigens and T-cell fractions at recurrence, suggesting a potential benefit of a combinatorial immune-targeted therapy in this specific patient population.
JS09.7.A Reirradiation for recurrent high grade glioma (HGG) patients: results of a single arm prospective phase 2 study
Authors: Clerici E , Navarria P , Bellu L , Pessina F , Simonelli M , Marini B , Bianchi S , Scorsetti M 
Published: September 2022

Abstract

Background
Standard of care for recurrent high grade glioma (HGG) is missing. Several treatment options have been investigated including re-irradiation (re-RT). Results are promising but provided by retrospective studies. We designed a single arm prospective phase II study aiming to evaluate efficacy, and toxicity of re-irradiation.

Material and Methods
Adults patients with good performance status, HGG diagnosis reclassified according to the new 2021 fifth edition WHO CNS classification, an interval time (IT) from previous RT ≥ 6 months were included. Outcome was evaluated by MRI imaging at 1 month, and every 3 months thereafter. Toxicities were evaluated in terms of radionecrosis occurrence, and neurocognitive status.

Results
Ninety recurrent HGG patients were treated, 11 oligodendroglioma grade 3, 18 astrocytoma grade 3 and 4, and 61 glioblastoma grade 4. The median age was 54 years, and majority had KPS 90-100. The median IT between first-RT and re-RT was 24 months. Re-surgery has been performed in 56.6%, and chemotherapy in 53.3%. The median follow up time was 64 months; median overall survival (OS) time,1,2,3-year OS rates were 17 months (95%CI 14-19), 66.7%±4.9, 32.6%±5.0, and 22.2 ± 4.7. Prognostic factors impacting on survival were age (p = 0.0154), IT between first RT and re-RT (p = 0.0051), glioma grade (p = 0.0090), and IDH status (p = 0.0001). Radionecrosis grade 2-3 occurred in 9 (10%) patients; neurocognitive functions remained stable until disease progression.

Conclusion
Re-RT proved to be a safe and feasible treatment option with low toxicity. Younger patients with grade 3 IDH mutated gliomas, and a longer IT had the better outcome.
OS01.5.A Neuron-specific enolase (NSE) and S100 serum levels in patients with active brain metastases from HER2-positive breast cancer treated with trastuzumab-deruxtecan (T-DXd): A biomarker analysis from the TUXEDO-1 trial
Authors: Berghoff A S , Bartsch R , Furtner J , Marhold M , Bergen E S , Roider-Schur S , Starzer A M , Forstner H , Rottenmanner B , Dieckmann K , Bago-Horvath Z , Widhalm G , Ilhan-Mutlu A , Minichsdorfer C , Fuereder T , Singer C F , Weltermann A , Haslacher H , Szekeres T , Puhr R , Preusser M 
Published: September 2022

Abstract

Background
T-DXd is a novel antibody-drug conjugate with high activity in HER2-positive metastatic breast cancer. The prospective, single-arm, single-centre phase II TUXEDO-1 trial showed clinically relevant activity of T-DXd in HER2-positive BC pts with active BM with an intracranial response rate of 73.3%. This biomarker sub-study of TUXEDO-1 aimed to investigate changes in the extent of metastases-induced brain damage in patients with and without response to therapy by measuring the serum levels of two proteins constitutively expressed in the human brain and measurable upon brain damage in the blood serum: NSE and S100.

Material and Methods
We assessed serum NSE (sNSE) and serum S100 (sS100) levels in a total of 37 blood samples drawn at cycles 1, 4 and end of treatment (EOT) in all patients of the intent-to-treat population of the TUXEDO-1 trial using commercially available ELISA assays. Intracranial radiological response was centrally assessed by a board-certified neuro-radiologist using RANO criteria. sNSE and sS100 levels were compared between responders and non-responders using the Mann Whitney U test and a significance level of 0.05.

Results
At baseline, we detected no significant difference of sNSE or sS100 levels between T-DXd responders and non-responders, respectively. Baseline median sNSE level was 10.6 ng/ml (interquartile range (IQR) 8.6-12.2) in T-DXd responders as compared with median 12.5 ng/ml (IQR 12.2-12.9) in the non-responder group (n.s.). At cycle 4, corresponding numbers were 8.1 ng/ml in responding patients (IQR 7-11.2) and 12.7 ng/ml (IQR 12.2-12.9) in non-responders, respectively (p=0.009). No differences in sS100 levels were observed between the groups at any time point.

Conclusion
In patients showing intracranial objective response to T-Dxd, sNSE levels were significantly lower at cycle 4 as compared with non-responders, suggesting a reduction in metastases-induced brain damage as a direct treatment effect. sNSE may be a clinically useful biomarker for longitudinal assessment of brain metastasis burden.
OS01.6.A Through the Looking Glass: CSF Proteomics for Glioma Monitoring and Response Assessment
Authors: Riviere-Cazaux C , Burns T 
Published: September 2022

Abstract

Background
The development of novel glioma therapies necessitates rapid, longitudinal, and individualized feedback from each patient's tumor. Due in part to the relative inaccessibility of dynamic gliomas, little information is available regarding mechanisms of in situ therapeutic response and resistance which may be needed to iteratively develop candidate therapies and combinations thereof. To address this challenge, we are performing glioma biomarker discovery by serial cerebrospinal fluid (CSF) sampling from Ommaya reservoirs to determine how the CSF proteome can reveal early longitudinal intelligence regarding glioma status, biology, and therapeutic response.

Material and Methods
Global proteomic analysis of CSF was performed on the Somalogic platform -- an aptamer-based technology for highly sensitive and specific analyses of over 7,000 proteins. Discovery analysis comprised of the top-500 ranked proteins in CSF from seven patients with high-grade gliomas (HGG) versus non-glioma controls. The top-500 HGG proteins were then preliminarily filtered to include only proteins that met two additional criteria: 1) decrease with lower tumor burden as defined by tumor resection, and 2) increase with greater tumor burden as defined by recurrence in individual paired patient samples.

Results
Proteomic enrichment analysis revealed a conserved HGG CSF proteomic signature defined by 79 proteins, including ones known to be over-expressed in solid tumor malignancies, such as retinoblastoma binding protein 4, heat shock protein 90, and sorcin. When queried in an independent validation cohort, the HGG proteomic signature was consistently enriched across 13 gliomas diverse in primary versus recurrent status, subtype, and grade, when compared to control CSF samples. In two patients for whom CSF was available prior to and immediately after resections, proteins in the HGG signature decreased as indicated by a lower tumor burden. Interestingly, the glioma CSF proteomic signature was highly enriched for blood-associated proteins (as defined by two paired sets of CSF samples with low vs. high hemoglobin), despite these patients' samples containing little-to-no hemoglobin proteins.

Conclusion
Global CSF proteomics acquired from longitudinal neurosurgical access to unique gliomas has the promise to yield biomarkers which may be used to gain insights regarding glioma biology, tumor burden, and evolution throughout a patient's disease and treatment course.
OS02.6.A Lacosamide in monotherapy in brain tumour-related epilepsy (BTRE): results from an Italian multicentre retrospective study
Authors: Bruno F , Mo F , Meletti S , Belcastro V , Quadri S , Napolitano M , Bello L , Dainese F , Scarpelli M , Florindo I , Mascia A , Pauletto G , Pellerino A , Giovannini G , Polosa M , Sessa M , Conti Nibali M , Di Gennaro G , Gigli G , Cavallieri F , Pisanello A , Rudà R 
Published: September 2022

Abstract

Background
Lacosamide (LCM) is a third-generation anti-seizure medication (ASM) approved for focal onset epilepsy in patients aged ≥4 years. Previous studies have reported an efficacy of LCM as add-on treatment in brain tumour-related epilepsy (BTRE). To date, there are no studies in the literature focusing on lacosamide used in monotherapy to treat BTRE. In our retrospective study we investigated efficacy and tolerability of LCM in monotherapy in a multicentre national cohort of primary brain tumour patients.

Patients and Methods
Adult patients who were treated with LCM in monotherapy were collected from 12 Italian Centres (either mainly involved in neuro-oncology or in epileptology). Main inclusion criteria were diagnosis of primary brain tumour; at least two focal-onset seizures in the disease course; LCM used either as primary or secondary monotherapy after withdrawal of previous ASMs. For each patient, we evaluated seizure freedom at 3 and 6 months (primary endpoints), side effects and drop-out rate (secondary endpoints).

Results
We collected 132 patients. The majority of patients had a diagnosis of diffuse gliomas, being those with lower-grade glioma 66 (50.0%) and those with glioblastoma 33 (25.0%). Overall, LCM led to seizure-freedom in 64.4% of patients at 3 months and 55% at 6 months. Patients who used two or more ASMs before LCM had a worse seizure control than patients in monotherapy with LCM as first choice.In 14 patients, we observed seizure control despite tumour progression on magnetic resonance (MRI). Multivariate analysis showed that gross-total resection at diagnosis and use of steroids were significantly associated with higher seizure freedom rate at 6 months. Side effects were mainly mild (grade 1-2 according to the CTCAE classification), and the drop-out rate was low (1.5%). The main side effects were dizziness and somnolence.

Conclusion
This is the first study on the role of LCM in monotherapy in BTRE. The study has shown a good efficacy and tolerability of LCM with more than a half of patients becoming seizure-free at 6 months and with a very low rate of drop-out. Further studies are needed to confirm these preliminary data in a prospective manner, adding quality of life and neurocognitive functions as endpoints.