bluuebunny/crossref_metadata_2025_split huggingface dataset:
P02.01 A strategy to personalize the use of radiation in patients with brain metastasis based on S100A9-mediated resistance
Authors: Miarka L , Monteiro C , Dalmasso C , Yebra N , Fustero-Torre C , Hegarty A , Keelan S , Goy Y , Mohme M , Caleiras E , Vareslija D , Young L , Soffietti R , Fernández-Alén J , Blasco G , Alcázar L , Sepúlveda J , Pérez A , Lain A , Siegfried A , Wikman H , Cohen-Jonathan Moyal E , Valiente M 
Published: September 2021

Abstract

BACKGROUND
Finding effective treatment options for patients with brain metastasis remains an unmet need. Given the limitations imposed by the blood-brain-barrier for systemic approaches, radiotherapy offers a superior ability to access the brain. While clinical practice recently adapted the use of stereotactic radiosurgery (SRS), Whole-Brain-Radiotherapy (WBRT) continuous to be an important treatment option, since many patients present with multifocal lesions or bad performance scores, rendering them ineligible for SRS. Unfortunately, overall survival of patients remains unaffected by radiotherapy. Despite this clinical data, the molecular mechanisms that allow metastatic cells to resist radiotherapy in the brain is unknown.

MATERIAL AND METHODS
We have applied WBRT to experimental brain metastasis from lung and breast adenocarcinoma and validated their resistance in vivo.

RESULTS
An unbiased search to identify potential mediators of resistance identified the S100A9-RAGE-NFκB-JunB pathway. Targeting this pathway genetically reverts the resistance to radiotherapy and increases therapeutic benefits in vivo. In two independent cohorts of brain metastasis from lung and breast adenocarcinoma patients, levels of S100A9 correlate with the response to radiotherapy, offering a novel approach to stratify patients according to their expected benefit. In order to make this biomarker also available for brain metastasis patients receiving palliative WBRT without preceding surgery, we complemented our tumor-specimen based approach with the less invasive detection of S100A9 from liquid biopsies. Here, serum S100A9 also correlated with a worse response to WBRT in brain metastasis patients. Furthermore, we have validated the use of a blood-brain-barrier permeable RAGE inhibitor to restore radio-sensitivity in experimental brain metastasis models in vivo and in patient-derived organotypic cultures of radio-resistant brain metastasis ex vivo.

CONCLUSION
We identified S100A9 as a major mediator of radio-resistance in brain metastasis and offer the molecular framework to personalize radiotherapy by exploiting it as a biomarker and as a therapeutic target, thus maximizing the benefits for the patient.
P03.06 Boolean logic puzzles as a neurosurgical mapping tool to preserve programming skill
Authors: Donders-Kamphuis M , Miller K J , van der Kallen B F W , Broekman M L D 
Published: September 2021

Abstract

BACKGROUND
In glioma surgery, awake craniotomy with Direct Electrical Stimulation (DES) is increasingly becoming the gold standard treatment to preserve language, cognition and motor function and to optimize extent of resection. Computer programming is historically seen as an integration of cognition, language, and mathematics but an intraoperative task to monitor computer programming does not exist yet. In this study we describe a new task for intraoperative monitoring, using visual Boolean Logic Puzzles.

MATERIAL AND METHODS
We describe a computer programmer who underwent awake craniotomy to resect an anaplastic astrocytoma in the left superior frontal gyrus. At the request of the patient we tested programming language. We developed a new task and set of logic puzzle visual stimuli to monitor underlying cognitive function used for programming language. This test was used during preoperative functional MRI (fMRI), direct electrical stimulation (DES) and ongoing monitoring during resection.

RESULTS
In fMRI this task showed bilateral activation in Brodmann area 6 and 8 and for left hemisphere in Brodmann area 10. These areas are below and lateral of the tumor. Monitoring of language, motor skills and Boolean mapping was performed during DES and while resection was performed. No deficits in programming ability could be identified intra- and postoperatively.

CONCLUSION
Boolean Logic Puzzles may be a useful intraoperative task to preserve programming skills.
P04.07 The molecular evolution of oligodendrogliomas
Authors: Padovan M , Vallentgoed W , de Heer I , Lombardi G , van den Bent M , French P 
Published: September 2021

Abstract

BACKGROUND
Oligodendroglioma (OD) is defined by the presence of both IDH1/2 mutation and 1p/19q codeletion. Although prognosis of OD patients is relatively favorable, tumours usually relapse and often evolve to a higher malignancy grade, with some acquiring the treatment induced hypermutated phenotype. To better understand how these tumours evolve in time, we examined the molecular differences between matched primary and recurrent ODs.

MATERIAL AND METHODS
We identified 21 patients who underwent surgery at least twice [male: 11, female: 10, median age: 44 years (31–66)]. Clinical data were available for 14/21 patients: 5/14 received a treatment between resections [4 radiotherapy, 1 radiotherapy followed by PCV chemotherapy]; median time from the first to the second surgery was 71.5 months (12–158). Whole genome DNA-methylation analysis was performed using Illumina’s MethylationEPIC ‘850K’ BeadChip. Results were evaluated using the Molecularneuropathology.org platform (version 3.1.5) and in R.

RESULTS
Most samples were WHO grade 2 ODs [14, 10 and 1 tumours in first, second and third resection group, respectively]; WHO grade 3 was found in 6, 10 and 3 tumours in first, second and third resection, respectively; in 4 patients the tumour showed malignant progression from grade 2 to 3. Most ODs exhibited an IDH1 R132H mutation [17/21 patients]; in no cases was IDH1/2 mutation lost during progression. DNA methylation analysis was successfully performed in 41/45 cases [primary OD: 17, recurrent OD: 24] for a total of 18 matched pairs. 37 samples were assigned to the “IDH mutant glioma, subclass 1p/19q codeleted OD”; the remaining 4 were assigned to various other methylation classes but CNV (copy number variation) analysis confirmed the 1p19q codeletion in all samples. Recurrent tumours exhibited de novo loss of chromosome 4 in 3/24 cases (12.5%) and loss of chromosome 13 in 3/24 cases (12.5%). In unsupervised analysis of the 1000 most variable CpG sites, samples from the same patient clustered together. This indicates that the inter-tumour variability is greater than the intra-, temporal- or grading variability between tumours. There were no overt differences in DNA methylation levels between the primary and matched recurrent OD. However, lower genome wide DNA methylation levels were observed in tumours that dedifferentiated to grade 3 ODs compared to those of grade 2, indicating that DNA demethylation is associated to higher malignancy grade.

CONCLUSION
DNA methylation analysis in a cohort of primary and recurrent oligodendrogliomas highlights the genomic and epi-genetic changes that are acquired at tumour progression. We are currently expanding the cohort and collecting/integrating the clinical data to better explore the evolution of recurrent ODs.
P04.17 Antigen heterogeneity in glioblastoma cell lines, patient-derived cells, and patients’ glioblastoma tissue is an obstacle for CAR-T cell therapy development
Authors: Dufner V , Schulz E , Monoranu C , Hudecek M , Ernestus R , Hagemann C , Löhr M , Nerreter T 
Published: September 2021

Abstract

BACKGROUND
Immunotherapy targeting surface antigens, e.g. CAR-T-cell therapy has become a promising therapeutic approach for glioblastoma (GBM) treatment. Antigen heterogeneity constitutes a major obstacle not only for preclinical in vitro studies but also for clinical translation. Here, we provide information about the surface expression of the eight in GBM CAR-T-cell therapy most targeted antigens (GD2, CSPG4, CD133, CD70, HER2, Il13Rα2, EGFRvIII and EphA2) by analyzing GBM cell lines (GCL), patient-derived cells (PDCL) and patients’ tumor tissue (PT) and comparing the expression profiles.

MATERIAL AND METHODS
We measured expression of the above-mentioned antigens in 7 GCL (GaMG, U87, U373, U343, U251, U138, DKMG), 7 PDCL and PT of 9 patients by flow cytometry (FACSCanto II). After evaluation with FlowJo software (TreeStar), we scored antigen expression (0–1.0: low expression, 1.1–2.0: medium expression, 2.1–3.0: high expression) and calculated the mean expression and range.

RESULTS
GD2 showed a medium expression in GCL (x̅=1.3) but was highly expressed in PDCL (x̅=2.6) and PT (x̅=2.4). In contrast, CSPG4 displayed low expression in GCL (x̅=0.3) and PT (x̅=0.4), but medium expression in PDCL (x̅=1.9). CD133, a stem cell marker, showed low expression in GCL (x̅=0.8) and PDCL (x̅=0.4), whereas the expression in PT was medium (x̅=1.4). Both CD70 and Il13Rα2 were weakly expressed in GCL, PDCL and PT (x̅=0.2, 0.4, 0.0 and 0.5, 0.6, 0.4, respectively). HER2 displayed medium expression in GCL (x̅=1.4) and PDCL (x̅=1.4) and low expression in PT (x̅=0.6). For EGFRvIII medium expression was detectable in all three entities (x̅=1.4, 1.1 and 1.1). EphA2 was mildly expressed in GCL (x̅=0.1), medium expressed in PT (x̅=2.0) and highly expressed in PDCL (x̅=2.6). Overall, there was high variability of antigen surface expression even within each of the groups.

CONCLUSION
GCL, PDCL and PT display heterogenic antigen surface expression with high variability within each group, thereby complicating clinical translation of in vitro results obtained using cell lines. This aspect should be taken into account in GBM target antigen research.
P04.22 Tumor treating fields in high-grade glioma patients: A retrospective single-center study
Authors: Lucaciu R , Suchorska B , Wettig M , Jung S , Scholz M 
Published: September 2021

Abstract

BACKGROUND
Tumor-treating fields (TTFields) are a modern anti-mitotic, non-invasive therapy for the treatment of patients with recurrent and newly diagnosed glioblastoma multiforme (GBM). In Europe, Optune® recieved in 2015 the CE certification. TTFields are a low-intensity (1–3 V/cm) approved therapeutic modality using a non-invasive application of intermediate frequency (200 kHz) alternating electric fields through four transducer arrays directly applied to the skin. The EF-14 study has shown that the addition of TTFields to temozolomide chemotherapy in patients with newly diagnosed GBM significantly improved overall survival (OS) and progression-free survival (PFS) without additional adverse events, apart from mild to moderate skin irritations (Stupp et al., JAMA 2017).

MATERIAL
We retrospectively analyzed data from TTFields-treated patients (2015–2020) that were treated at our department. Patient characteristics such as MGMT promoter methylation status, age, and diagnosis, as well as treatment duration and TTFields therapy usage, were evaluated for this study.

RESULTS
29 patients were treated with TTFields therapy between 2015 and 2020 at our hospital. Most patients received TTFields as primary treatment together with temozolomide maintenance therapy. In detail, 48% of patients were diagnosed with newly diagnosed GBM, 41% received TTFields therapy after tumor recurrence and 10% were diagnosed with other high-grade gliomas. In summary, patients could integrate TTFields therapy into their daily life and showed high adherence to the therapy.Particularly, one of our patients (with MGMT-promoter methylation positive) receives TTFields therapy now for almost 1229 days (approx. 41 months) and is still on therapy. Additionally, this patient shows a high usage rate of 86% indicating well integration of the therapy into daily life.

CONCLUSION
Taken together, our data provided the outcomes of using TTFields together with chemotherapy in the treatment of recurrent and newly diagnosed GBM in our department. Therapy with TTFields has been showing to provide significant clinical benefit for GBM patients.
P06.04 Tertiary center experience in the treatment of intracranial germinoma
Authors: Jabłońska I , Miszczyk M , Nowicka E , Magrowski  , Tarnawski R 
Published: September 2021

Abstract

BACKGROUND
Intracranial germinoma is a rare malignant neoplasm, accounting for approximately two-thirds of central nervous system germ cell tumors, which occurs in the suprasellar region, pineal gland, or basal nuclei in children and young adolescents. Due to the rare occurrence, there is relatively high variability in treatment modalities. This article aims to assess the symptoms, and treatment outcomes of radiotherapy and chemotherapy for intracranial germinoma, based on tertiary center experience.

METHODS
The study includes retrospectively gathered data from 35 consecutive patients treated for intracranial germinoma between 1999–2020 at a single institution. The statistical analysis used basic statistical tools and the Kaplan-Meier method.

RESULTS
The median age at diagnosis was 17 years (IQR 14–22), 85.7% of the patients were male. The majority of the patients had histopathological confirmation of the diagnosis (88.5%), 76% of which were non-secreting germinomas. The primary tumor was most frequently localized in the area of the pineal gland (34.3%), followed by bifocal (25.7%), suprasellar (17.1%), and basal germinoma (8.6%). The remaining patients had disseminated disease (14.3%). The most common symptoms at the onset of the disease were headache (54.3%), visual impairment (45.7%), vomiting (25.7%), polydipsia (22.9%), weight loss (17.1%), or minor neurological deficits (11.4%). As much as 54.3% of the patients presented with neuroendocrine disorders at diagnosis, and 42.9% of the patients presented radiological symptoms of hydrocephalus. Each patient received radiotherapy, which was preceded by chemotherapy in 77.1%, and surgery in 31.4% of the cases. The majority of the patients received radiotherapy to the ventricular system (51.4%), craniospinal irradiation (34.3%), or whole-brain radiotherapy (8.6%) followed by a focal boost in 88%. The remaining patient was treated with focal radiotherapy only. The 5- and 10-year overall survival rate was found to be 97% and 87% respectively, including two patients who died despite disease control (pulmonary and ventricular embolism). The 5-year progression-free survival was 83%.

CONCLUSIONS
Despite variability in treatment methods, there is a relatively high cure and survival rate in patients with intracranial germinoma. However, the rare occurrence of the disease seems to negatively impact the diagnostic process. The tumor is often diagnosed at an advanced stage, presenting significant, often irreversible symptoms.
P06.07 Germline mutation of SMARCE1 gene in a family with spinal meningiomas
Authors: Giunti L , Rinaldi B , Serio V , Buccoliero A , Fiorentini E , Casati G , Iorio A , Marturano A , Genitori L , Sardi I 
Published: September 2021

Abstract

BACKGROUND
Meningioma is the most common benign primary intracranial tumor, arising from arachnoid cells of the meninges, but in 20% of cases displays aggressive behavior. Meningiomas are mainly sporadic and the familial forms are very rare. Meningioma account for a small subset (1–4%) of all pediatric brain tumors and may be associated with hereditary tumor predisposition syndrome caused by germline mutations of NF2, SMARCB1, SUFU, and SMARCE1 genes.

MATERIAL AND METHODS
We present a case of a 16-year-old girl with spinal clear cell meningiomas (CCMs) WHO II with a second spinal lesion identified during the follow-up. Considering the multiple lesions, we performed Whole Exome Sequencing (WES) on DNA from peripheral blood to search for an underlying CCMs tumor predisposition syndrome (#607174).

RESULTS
We identified a heterozygous frameshift variant c.439delA (p.Ser147fs) in SMARCE1, chromatin remodelling factor that acts as a tumor suppressor gene. Meningioma analysis by Sanger sequencing showed a loss of heterozygosity (LOH) of the wild-type allele. We identified the c.439delA in the constitutional DNA of the father and the sister but not in the mother. At the moment, the father is asymptomatic and the 14 years old sister showed two spinal lesions (meningiomas likely) at the first MRI.

CONCLUSION
We report a family study of hereditary tumor predisposition syndrome to CCMs with SMARCE1 mutation in which are present two asymptomatic carriers with different ages and gender. The asymptomatic carriers will undergo neurological examination and MRI of the brain and spine, according to a screening protocol. The incomplete penetrance phenomenon is known in SMARCE1-related families with CCMs and it is probably due to the interaction of SMARCE1 with yet unidentified genes.
P07.02 Robot-assisted stereotactic brain biopsy combined with cortical mapping using navigated transcranial magnetic stimulation
Authors: Petrescu G E D , Radu R , Gorgan C , Giovani A , Brehar F M , Gorgan R M 
Published: September 2021

Abstract

BACKGROUND
Frame-based stereotactic biopsy has been for decades the gold-standard method for taking samples of brain tumors for the histopathological diagnostic in cases when surgery was contraindicated. However, novel frameless techniques have been developed in order to facilitate the procedure for the neurosurgeon, and for the patient as well. Preoperative cortical mapping techniques enable the planning of the trajectory with the sparing of eloquent areas.

MATERIAL AND METHODS
A preoperative cortical mapping using navigated transcranial magnetic stimulation was performed in the case of a 37-year-old male that presented with headache. The MRI scan revealed multiple lesions located frontal lobe and temporal lobe on the right hemisphere and frontal and occipital lobes on the left hemisphere. The results of the preoperative cortical mapping were integrated into the neuronavigation system and used for the planning of the frameless based stereotactic brain biopsy. A biopsy procedure was performed using a robotic arm according to the planned trajectory.

RESULTS
The targeted lesion was the right frontal one. The planned trajectory took into account the results from the cortical mapping using nTMS, and the eloquent areas were avoided. The robotic arm guided the procedure and aligned to the entry point and trajectory. According to the histopathological result the lesion was a grade II diffuse astrocytoma. There were no perioperative complications.

CONCLUSION
To our knowledge, this is the first report that describes the use of a robot-guided frameless brain biopsy system combined with the preoperative mapping of the eloquent cortical areas using navigated transcranial magnetic stimulation. This approach is a safe one and carries less burden for the patient as well as for the surgeon.
P08.01 Immune-Related Acute Motor Axonal Neuropathy: A Small Case Series and Review of the Literature
Authors: Pina Y , Tran N , Forsyth P , Mokhtari S , Peguero E 
Published: September 2021

Abstract

BACKGROUND
Immunotherapy have revolutionized cancer treatment in the past decade, with a significant increased survival in patients with solid tumors. However, the use of immune checkpoint inhibitors (ICIs) has been associated with a growing number of neurotoxicities, some of which can be fatal if not recognized and treated promptly. Some of these neurotoxicities include very uncommon syndromes like Acute Motor Axonal Neuropathy (AMAN). Herein we present four oncological cases of patients who underwent immunotherapy and developed AMAN.

METHODS
Four patients were diagnosed with immune-related AMAN between 2017 and 2000 at H. Lee Moffitt Cancer Center. The patients were treated with standard of care and currently follow up in clinic.

RESULTS
We describe four oncological patients who developed a motor axonal neuropathy (i.e., AMAN) confirmed on nerve conduction studies following 2 cycles of immunotherapy, including a 28 year old woman with melanoma brain metastasis and a 50 year old woman with renal cell carcinoma both treated with ipilimumab and nivolumab, a 32 year old man with Hodgkin lymphoma who was treated with nivolumab and brentuximab, and a 77 year old woman with renal urothelial cancer who was treated with pembrolizumab and cabozantinib. All four patients were promptly recognized as having immune-related neurotoxicity (irNs), were promptly treated (i.e., high dose steroids +/- IVIG +/- other immunomodulators), and significantly improved and have remained stable.

CONCLUSION
This is the first case series of patients with AMAN following two cycles of immunotherapy, who were successfully treated. It is crucial to develop a better understanding of the irNs associated with ICIs, including those rare conditions that are difficult to diagnose and treat, as the utilization of these immunomodulating therapies continues to increase and expand to include other solid malignancies. Neurologists should be involved early on in any case of suspected irN to assist in the management of these complicated patients and a swift work up should be initiated for timely diagnosis and treatment.
P08.02 Harnessing T cells to target brain metastasis
Authors: Gregory S R , Fife C , Williams J , Carrasco Hope H , Andreou T , James F , Brownlie R , Newton-Bishop J , Salmond R , Lorger M 
Published: September 2021

Abstract

BACKGROUND
Up to 60% of melanoma patients develop brain metastases (BrM). These patients have a poor prognosis and limited treatment options. Immune checkpoint inhibitors (ICI) targeting Cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) and Programmed cell death protein-1 (PD-1) have revolutionized the treatment of melanoma and their efficacy has been also demonstrated in melanoma BrM. Our group previously demonstrated that ICI (combined α-PD-1 and α-CTLA-4) enhances chemokine-dependent infiltration of cytotoxic T lymphocytes (CTLs) into melanoma BrMs in preclinical models, accompanied by upregulated expression of T cell attracting chemokines in tumours. Notably, CTLs infiltrating BrM expressed only some of the chemokine receptors (CRs) interacting with ICI-induced chemokines in BrM, providing a rationale to over-express the “missing” CRs in T cells to enhance their homing to tumours in the context of adoptive T cell therapy (ACT).

MATERIALS AND METHODS
OT-I cells were isolated from OT-I mice and differentiated ex vivo into effector (TEF) and memory (TCM) CD8+ T cells. Tumour infiltrating lymphocytes (TILs) from B16 tumour-bearing mice treated with ICI were isolated using magnetic beads, activated and expanded ex vivo. Expression of CRs and activation markers in ex vivo cultured T cells were quantified by qPCR and/or flow cytometry. The migration of human blood CD8+ T cells towards chemokines of interest were measured in ex vivo migration assays.

RESULTS
The same CRs that were missing on BrM-infiltrating CTLs in vivo models were also absent from OT-I TEF (CCR7low/CD44high/CD62Llow) and TCM (CCR7high/CD44low/CD62Lhigh) cells, as well as from TILs expanded ex vivo for use in ACT. Furthermore, we observed no increase in migration of human T cells towards chemokines interacting with the “missing” CRs in comparison to the baseline migration, suggesting that these CRs are also absent from human T cells.

CONCLUSION
Ex vivo expanded T cells that are used in ACT are missing several CRs that are interacting with chemokines upregulated in BrM. We hypothesise that the use of genetically engineered T cells expressing the “missing” CRs in ACT has the potential to enhance ACT efficacy in combination with ICI.