bluuebunny/crossref_metadata_2025 huggingface dataset:
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

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

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

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

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

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

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

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

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.
P09.04 T2 hyperintense regions on MRI in gliomas: a comparison between routine clinical MRI and 7T MRI
Authors: Schmitz-Abecassis B , van Osch M J P , Dirven L , Taphoorn M J B , Koekkoek J A F , de Bresser J
Published: September 2021

BACKGROUND

Gliomas can be highly heterogeneous on brain MRI, especially at higher grades. These tumors often include a low-grade component and/or surrounding edema. Both these components appear as hyperintense regions on clinical T2-weighted MR images and cannot be accurately distinguished. Ultrahigh field 7T MR systems have the potential for a higher sensitivity due to its increase signal-to-noise ratio (SNR). This could allow for enhanced detailed visualization of gliomas. Therefore our goal was to assess the difference in extent of T2 hyperintense regions in glioma patients between clinical (1.5T/3T) and 7T MR images.

MATERIAL AND METHODS

We prospectively scanned 6 glioma patients (3 glioblastomas (GBM) WHO grade IV post-operative, 1 anaplastic diffuse glioma (ADG) WHO grade III, 1 biopsied oligodendroglioma (OD) WHO grade II and 1 suspected low-grade glioma (LGG); 4 Females, mean age: 56.8 years and 2 Males, mean age: 45.5 years) on a routine clinical MRI scanner (3T or 1.5T) and on a 7T MRI scanner (Philips Achieva). Resolution of the T2-weighted image at 7T, 3T and 1.5T: 0.75mm3, 3mm3 and 5mm3, respectively. T2-weighted scans were visually assessed by an independent researcher and experienced neuro-radiologist. The T2 hyperintense regions were measured in 3 directions and compared brain structures as reference points between the clinical and 7T scans (e.g. brain stem, gyri), also considering differences in slice thickness and spatial resolution.

RESULTS

T2 hyperintensity lesion measurements in the AP direction were as follows: GBM: 114.7mm (clinical field strength) vs 115.56mm (7T); ADG: 45mm vs 58.87mm and 24.7mm vs 25.55mm; OD: 45.1mm vs 48.5mm; GBM: 45.3mm vs 44.75mm; suspected LGG: 47.4mm vs 51.57mm; GBM: 105.8mm vs 114.5mm. We observed the largest difference between 3T and 7T T2 hyperintense region measurement to be 13.87mm (30%), belonging to a GBM WHO grade IV patient. For all patients the T2 hyperintense region was measured on average 8.3% larger at 7T MRI compared to the routine clinical MRI scan. Overall the T2 hyperintense regions at 7T appeared sharper and tumor boundaries were better defined. Likewise, the contrast between the tumor and healthy tissue was enhanced, most likely because of the increase in spatial resolution.

CONCLUSION

In gliomas the T2 hyperintense regions were more extensive at 7T MRI compared to the routine clinical MRI. These preliminary results might indicate that at clinical field strength the extent of the lesion is underestimated and that 7T MRI can potentially aid in detecting this more extensive disease process. Therefore, 7T MRI scan in gliomas might have a future role in treatment decisions regarding the extent of tumor resection and radiotherapy planning.
P10.01 Effect of mesenchymal cells on infiltration and phenotype of T cells in a 3D glioblastoma spheroid model
Authors: Svablova T , Ternerova N , Houdova Megova M , Busek P , Sedo A
Published: September 2021

BACKGROUND

Glioblastoma (GBM), the most malignant primary brain tumor with a median survival less than two years, is characterized by aggressive invasive growth, presence of hypoxic and necrotic regions, and T-cell dysfunction. Mesenchymal cells with characteristics of cancer associated fibroblasts are present in GBMs, but it remains to be established whether they contribute to T cell sequestration in the tumor stroma and functional inactivation similarly to extracranial tumors. Murine models do not reflect several aspects of human immune system and 2D cell culture systems often fail to recapitulate complex interactions in the tumor microenvironment. 3D spheroids prepared from patient-derived cell cultures offer higher degree of complexity and biological relevance. The aim of this study was to establish a 3D GBM spheroid model to determine the effect of patient derived mesenchymal cells on human T cell infiltration and phenotype.

MATERIAL AND METHODS

Glioma stem-like cell and mesenchymal cell cultures were derived from human GBMs. Naïve T lymphocytes were isolated from buffy coats of healthy donors by Ficoll paque gradient separation, followed by negative magnetic isolation techniques using Naïve Pan T Cell Isolation Kit (Miltenyi Biotec). 3D spheroids were prepared by embedding the cells in 20 µl of Geltrex (Thermo Fisher Scientific). T cells activated by magnetic beads with anti-CD2, anti-CD3 and anti-CD28 antibodies (Miltenyi Biotec) and IL-2 were subsequently added to the spheroids. After 5 days of co-culture, spheroids were dissociated, and viable cells were counted using automated cell counter (Biorad). Expression of a T-cell activation marker CD69 and immune checkpoint molecules LAG3, and PD-1 in CD3+ cells was analyzed by flow cytometry. Mesenchymal, stem cell and lymphocyte markers TE-7, Nestin and CD45 respectively, were analyzed by immunohistochemistry (IHC) on frozen spheroid sections.

RESULTS

We prepared spheroids comprising glioma stem-like cells with and without mesenchymal cells. Glioblastoma-derived cells were evenly dispersed throughout the spheroids as demonstrated by IHC. T cells infiltrated into both types of spheroids, but their number in spheroids containing mesenchymal cells was about 40% (p=0.002) lower compared to the ones without mesenchymal cells. In both types of spheroids, the presence of activated allogeneic T cells led to more than a 50% reduction of the glioblastoma-derived cells. Ongoing studies evaluate the effect of mesenchymal cells on the phenotype of spheroid infiltrating T cells.

CONCLUSION

We have successfully established a 3D spheroid model to study the role of mesenchymal cells in GBM microenvironment. Our results indicate that mesenchymal cells may influence the infiltration of T cells and modulate their phenotype.

SUPPORT

Project was financed by the Center for Tumor Ecology (CZ.02.1.01/0.0/0.0/16_019/0000785).
P12.05 Pulmonary embolism in neuroncological patients: Monoistitutional experience
Authors: Gaviani P , Simonetti G , Redaelli V , Botturi A , Corsini E , Silvani A
Published: September 2021

BACKGROUND

Venous thromboembolism (VTE) is a frequent and potentially fatal event in cancer patients. Patients with brain tumors in particular have one of the highest risk of developing VTE among cancer patients (25–39%), contributing significantly to mortality and morbidity. VTE is particularly high in the postoperative period, with almost half of the events occurring at that time, but it also persists in the first 12 months, with a risk ranging between 7–28%. Despite the high incidence of VTE in patients with brain tumors, to date there are no sufficient data to predict teh real risk or to lead to a standardized approach in the management of these patients. We conducted a retrospective analysis to assess the prevalence of pulmonary embolism complication in patients with brain tumors treated by our Institution in the last 3 years.

MATERIAL AND METHODS

Clinical data, treatment modalities, and patients outcome were analyzed and described. In particular, In particular, the dosages of D-dimer performed in the clinical suspicion of thromboembolic complication were reviewed, and the data of patients with pulmonary embolism confirmed by chest CT scan were recorded.

RESULTS

Overall 372 patients were treated at our Institute in the last 3 years for brain tumors. 14 patients (3.7%) 9 males and 5 females, with a median age of 62 years and a median KPS of 80, affected by glioblastoma (69%), cerebral lymphoma (23%) and low-grade gliomas (8%) had pulmonary embolism during the course of treatment. None of the 14 patients was on prophylactic anticoagulant treatment. One patient developed the embolic event during radio and chemotherapy concomitant treatment, 5 patients during chemotherapy only (2 with PCV scheme and 3 with fotemustine scheme), 2 patients with primary nervous system lymphoma during methotrexate infusion. Six patients were not receiving any chemotehrapy treatment at the onset of pulmonary embolism. At the time of pulmonary embolism diagnosis, more than half of the patients had clinical signs suggestive of deep venous thrombosis, confirmed by echocolor Doppler, 10/14 patients were treated with high-dose enoxaparin, the others with fondaparinux and calcium nadroparin.

CONCLUSION

Despite the high incidence of VTE in patients with brain tumors, there is currently no gold standard in the prevention and treatment of this complication. In fact, many questions are still open, for example the efficacy of low molecular weight heparins vs oral anticoagulants as a prophylactic treatment, the timing of onset and the real risk of bleeding. Future prospective studies should be designed to identify parameters for optimize stratification of thrombotic / haemorrhagic risk in this group of patients. This could allow patients at high risk to undergo more aggressive prophylactic therapy or closer clinical-instrumental surveillance, without incurring the opposite risk of bleeding.
P12.06 Unmet needs and wish for support of informal caregivers of primary brain tumour patients
Authors: Pointon L , Grant R , Peoples S , Erridge S , Sherwood P , Klein M , Boele F
Published: September 2021

BACKGROUND

Most primary brain tumour patients rely on informal caregivers (i.e. family members or friends) for practical and emotional support. While caregiving can be rewarding, it also commonly leads to significant burden. In developing support for caregivers, it is vital to distinguish between caregivers’ unmet needs, and their actual wish for support to resolve unmet needs. We aimed to 1) identify the presence and magnitude of unmet needs; 2) examine associations between unmet needs and desire for support; 3) evaluate perceived usefulness of caregiver needs screening in clinical practice.

MATERIAL AND METHODS

Family caregivers of patients with primary brain tumours were recruited and asked to complete an adapted version of the Caregiver Needs Screen (CNS). This covered the level of distress resulting from 33 common issues in neuro-oncology caregiving (scale 0–10), and wish for information or support for any issue (yes/no). In addition, participants were asked to rank (0–7) their experience of using the CNS based on items covering ‘ease of us’, ‘usefulness’ and ‘satisfaction’. Descriptive and correlational analyses were applied.

RESULTS

Caregivers (N=79) reported between 1–33 unmet needs (M=17.20, sd=7.98) but did not always wish for support for each need (range 0–28, M=4.71, sd=6.63). Most distressing items were patient’s fatigue (M=5.58), recognising signs of disease progression (M=5.23), changes in patients’ thinking or behaviour (M=5.04), patient distress or sadness (M=4.68), and changes in caregivers’ own emotional health (M=4.44). A weak correlation was found between the total number of unmet needs and the desire for support (r=0.296, p=0.014). Caregivers most often desired support with recognising disease progression (N=24), managing medications and side-effects (N=18), and least often with managing spiritual issues (N=0), communication with (grand)children (N=2) and communication with family members and friends (N=3). Caregivers evaluated the CNS tool positively (mean item scores ranging 4.19–6.21 out of 7).

CONCLUSION

Family caregivers of brain tumour patients experience distress resulting from many neuro-oncology specific needs, but this is not directly related to a wish for support or information. Caregiver needs screening could be useful to tailor support or information to suit caregivers’ preferences in clinical practice.
P12.08 Efficacy of trazodone slow release in insomnia associated with high-dose steroid therapy in neuro-oncological patients
Authors: Botturi A , Gaviani P , Redaelli V , Simonetti G , Lucchiari C , Silvani A
Published: September 2021

BACKGROUND

Insomnia linked to therapeutical intake of intravenous (IV) megadoses of steroid (Mgds, 8–16 mg) is a common side effect in neuro-oncology patients. Hypno-inducing drugs (IP) and Benzodiazepines (BDZ) can provoke drug interference and daytime sedation. Trazodone (Trz) is an atypical antidepressant with poor liver metabolism; it has moderate histamine-1 (H1) receptor antagonism and possesses some anxiolytic and hypnotic properties. We tested the use of the Trz retard (RP) formulation as a hypnotic drug in patients undergoing a therapeutic regimen with IV Mgds. To evaluate anxiety and side effects.

MATERIAL AND METHODS

10 patients (6 females and 4 males) admitted to the Neuro-oncology Department of the Neurological Institute “Carlo Besta” treated with Mgds IV. The average age was 55 years and the mean HAM-A score was 25. Instruments included the Hamilton Anxiety Scale (HAM-A), the Clinical Global Impression (CGI), and the Pittsburgh Sleep Quality Index (PSQI). Trz RP was administered at a dosage of 25-50-75 mg/day in the evening.

RESULTS

All 10 patients reported improved hypnotic profiles within the third day of Trz RP administration. Four patients improved on the first day. Reduction of the HAM-A score was found on the third day. No adverse events (epilepsy, daytime sedation, incontinence) were observed in 3 weeks.

CONCLUSIONS

Trz RP proved to have a swift beneficial effect on sleep and anxiety without side effects in the short term. Trz may be preferred to IP and BDZ in patients receiving IV Mgds, considering the lack of daytime sedation and the reduced pharmacological inference. Larger samples will enable future research to better describe the characteristics and the indication of Trz.
P13.12 Effect of tumor treating fields on tumor microtubes in glioma
Authors: Ratliff M , Schlieper-Scherf S , Hausmann D , Jung E , Maier E , Ratliff T M , Etminan N , Winkler F
Published: September 2021

BACKGROUND

Tumor microtubes (TMs) are ultralong membrane protrusions of tumor cells in astrocytic gliomas, including glioblastomas. TMs are used as routes for brain invasion and for cells to interconnect over long distances resulting in a functional network that allows multicellular communication. This network mediates resistance against the cytotoxicity of radiation and chemotherapy. One explanation for TM network protection is a better homeostasis of calcium ions that would otherwise increase to toxic intracellular levels in response to these therapies.

Our working hypothesis is that interfering with the integrity of the glioblastoma cell network is key to a potential breakthrough in glioma therapy. Many cellular structures are polarized and composed of charged elements and are thus potential subjects to electrical forces; this might also influence the complex intercellular calcium waves (ICWs) that are characteristic for glioma networks. We were therefore interested in the effect of TTF on glioma network maintenance.

MATERIAL AND METHODS

To examine the effect of TTF on glioma TMs we have established a 2D in vitro glioma model using glioblastoma stem cells (GBSCs) grown in high-glucose medium and a 3D model using glioma tumor organoids. Both models reliably reproduce functionality and complexity of morphological features we observe in our mouse model. We analyzed the disruption of tumor network complexity and disruption of functionality by measuring intercellular calcium waves. Tumor cell death and proliferation was investigated in the 2D in vitro glioma model using the inovitroTM-System.

RESULTS

A peculiar “cricked-TM” phenotype that rarely (0.2% ±0.14) occurred under standard or control conditions was observed in TTF-treated cells (16.22% ±5.12). Cell number was reduced by 75% in two lines of GBSCs after 5 days of TTF exposure; predominantly TM-rich GBSCs (> 4 TMs) were affected. This reduction in tumor cell number corresponded with an increase in cell death (0.3% ±0.09 in untreated cells; 1.4% ±0.45 at day 5 of TTF exposure). The frequency of intercellular calcium transients, a measurement for calcium wave frequency in the glioma networks, was instantly reduced after TTF exposure to 58% ±20.42 of control levels in the primary GBSC 2D culture, and to 57.78% ±12.34 in tumor organoids derived from 3 glioblastoma patients.

CONCLUSION

This data suggests a potential effect of TTF application on tumor cell networks, at least in vitro. Interestingly, particularly those glioblastoma cells that have so far been proven to be resistant to radio- and chemotherapy appeared to be affected. We will confirm the observed effects of TTFs on tumor cell calcium signaling in our in vivo chronic cranial window mouse model. We anticipate that the results of our project will provide important insights into the underlying mechanism of TTF therapy.
P14.24 Estimating survival outcomes in elderly (70+ years) patients with primary glioblastoma
Authors: Zorman M J , Webb P , Nixon M , Sravanam S , Honeyman S , Nandhabalan M , Apostolopoulos V , Stacey R , Hobbs C , Plaha P
Published: September 2021

BACKGROUND

Elderly patients with glioblastoma are perceived to face a poor prognosis, with perceptions around older age and a relative lack of randomized data raising a concern about their undertreatment. The EANO guidelines recommend >70-year-old patients with good performance status to undergo maximal safe resection followed by hypofractionated (40 Gy in 15 fractions, i.e. RT40/15) radiotherapy with or without concurrent and adjuvant Temozolomide (TMZ), depending on MGMT promoter methylation. This study evaluated the relative survival impact of biological, histological, surgical and oncological factors and aimed to devise a scoring system to estimate the survival of elderly glioblastoma patients, with an aim to more accurately guide treatment in this cohort.

METHODS

The records of 169 elderly (≥70 years) patients with a new diagnosis of IDH-wild type glioblastoma were retrospectively examined for gender, age, WHO performance status (PS), comorbidities, MGMT methylation, surgical intervention and chemoradiation regime. The adjusted survival impact of these factors was determined using Cox proportional hazards model and used to devise a two-stage scoring system to estimate survival of patients at the stage of surgical (Elderly Glioblastoma Surgical Score, EGSS) and oncological management (Elderly Glioblastoma Oncological Score, EGOS).

RESULTS

The overall median survival (MS) of the cohort was 28.8 weeks. Subtotal resection (MS=27.7 weeks, 95%CI 24.1–31.6 weeks, HR=0.58) and gross-total resection (MS=77.8 weeks, 95%CI 67.0–88.6 weeks, HR=0.36) were associated with significant overall survival benefit compared to biopsy alone (MS=18.2 weeks, 95%CI 15.7–20.7 weeks, HR=5.23), p<0.05. Hypofractionated radiation with Temozolomide (RT40/15+TMZ, MS=60.9 weeks, 95%CI 49.9–71.8 weeks, HR=0.13) was non-inferior to the Stupp protocol (RT60/30+TMZ, MS=50.6 weeks, 95%CI 32.4–66.7 weeks, HR=0.11), p=0.72. Negative prognosticators included age above 75 years, biopsy alone and no chemoradiotherapy. Subgroup analysis revealed that MGMT unmethylated 70–75 year old patients who received the Stupp protocol had significantly improved overall survival (MS=57.6 weeks, 95%CI 27.7–88.1 weeks) compared to standard of care RT40/15 alone (MS=29.7 weeks, 95%CI 7.1–51.6 weeks), p=0.002. EGSS and EGOS scores estimated survival with 65% and 73% accuracy, respectively.

CONCLUSION

When appropriate and safe, a subgroup of elderly glioblastoma patients may benefit from more aggressive surgical and oncological management. The proposed EGSS and EGOS scores takes into account important prognostic factors to help guide which patients should receive such treatment.
P14.25 Melanoma brain metastases in the era of novel therapies: a single-center, Dutch cohort study
Authors: Derks S H A E , Jongen J L M , Slagter C , Joosse A , Schouten J W , van den Bent M J , van der Veldt A A M
Published: September 2021

BACKGROUND

Until recently, patients with melanoma brain metastases (MBMs) had limited therapeutic options. With the arrival of immune checkpoint inhibitors (ICIs), targeted therapy (TT) and advances in stereotactic radiotherapy (SRT), treatment has improved. We evaluated treatments and patient outcome before and after the introduction of these novel therapies.

MATERIAL AND METHODS

In this retrospective, single-center study, patients presenting with MBMs at the Erasmus MC between November 2005 and January 2021 with sufficient follow-up were included. Overall survival (OS), measured from date of MBM diagnosis, was calculated using the Kaplan-Meier method. Patients were stratified according to MBM diagnosis before and after January 1, 2016, since novel therapies were mostly prescribed in our clinic after this date. Results were significant (p<0.05), unless otherwise stated.

RESULTS

Overall, 413 patients were included. Median [IQR] age was 56.6 years [52–71] with a 60% male predominance. A BRAF mutation was present in 46.7% of patients. A single MBM was found in 29.3% and ≥4 MBMs were found in 49.0% of patients. Before January 1, 2016, 191 patients were treated, and 222 patients after that date. Chemotherapy was more frequently used before 2016, both prior to (3.9% pre-2016 vs. 0.9% post-2016) and after (7.0% vs. 0.0%) the diagnosis of MBMs. In contrast, treatment with TT was more frequent after 2016, both prior to (3.7% vs. 16.2%) and after (7.9% vs. 41.4%) the diagnosis of MBMs. Comparable changes were observed for treatment with ICIs (prior to MBM diagnosis: 0.5% vs. 25.2%; after MBM diagnosis: 18.3% vs 39.2%). The application of SRT did not differ significantly before and after 2016 (12.0% vs. 19.4%, p=0.89), while the application of whole brain radiotherapy (WBRT) decreased (52.4% vs. 13.5%). Surgical resection was not significantly different between those periods (15.7% vs. 16.7%, p=0.90). Before 2016, median OS [IQR] was shorter than after 2016 (4.6 [1.9–10.9] vs. 6.6 [1.8–24.5] months). The effect of novel therapies on OS was further analysed in patients diagnosed after 2016; treatment vs. no treatment was compared. ICI treatment prior to MBM diagnosis was associated with worse OS (median OS 4.0 vs. 7.5 months). ICI treatment after MBM diagnosis was associated with better OS (median OS 24.5 vs. 3.0 months). In patients with a BRAF mutation, TT before MBM diagnosis was associated with worse OS (median OS 1.8 vs. 9.4 months). TT after MBM diagnosis in those patients was not significantly associated with improved OS (median OS 7.6 vs. 5.2 months, p=0.96).

CONCLUSION

Recent therapeutic advances for MBM replaced WBRT and chemotherapy with SRT, TT and ICIs. In that period, prognosis of MBM patients increased significantly. OS in patients treated with ICIs or TT prior to MBM diagnosis is still poor, but OS is improved in patients treated with ICIs after the diagnosis of MBM.
P14.27 Exploring end-of-life care in the GlioCova national brain tumour patient cohort
Authors: Mauricaite R , Le Calvez K , Droney J , Caldano M , Alam M , Williams M
Published: September 2021

BACKGROUND

Brain tumours are the leading cause of cancer deaths in the under-40s. Research on end-of-life care, especially in brain tumour patients is rare, yet important to patients and carers. The GlioCova project holds data on all adult brain tumour patients in England diagnosed between 2013 and 2018. Using this linked data set, we performed preliminary analysis on end-of-life care, focusing on treatment close to death and place of death.

MATERIAL AND METHODS

We used data from the English National Cancer Registry and identified all patients with a primary CNS tumour (ICD-10: C70, C71, C72) who were diagnosed between 2013 - 2018. We examined demographics, tumour morphology and grade, primary cause of death, treatment received within the last 3 and 1 month of life, and the location of death. For patients with unclear location of death (‘unknown’, ‘other’, ‘NA’), we looked at their final destination of discharge recorded in their last inpatient admission.

RESULTS

We identified 26,239 brain tumour patients of whom 20,715 had died. 41.7% were female and median age was 68 (IQR=19). Most patients had a malignant neoplasm of brain (98.6%), followed by meninges (0.7%) and spinal cord, cranial nerves and other parts of central nervous system (0.7%). The most common primary cause of death was malignant neoplasm (70%). Of the 10,021(48.4%) patients who received radiotherapy at any time between diagnosis and death, 1,341 (6.5%) received it within the last three months of life and 254 (1.3%) received it within the last month of life. Of the 5,957 (28.8%) patients who received chemotherapy, 1,358 (6.6%) started a chemotherapy regimen 3 months and 200 (0.97%) 1 month before death. 36.0% of all patients died at home, 23.8% at hospital, 14.7% in a hospice and 8.8% in a nursing home. For 16.7% of patients with an unclear location of death, the most common destination of discharge during their last hospital admission was usual place of residence (54.5%), non-NHS run Care Home (13.9%), NHS run Care Home (11.2%).

CONCLUSION

To the best of our knowledge, this is the first national analysis of end-of-life care in brain tumour patients. Active treatment towards the end of life and in a hospital deaths appear lower in brain tumour patients than in studies of other cancer groups.
P14.62 Overall survival from glioblastoma: partial resection versus biopsy
Authors: Bjorland L S , Fluge Ø , Kurz K D , Gilje B , Mahesparan R , Ushakova A , Farbu E
Published: September 2021

BACKGROUND

Maximal safe resection is standard of care in patients with glioblastoma. Partial resection or biopsy are alternative surgical approaches when macroscopic complete resection is unachievable. Survival benefit from partial resection remains uncertain. We aimed to evaluate overall survival from glioblastoma in patients having undergone partial resection compared to biopsy.

MATERIAL AND METHODS

We retrospectively identified all patients with histologically confirmed glioblastoma having undergone partial resection or biopsy in Western Norway between 1.1.2007 and 31.12.2014. Clinical characteristics and radiology reports were extracted from electronic medical records. Categorical data were compared by chi square test or Fishers exact test, and continuous data by non-parametric tests. Kaplan Meier method and log rank test were used for survival analyses.

RESULTS

We identified 158 patients diagnosed with glioblastoma and having undergone biopsy or partial resection. Biopsy was performed in 52 patients (32.9%) and partial resection in 106 patients (67.1%). Median age (range) was 62.5 (18.1–82.3) in the biopsy group and 62.2 (27.9–85.1) in the partial resection group (p=0.90). Median Charlson comorbidity score was four in both groups. Multifocality was observed in 46.2% of patients in the biopsy group, compared to 27.4% of patients in the partial resection group (p=0.02). Deep-seated tumour localisation was also more frequent in the biopsy group than in the partial resection group, seen in 17.3% vs 5.7% of the patients (p=0.04). There was no difference in chemoradiotherapy (CRT) treatment between the groups. CRT according to the Stupp protocol, less intensive CRT and best supportive care was performed in 36.5%, 50.0% and 13.5% of patients in the biopsy group, compared to 45.3%, 49.1% and 5.7% in the partial resection group (p=0.20). Median overall survival in the biopsy group was 8.1 months (95% CI 5.2–11.1) compared to 11.1 months (95% CI 9.4–12.8) in the partial resection group (p=0.19). Median survival in the biopsy group was 13.8 months (95% CI 10.1–17.5), 6.5 months (95% CI 3.6–9.4), and 3.5 months (95% CI 0.0–7.7) for patients receiving CRT according to Stupp protocol, less-intensive CRT and best supportive care, respectively (p<0.001). The corresponding numbers in the partial resection group were 15.1 months (95% CI 13.2–16.9), 9.1 months (95% CI 7.5–10.6), and 1.5 month (95% CI 0.0–4.7) (p<0.001).

CONCLUSION

Median overall survival was slightly longer in patients having undergone partial resection compared to biopsy, however not statistically significant. Prospective studies are needed to evaluate the survival benefit from partial resection.