bluuebunny/crossref_metadata_2025 huggingface dataset:
P02.09.B Valproic acid changes total DNA methylation level and influences temozolomide effect in glioblastoma cell lines
Authors: Barciszewska A , Belter A , Glodowicz P , Naskret-Barciszewska M
Published: September 2022

Background

Valproic acid (VPA) is a first-line antiepileptic drug for glioblastoma (GBM) patients. There is also some evidence it improves the clinical outcome in those patients. However, the exact mechanism of VPA action is vague. Temozolomide (TMZ) is a first-line chemotherapeutic in GBM. Epigenetics offers a connection between genetic and environmental factors that influence the development of the disease. The best-characterized epigenetic mark is 5-methylcytosine (m5C) in DNA. The aim of that project is to show the effects of VPA administration on the total DNA methylation level.

Material and Methods

Using the nucleotide post-labeling method, we analyzed the total amount of m5C in DNA of GBM (T98G, U118, U138), cancer (HeLa) and normal (HaCaT) cell lines treated with VPA, and a combination of VPA and with TMZ.

Results

We adjusted the VPA doses to the ones achieved in the central nervous system during treatment. We observed dose-dependent changes in the total DNA methylation in neoplastic cell lines and the lack of such effect in a normal cell line. VPA alone produced a clear dose-dependent increase in total DNA methylation in GBM cell lines and scarce in the non-neoplastic cell line. In GBM cell lines, TMZ decreased the level of m5C. However, the exposition of GBM cells to the combination of VPA and TMZ caused an adverse synergistic effect resulting in DNA demethylation. The highest loss of m5C was observed at the highest concentration of TMZ (100 μM) and VPA (350 μM), after 3 h of incubation in the T98G cell line.

Conclusion

Total DNA methylation changes in glioma cell lines under VPA treatment suggest the new mechanism of that drug action and promote clinical implications for adjusting VPA and TMZ therapy in GBM patients. Our results show the potential and possible obstacles of the combined therapy of TMZ with VPA. Our experiments show that combined therapy with both drugs leads to total DNA hypomethylation. Therefore the conclusion would be to stop VPA administration during TMZ chemotherapy temporarily.
P03.01.A Late pseudoprogression of vestibular schwannoma after robotic guided stereotactic radiosurgery - Implications for follow-up
Authors: Rueß D , Schütze B , Kocher M , Ruge M
Published: September 2022

Background

Stereotactic radiosurgery (SRS) may cause transient changes of morphology and volume in vestibular schwannomas (VS). This may lead to difficulties in distinguishing treatment-related changes (pseudoprogression) from tumor recurrence (true progression), especially at 12-24 months after treatment. Therefore, we investigated the time course of volume changes of VS after robot-guided SRS.

Material and Methods

We included all patients with unilateral VS who underwent single fraction robotic guided SRS using the Cyberknife® with a minimum follow-up (FU) of 24 months and MR images ≤3 mm slice thickness. Tumor volumes were measured on T1-weighted contrast enhanced images. Volume changes (percentage of tumor volume change compared to baseline) during FU were classified according to RANO criteria (“partial response” (PR) (≥65% decrease), “stable disease” (SD) (<65% decrease; <20% increase), or “progressive disease” (PD) (≥40% increase)). A new status “pseudoprogression” (PP) (>20% transient increase) was defined and divided into early (ePP, occurrence within first <12 months) and late (lPP, >12 months) PP.

Results

Overall 63 patients fulfilled the inclusion criteria. The median age was 56 years (range: 20-82) and the median initial tumor volume was 1.5 cm3 (range: 0.1 - 8.6). All patients received 13 Gy with an isodose level of 80%. The median radiological and clinical FU was 66 months (range: 24-103).

We found PR in 36% (n=23), SD in 35% (n=22) and PP in 29% (n=18). The latter was separated in ePP in 16% (n=10) and lPP in 13% (n=8). The median time to peak in the ePP was six months (range: 4 - 10) and in the lPP 35 months (range: 14 - 61). The median time to return from peak to baseline was seven months in the ePP (range: 5 - 20) and 18 months (range: 6 - 33) in the lPP group. Using these criteria no PD was observed. Additionally, we did not find any significant impact of radiation parameters (coverage, nCi, prescription dose, maximal dose) or patient related parameters (tumor volume, age) on the onset of early and/or late PP.

Conclusion

In our study, we demonstrated that any volume increase assumed to be PD turned out to be ePP or lPP. This might impact the management of VS treated with robotic SRS during FU in favour of further observation.
P03.04.B Garcin syndrome and hippocampal-sparing WBRT: successful resolution of a rare case
Authors: Bonzano E , Russo R , Colombo S , Francia A , Di Liberto R , Filippi A
Published: September 2022

Background

first case of a rare Garcin syndrome resolution in a young metastatic breast cancer(BC) patient treated with a hippocampal-sparing approach.

Material and Methods

we report a case of a 49-year-old caucasian female. The medical record review was relevant for BC diagnoses in 1997, when she was 26yo; complicated by bone and liver metastasis appeared in 2008. In March 2020, she was referred to our department complaining about increasingly worsening left otalgia with initial hearing loss, left facial numbness, and homolateral decreased facial sensitivity, left increased lacrimation, and tingling tongue. Clinical presentation was suggestive for a Guillain-Alajouanine-Garcin Syndrome (Garcin Syndrome), caused by a lytic lesion in the left sphenoid wing. A contrast MRI (02/04/2020) of the brain demonstrated a lytic lesions in the left sphenoid wing, that was noted to infiltrate surrounding bone of the sphenoid sinus wall, including clivus, left pterygoid process and petrous bone; two parietal and occipital bone lesions were identified with a partial leptomeningeal involvement. According to the good PS, she underwent to a hippocampal-sparing WBRT VMAT plus a sequential boost on sphenoid lesion. PTV and OARs were delineated according to a fused planning MRI/CT image. Bilateral hippocampal contours were generated on the set according to RTOG 0933 contouring atlas. After that, a hippocampal avoidance(HA) region was created by expanding the hippocampal contours by 5 mm in all directions according to Brown et al.The PTV-HA was defined as the WB parenchyma, meninges and skull, excluding the HA-region, dose prescription 30Gy/10fx; the PTV-Boost was defined as the sphenoidal metastases, dose prescription of sequential boost was 12Gy/4fx. VMAT was used to deliver the conformal RT plan. Planning priorities that should be followed were:Hippocampus, OpticChiasm, OpticNerve_L or OpticNerve_R, Lens_L or Lens_R.

Results

The neurological symptoms improved after the end of RT with a complete resolution two months later. At the last MRI, a year and a half from the end of RT, there was no evidence of brain lesion, and no neurological symptoms were referred. These are our results of plan sum: for PTV-HA D2%=43.43 Gy, D98%=26.36 Gy, V30=94.96%; for Hippocampus D100%=8.78 Gy, Dmax=17.24 Gy; for Left OpticNerve Dmax=33.51%; for Right OpticNerve Dmax=29.25%; for OpticChiasm Dmax=35.93%.

Conclusion

To our knowledge, this is the first described case using the VMAT technique to spare the hippocampus plus a boost in a rare case of Garcin Syndrome. Prevention of neurocognitive sequelae by hippocampal avoidance has shown promise in several studies as in this case. Sequential boost demonstrated to be feasible and effective.Advanced RT techniques may be used to customize a treatment that allows preserving cognitive impairment achieving good clinical results in the long-term survival of metastatic patients.
P04.04.A A comprehensive genomic study of 390 H3F3A-mutant pediatric-type diffuse high-grade gliomas WHO CNS grade 4
Authors: Willimas E A , Brastianos P K , Wakimoto H , Santagata S , Cahill D P , Juratli T A
Published: September 2022

Background

Histone gene mutant malignant gliomas - H3K27-altered diffuse midline glioma (DMG) and diffuse hemispheric glioma (DHG) H3G34-mutant - occur in all age groups and can have significant variation in clinical outcomes. Here, we report comprehensive genomic profiling from one of the largest collections of H3F3A-mutant gliomas analyzed to date, identifying subsets defined by recurrently co-mutated genes.

Material and Methods

We identified 390 H3F3A-mutant diffuse gliomas WHO grade 4 (201 females and 189 males) that were profiled in the comprehensive genomic profiling program at Foundation Medicine between 2013-2020. Information from pathology reports, histopathology review, and patient clinical data was assessed

Results

Our cohort comprised 304 (77.9%) H3K27M-mutant DMG WHO grade 4 (156 females and 148 males) and 86 H3G34-mutant DHG (45 females and 41 males) with a median age of 20 years (1- 74 years). H3K27M-mutant DMG distributed equally between pediatric and adult patients, with 52% of the patients older than 20 years, 30% older than 30 years, and 18% older than 40 years at the time of first diagnosis. Clonal FGFR1 hotspot mutations were exclusively detected in K27M-mutant DMG (n = 64/304, 21%; p=0.0001), with a significant association with a higher age at first diagnosis (median 32.5 years), and with a wide tumor distribution across the diencephalon. Additional genes which were significantly more frequently altered in K27M-mutant compared to G34-mutant diffuse gliomas included NF1 (31% vs. 8.1%; p=0.0001) and PIK3CA/PIK3R1 (27.9% vs. 15.1%; p=0.016). Conversely, targetable alterations of the cell-cycle pathway (CDK4/6 amplifications and CDKN2A/B deletions) were enriched in H3G34-mutant DHG (26%) compared to H3K27M-mutant DMG (7%). Potentially targetable PDGFR alterations were present in 32.5% of H3G34-mutant DHG and in 18% of H3K27M-mutant DMG.

Conclusion

These data expand our understanding of the tumor-specific molecular features of pediatric-type high-grade gliomas, identifying cohort sub-structure by recurrent co-mutations, which can inform diagnosis and clinical trial design.
P05.05.B A new IDH-wildtype glioma subtype characterized by highly diffuse growth pattern, distinct epigenetic profile and relatively favorable prognosis
Authors: Münch A , Teichmann D , Kuzman P , Spille D , Perez E , May S , Mueller W , Kombos T , Nazari-Dehkordi S , Onken J , Vajkoczy P , Ntoulias G , Paulus W , Heppner F , Koch A , Capper D , Kaul D , Thomas C , Schweizer L
Published: September 2022

Background

DNA methylation profiling has emerges as a powerful approach to CNS tumor classification and the discovery of novel, molecularly distinct entities. With the release of the 12.5 version of the Heidelberg Brain Tumor Classifier, some unclassifiable cases can be assigned to novel methylation classes. We retrospectively reviewed our databases and identified 16 previously unclassifiable cases, all of which belong to the provisional methylation class “adult-type diffuse high-grade glioma, IDH-wildtype, subtype F (HGG_F)”.

Material and Methods

We clinically, radiologically and morphologically characterized 16 HGG_F cases and compared them to 347 glioblastomas. We additionally analyzed copy-number alterations and performed DNA exome sequencing.

Results

Median age at diagnosis of the 12 males and 4 females was 65 years. Upon initial diagnostic workup, specimens were classified as CNS tissue with reactive changes (n=3) or suspicious for the infiltration zone of a diffuse glioma (n = 13). None of the cases demonstrated endothelial proliferation or necrosis and 10/16 tumors had flat copy number profiles. Radiological characteristics were reminiscent of gliomatosis cerebri in eight cases and 9/9 cases had normal FET-PET scans. Whole-exome sequencing revealed genetic alterations frequently found in IDH-wildtype glioblastomas, including TERT promoter mutations in 11/14 (78.6%) and PIK3 mutations (10/14, 71.4%). Outcome was significantly better compared to TCGA IDH-wildtype glioblastomas with a median progression-free survival of 58 months and overall survival of 73 months (both p<0.001).

Conclusion

We provide evidence that TERT promoter mutations in diffusely infiltrating gliomas without further morphological or molecular signs of high-grade glioma should be interpreted in the context of the clinico-radiological presentation as well as epigenetic prolife and may not be suitable as standalone diagnostic marker for glioblastoma, IDH wildtype.
P06.03.A Combination of EGFRvIII CAR T cell therapy and paracrine GAM modulation for the treatment of GBM
Authors: Martins T A , Tatari N , Ritz M , Shekarian T , Schmassmann P , Kaymak D , Hutter G
Published: September 2022

Background

The glioblastoma (GBM) immune microenvironment mainly consists of protumoral glioma-associated microglia and macrophages (GAMs). Previously, we showed that blockade of the don't-eat-me signal CD47, overexpressed by GBM cells, rescued GAMs' phagocytic function in mice. However, CD47 blockade monotherapy has been ineffective in treating human solid tumors to date. Thus, we propose a combinatorial approach of local chimeric antigen receptor (CAR) T cell therapy with paracrine GAM modulation for a synergistic elimination of GBM.

Material and Methods

We lentivirally transduced healthy donor human T cells to generate humanized EGFRvIII-directed CAR T that constitutively secrete a SIRPγ-related protein (SGRP) with high affinity to CD47. Killing assays were performed with endogenous EGFRvIII-expressing BS153 or EGFRvIII-overexpressed U251 GBM cells and assessed by Incucyte time-lapse imaging analysis. CAR T cell activation was confirmed by flow cytometry (FC) and IFNγ was detected from co-culture supernatants or mouse plasma by ELISA. The CAR T cell secretome was analyzed by liquid chromatography-mass spectrometry (LC-MS) to confirm the secretion of SGRP. NSG mice were orthotopically implanted with either EGFRvIII+ BS153 or U251 cells and treated intratumorally with one or two CAR T cell infusions.

Results

EGFRvIII and EGFRvIII-SGRP CAR T proliferated and killed tumor cells in vitro in a dose-dependent manner within 72h with complete cytotoxicity at E:T 1:1 compared to CD19 CAR T. CAR T cells specifically co-expressed CD25 and CD107a and secreted IFNγ in the presence of tumor antigen (24h CD25/CD107a co-expression: EGFRvIII=59.3±3.00%, EGFRvIII-SGRP=52.6±1.42%, CD19=0.1±0.07%; 24h IFNγ secretion: EGFRvIII=173.6±2.50%, EGFRvIII-SGRP=113.8±6.42%, CD19=4.5±1.49%). Differential expression analysis of the CAR T cell secretome identified SGRP in EGFRvIII-SGRP CAR T supernatants (-Log10qValue/Log2fold-change=13.72/6.62). Consistent with studies of systemic EGFRvIII CAR T cell therapy, our data suggest that intratumoral EGFRvIII CAR T were insufficient to eliminate BS153 tumors with endogenous EGFRvIII (Overall survival; EGFRvIII: 20%, CD19: 0%, n=5/group).

Conclusion

Here, we show that EGFRvIII CAR T specifically targeted and killed EGFRvIII+ GBM cells in vitro, but failed to control tumor growth in vivo without GAM modulation. EGFRvIII-SGRP CAR T secretome analysis identified SGRP from the supernatants of unstimulated monocultures. SGRP impaired the binding of SIRPα-Fc to CD47-upregulated GBM cells in vitro, but did not elicit macrophage-mediated phagocytosis of GBM cells in our current in vitro experimental setup. Future work will focus on the functional characterization of SGRP and on further investigating the additive effect of CAR T cell therapy and GAM modulation using translational in vivo and ex vivo models.
P07.09.A Intra operative mapping and monitoring of the cortico-spinal tracts with neurophysiological assessment in intra axial brain tumor resection
Authors: oxman l , emanuel s , zarchi o
Published: September 2022

Background

Preserving motor function is a major challenge in surgery for intra axial brain tumors. In the past two decades, rapid developments in neuroscience, have fueled the growth of intraoperative neurophysiologic monitoring and mapping. Neurophysiological motor mapping allows identification with subsequent preservation of functionally viable nervous tissue. Currently, continuous mapping is typically achieved by electrostimulating via connection to a surgical tool, )e.g., suction(, establishing a stimulation threshold for inducing a motor response, and stopping the resection when reaching motor responses at low electrostimulation levels of 2-10 mA. While most authors report the use of monopolar electrostimulation, which tends toward high sensitivity - low specificity, others report the use of bipolar electrostimulation, which tends toward high specificity - low sensitivity results. Here we report an investigation of the differences between monopolar and bipolar electrostimulation for motor mapping, comparing the sensitivity and specificity of the two methods.

Material and Methods

Gross motor function was evaluated preoperative and 1d postoperative. During the resection, a minimal monopolar electrostimulation threshold was determined, bordering motor tracts. Next, a bipolar probe was used to assess the bipolar electrostimulation threshold at the same location, and a neuro-navigation system was used to mark these locations. The respondent myotomes at each location was documented, as well as the neuromonitoring MEP responses. Postoperatively, the distance between the stimulated marked location, resection borders, and the motor brain structures were assessed. Analysis probed the differences between monopolar and bipolar thresholds in mapping cortical and subcortical motor system and their association with motor neuromonitoring and postoperative motor function.

Results

A prospective intraoperative analysis was conducted on two patients undergoing resection of intra axial tumors at the authors' institution in January 2021. The resection was performed by all clinical standard procedures. Following the resection, additional stimuli were applied by the bipolar probe, to assess the accuracy of the threshold that was needed to evoke a clinical motor response. We found that the bipolar threshold was higher than the conventional threshold used by the monopolar probe in the borders of the resection.

Conclusion

Our findings suggest the bipolar stimuli can give more accuracy in determining the motor function of certain anatomical structures which can lead to better results in the maximal safe resections goal and allow neurosurgeons another intra operative tool to achieve the best outcomes for their patients.
P07.12.B Brain Biopsy with Optical Guidance
Authors: Richter J , Klint E , Wårdell K
Published: September 2022

Background

Accurate stereotactic biopsies of brain tumors are imperative for diagnosis and decisions on therapy. Repetitive needle insertions owing to inconclusive tissue samples enhance increased risks of brain lesioning, hemorrhage and prolonged procedure. Previously we reported on frame-based stereotactic biopsies with a combined 5-ALA fluorescence and laser Doppler flowmetry detection system[1]. The system has now been adapted to frameless navigation with a modified biopsy needle and a new registration system[2].

Material and Methods

Planning was effected with the Medtronic Stealth System. The optical probe was inserted inside the outer cannula of the biopsy needle, which had an opening at the tip, enabling optical measurements ahead of the needle in real-time while manually forwarding it along the trajectory to the target. Fluorescence spectra, microvascular blood flow, and tissue grayness were recorded during insertion. The biopsies were taken where the fluorescence indicated tumor tissue; the optical probe was replaced by the inner cannula. The diagnoses were compared with the fluorescence signals.

Results

In the 9 examined patients the fluorescence measurements and pathological diagnosis of high-grade gliomas or lymphomas matched. Only one needle insertion was necessary. The optical measurements along the trajectory took 5-10 min to the target, the pathological diagnosis was reported after 30-70 min. The probe provided direct feedback of increased blood flow along the trajectory and of malignant tissue in the vicinity of the target.

Conclusion

The optical probe can detect tumor before any tissue is retrieved. If fluorescence is registered, pathological tissue is safely identified. The method can increase the precision and safety of the biopsy and shorten the procedure. The new multimodal probe and the improved registration unit will be tested with other stereotactic and navigation systems and at other neurosurgical centers.

Also, the parallel project on fluorescence guided resection of high-grade gliomas is continued[3].

References

[1] Johan Richter, Neda Haj-Hosseini, Peter Milos, Martin Hallbeck, Karin Wårdell, (2021), Optical Brain Biopsy with a Fluorescence and Vessel Tracing Probe, Operative Neurosurgery, 217-224, 21(4) [2] Elisabeth Klint, Stina Mauritzon, Bengt Ragnemalm, Johan Richter, Karin Wårdell, (2021), FluoRa - a System for Combined Fluorescence and Microcirculation Measurements in Brain Tumor Surgery, Annual International Conference of the IEEE , 1512-1515 [3] Johan Richter, Neda Haj-Hosseini, Martin Hallbeck, Karin Wårdell, (2017), Combination of hand-held probe and microscopy for fluorescence guided surgery in the brain tumor marginal zone, Photodiagnosis and Photodynamic Therapy, 184-192, 18
P08.01.A Evaluation of a multimodal rehabilitative palliative care programme for patients with high-grade glioma and their family caregivers
Authors: Nordentoft S , Dieperink K , Johansson S , Jarden M , Piil K
Published: September 2022

Background

When a family member is diagnosed with high-grade glioma, it not only affects the patient, but also the entire family. Due to an intense disease- and treatment trajectory and a complex symptom burden, patients often depend on support from their family caregivers. Family caregivers struggle to adjust to a change in family roles. Hence, proper information and supportive care are essential for patients and family caregivers to help them manage their changed life situations.

Material and Methods

This was a longitudinal multi-methods study applying qualitative interview data and quantitative survey data to explore and evaluate the programme. A multimodal rehabilitative palliative care programme was designed by a multidisciplinary cross-sectoral team of clinical specialists and researchers. The purpose was to provide patients and family caregivers with information and facilitate the exchange of perspectives and experiences among peers e.g. on daily living and family function. Additionally, to provide participants with strategies to manage this life transition

Results

Adult patients with high-grade glioma (n = 17) and their family caregivers (n = 16) completed a 4-day residential programme and a 2-day follow-up programme 3 months later. Qualitative data were collected during focus group interviews (n = 4) with patients and caregivers. Participants responded to self-developed questionnaires after each programme, scoring all sessions for relevance and satisfaction on a 5-point Likert scale (0, not relevant/satisfied; 5, very relevant/highly satisfied). Three themes emerged in the focus group interviews: 1) meeting peers strengthens social well-being, 2) the value of information and focusing on individual needs, and 3) accepting life as an unpredictable passage. The mean overall satisfaction score was 4.80 (standard deviation [SD], 0.55) for the initial 4-day programme and 4.28 (SD, 0.83) for the follow-up programme.

Conclusion

The multimodal rehabilitative palliative care programme addressed unmet patient and caregiver needs and may have the potential to enhance family function or coping mastery. The programme was feasible, and all sessions received high scores for satisfaction and relevance, as well as positive evaluations. Qualitative findings confirmed the value of individualized information and peer interactions. In particular, peer-to-peer interventions for family caregivers may address individual support needs, including sharing experiences and strengthening social well-being.
P08.02.B The Clinical Frailty Scale as predictor of overall survival after resection of high-grade glioma
Authors: Klingenschmid J , Krigers A , Pinggera D , Kerschbaumer J , Thomé C , Freyschlag C F
Published: September 2022

Background

The Clinical Frailty Scale (CFS) describes the general level of fitness or frailty and is widely used in geriatric medicine, intensive care and orthopaedic surgery. This study was conducted to analyze, whether CFS could be used for patients with high-grade glioma.

Material and Methods

Patients harboring high-grade gliomas, undergoing first resection at our center between 2015 and 2020 were retrospectively evaluated. Patients’ performance was assessed using the Rockwood Clinical Frailty Scale and the Karnofsky Performance Scale (KPS) preoperatively and 3-6 months postoperatively.

Results

289 patients were included. Pre- as well as postoperative median frailty was 3 CFS points (IqR 2-4) corresponding to “managing well”. CFS strongly correlated with KPS preoperatively (r = -0.85; p < 0.001) and at the 3-6 months follow-up (r = -0.90; p < 0.001). The reduction of overall survival (OS) was 54% per point of CFS preoperatively (HR 1.54, CI95% 1.38-1.70; p < 0.001) and 58% at the follow-up (HR 1.58, CI95% 1.41-1.78; p < 0.001), comparable to KPS. Patients with IDH mutation showed significantly better preoperative and follow-up CFS and KPS (p < 0.05). Age and performance scores correlated only mildly with each other (r = 0.21⋯0.35; p < 0.01), but independently predicted OS (p < 0.001 each).

Conclusion

CFS seems to be a reliable tool for functional assessment of patients suffering from high-grade glioma. CFS includes non-cancer related aspects and therefore is a contemporary approach for patient evaluation. Its projection of survival can be equally estimated before and after surgery. IDH-mutation caused longer survival and higher functionality.
P08.04.B The Clinical Frailty Scale is superior to the Karnofsky Performance Status as predictor of overall survival in patients with surgical treatment of brain metastases
Authors: Krigers A , Pichler N , Kerschbaumer J , Demetz M , Klingenschmid J , Thomé C , Freyschlag C F
Published: September 2022

Background

The Clinical Frailty Scale (CFS) evaluates patients’ level of frailty on a scale from 1 (very fit) to 9 (terminally ill) and is commonly used in geriatric medicine, intensive care and orthopaedics but not in patients harboring neuro-oncological diseases. Our study was conducted to reveal if the usage of CFS generates more reliable prediction of overall survival in patients after brain metastases resection rather than Karnofsky Performance Status (KPS).

Material and Methods

All patients which were operated for brain metastatic disease at our department from 2005-2019 were included. CFS and KPS were retrospectively assessed for the timepoints pre- and postoperatively as well during follow-up 3-6 months after resection.

Results

205 patients with mean follow-up of 22.8 months (CI95% 18.4-27.1) were evaluated. Mean estimated OS was 32.1 months (CI95% 25.0-39.1). CFS showed a median of 3 points (IqR 2-4) at all 3 assessment-points which means patients were “managing well”. Median KPS was 80 preoperative (IqR 80-90) and 90 (IqR 80-100) postoperative as well as on follow-up after 3-6 months. CFS strongly correlated with KPS: preoperatively (r=-0.92; p< 0.001), postoperatively (r=-0.85; p<0.001) and at follow-up (r=-0.93; p<0.001). In the same time, CFS pre- and postoperatively showed only weak correlation with CFS at follow-up after 3-6 months (r=0.30, p<0.001; and r=0.37, p<0.001, correspondingly). In multivariate integrated Cox regression model, the CFS predicted the expected reduction of OS superior to KPS at all 3 assessment-points. One point increase of preoperative CFS represented 30% additional hazard to decease (HR=1.30, CI95% 1.15-1.46; p<0.001), correspondingly postoperative CFS provides 39% (HR=1.39, CI95% 1.25-1.54; p<0.001) and at follow-up 42% of hazard (HR= 1.42, CI95% 1.27-1.59; p<0.001). In case of KPS, decrease of 10 points resulted in additional hazards to decease of 26% (HR=0.974/point, CI95% 0.962-0.987; p<0.001) postoperatively 14% (HR=0.986/point, CI95% 0.978-0.993; p<0.001) and 31% (HR=0.969/point, CI95% 0.959-0.978; p<0.001) at follow-up.

Conclusion

CFS is a feasible and reliable performance scoring in patients undergoing brain metastasis resection, that provides better OS prediction as compared to KPS. Whereas, CFS at follow-up after 3-6 months specifies the expected OS most accurately. Due to weak correlation between CFS preoperatively vs. postoperatively and in 3-6 months, initial frailty does not predict the patients’ postoperative frailty score.
P08.07.A Long-term multidimensional assessment of fatigue and fatigue as predictor of survival in patients with brain metastases after Gamma Knife radiosurgery
Authors: Verhaak E , Schimmel W , Butterbrod E , Sitskoorn M , Hanssens P , Gehring K
Published: September 2022

Background

The aim of this study was to assess long-term multidimensional fatigue and (change in) fatigue as predictor for survival in patients with brain metastases (BM) up to 21 months after Gamma Knife radiosurgery (GKRS).

Material and Methods

Patients with 1 to 10 BM, expected survival >3 months, and Karnofsky Performance Status ≥70 were included. Fatigue was measured with the Multidimensional Fatigue Inventory (MFI). Linear mixed models were used to evaluate fatigue up to 21 months after GKRS. Fatigue before GKRS and changes in fatigue in the first three months after GKRS were evaluated as predictors for survival duration.

Results

Patients with BM experienced significantly higher levels of fatigue on all subscales prior to GKRS (n=92) compared to Dutch controls (n=104), all p’s≤.001. Over 21 months, levels of physical fatigue increased significantly (p=.001), and levels of mental fatigue decreased significantly (p=.004). Between pre-GKRS and 3 months, there was a significant increase in levels of general (p<.001) and physical fatigue (p<.001), followed by stable fatigue scores between 3 (n=67) and 6 (n=53) months, 6 and 12 (n=34) months and 12 and 21 (n=21) months. Minimal clinically important (MCI) increases in general (p=.023, time ratio=0.61) and in physical fatigue (p=.008, time ratio=0.56) from pre-GKRS to 3 months thereafter were independent negative predictors of survival time (i.e., an MCI increase in these domains predicted a reduction of 39% and 44% respectively in survival time compared to stable or decreased fatigue).

Conclusion

Results indicate that up to 21 months after GKRS fatigue is a persistent problem in patients with BM. Except for an increase in general and physical fatigue up to 3 months after treatment, fatigue remained stable up to 21 months after GKRS. In addition, an MCI increase in general or physical fatigue within three months after GKRS may be related to worse survival outcome.
P08.09.A Improving support for family carers: Creating a cross-sector collaborative working group
Authors: Nicklin E , Jopson J , Boele F
Published: September 2022

Background

Family carers of people with brain tumours and other progressive neurological conditions have unique but overlapping support needs. This is because caring can be particularly challenging due to patients’ cognitive issues, behavioural changes, and neuropsychiatric symptoms. We undertook stakeholder engagement work to bring together family carers, academics, service providers and policy makers to form a working group and highlight opportunities for improvement of family carer (FC) support.

Material and Methods

Sixteen stakeholders (academics, carers, charity representatives, clinicians and policy makers) participated in two one-hour online workshops (N=8 in each). Workshops started with introductions, an outline of meeting objectives, and a specially created animated video introducing the topic. A structured discussion followed, focusing on current FC support and barriers in accessing support. Finally, we covered blue-sky thinking exercises, with attendees describing their ideal vision of FC support in the future; and how the group can work together to improve support. Workshop findings were integrated into a position statement.

Results

The position statement covers five pillars for joint action. 1) Collaboration, coordination, and co-design - current support is fragmented. Better collaboration is needed between the social care sector, the third sector, and healthcare systems, to stop struggling FCs falling through the net. 2) Valuing carers - there is a need to acknowledge and enhance the awareness of FC contributions, e.g. through co-producing research publications highlighting the value FCs bring. 3) Redefine personalised medicine- carer support needs are varied and no one size fits all. Personalised care is key to identify specific needs of carers arising from aspects of diversity, such as ethnicity and age. 4) Flexible evidence-based support- we need to build a better evidence-base for FC support; and prioritise evidence-based support. This is especially important given the scarcity of funds and resources for FCs. 5) Promotion of current support services- many FCs do not know where to get support locally. More research can help to identify barriers and facilitators to support carers’ access to formal support.

Conclusion:

To improve support for FCs, we need to move away from fragmented approaches and move towards a more collaborative approach with carers at the centre. Our collective vision is that future support is based on what matters to them as individuals and what is effective in meeting their needs. We strive to provide flexible, accessible, responsive and inclusive support for FCs, and invite other carers, service providers, academics and policymakers to join our effort.
P08.10.B Family-centred care in neuro-oncology: a longitudinal mixed-methods feasibility study
Authors: Piil K , Locatelli G , Laegaard Skovhus S , Tolver A , Jarden M
Published: September 2022

Background

A diagnosis of a malignant brain tumour represents a fearful event for patients, often followed by severe physical, cognitive, emotional, and psychosocial impairments. In turn, being a family member and an informal caregiver of a person with an oncological disease is also a burdensome experience. Family and network can influence patient outcomes, and family-centred intervention may help both patients and caregivers to face illness-related issues. However, studies aiming at implementing family-centered interventions in patients with high grade glioma (HGG) and their families are scarce. Therefore, this study aims to understand how patients with HGG and their families experienced the course of illness and investigate the impact of family and network consultations (FNCs) on both of them.

Material and Methods

We adopted a quasi-experimental feasibility study using a longitudinal mixed-methods design. The intervention consisted of three FNCs delivered over a 1-year period. Quantitative data on physical activity level, anxiety, depression, family functioning, perceived nursing support, symptom burden and interference on daily living, caregiver burden and quality of life were collected at four time points. Qualitative data on patients’ and families’ perspectives on the intervention were explored through telephone interviews.

Results

A total of 21 patients with HGG and 47 family members were included in the study. Patients mean age was 66 years and they were mainly male (86%), married and living with the patient (95%), and retired (54%). Caregivers mean age was 47 years, and they were mainly female (62%), children of the cared person (47%), and employed (55%). The integration of quantitative and qualitative data showed that many variables improved over time (e.g., symptom interference in patients, family functioning in caregivers, quality of life) or remained stable (e.g., anxiety and depression), apart from physical functioning and symptom burden that worsened. Families described FNCs as a valuable strategy to holistically address the needs and concerns of the entire family and to strengthen the family dialogue and union.

Conclusion

FNCs can be a valuable strategy to implement family-centred care practices. However, advanced nursing competencies are required to provide optimal family-centred care. Plus, the intervention should be personalized and based on the needs of each family.
P10.01.A Reversible blood-brain barrier (BBB) disruption by Tumor Treating Fields (TTFields) in a human 3Din vitro model
Authors: Salvador E , Kessler A F , Köppl T , Schönhärl S , Burek M , Tempel Brami C , Voloshin T , Giladi M , Ernestus R , Löhr M , Förster C , Hagemann C
Published: September 2022

Background

Drug delivery to the central nervous system (CNS) is often impeded by the restrictive nature of the blood brain barrier (BBB). Since many therapeutic molecules are not able to traverse this barrier, the development of new methods to disrupt the BBB is of paramount importance. Tumor Treating Fields (TTFields) are alternating electric fields of low intensity (1-3 V/cm) and intermediate frequency (100-300 kHz), which are approved and effective for the treatment of glioblastoma at a frequency of 200 kHz. We recently demonstrated that TTFields at lower frequencies are able to transiently induce BBB permeability in in vitro and in vivo murine models. Here, we explored whether the transient opening of the BBB by TTFields in our murine systems also translates to a human cell-based 3D model.

Material and Methods

A three-dimensional BBB model was established by co-culturing primary human brain microvascular endothelial cells (HBMVEC) on a transwell insert together with human pericytes on the bottom of a well-plate. The model was treated with TTFields at 100-300 kHz for 2496 h using the inovitro™ TTFields Lab Bench System (Novocure®). Afterwards, the cells recovered for 24-96 h. In order to analyze the effects of TTFields on barrier integrity and compromise, transendothelial electrical resistance (TEER) of the HBMVEC monolayer was measured before the start of TTFields treatment, immediately after TTFields cessation, as well as 24-96 h after TTFields treatment. Permeability of the barrier was assessed by visualizing the movement of FITC-dextran through the HBMVEC monolayer. In addition, changes in expression and localization of the tight junction protein (TJP) claudin-5 (Cl-5) after application of TTFields were analyzed by fractionated Western-blotting and immunofluorescence (IF) staining, respectively.

Results

Application of TTFields at all investigated frequencies significantly decreased TEER across the HBMVEC monolayer after as early as 24 h, with the strongest effects seen after 72 h at a TTFields frequency of 100 kHz. TTFields treatment delocalized TJP Cl5 from the cell boundaries to the cytoplasm as evidenced by Western-blots and IF stainings. Restoration of the cell barrier was already measurable as early as 24 h after TTFields cessation and a complete recovery was evident after 48 h.

Conclusion

These results in a human 3D in vitro model confirm our previous observations from mouse models that TTFields could transiently open the BBB. These fundamental pre-clinical data demonstrate the feasibility of facilitating drug delivery to the CNS via concomitant application of TTFields. This method opens up the prospect of improved drug-based treatment of devastating CNS diseases such as GBM if these results could be translated to the clinical setting in the future.
P10.03.B Insights into the development of tunable brain implants for local chemotherapy
Authors: Waldherr L , Handl V , Abrahamsson T , Arbring Sjöström T , Seitanidou M , Erschen S , Honeder S , Tomin T , Birner-Grünberger R , Ghaffari Tabrizi-Wizsy N , Ropele S , Ücal M , Nowakowska M , Schäfer U , Patz S , Simon D , Schindl R
Published: September 2022

Background

Glioblastomas (GBMs) remain an unmastered medical challenge. Poor delivery and systemic toxicity of many chemotherapeutic agents limit their therapeutic success in GBM treatment. Bioelectronic implants for local chemo drug delivery can optimize drug concentrations at the tumor site, duration of treatment and tumor suppression, while systemic effects remain at an acceptable low level. We present miniature bioelectronic devices for drug delivery able to administer chemotherapeutics via electric control with high spatiotemporal precision.1 The drug delivery is based on the electro migration of drug molecules in an ion selective matrix towards a target of choice. These bioelectronic devices, called chemotherapeutic ion pumps (chemoIPs), can be used for triggered drug release of chemotherapeutics that are usually shielded by the blood brain barrier.

Material and Methods

The performance of chemoIPs is studied in different brain tumor models with increasing complexity (cell culture and different in vivo models). With chemoIPs it is possible to constantly administer drugs with highest precision (delivery rates at pmol*min-1 precision) towards cell culture spheroids, ex ovo-grown tumors and in vivo brain tumors

Results

The treatment efficiency was analyzed via flow cytometry quantifying apoptosis and cell cycle arrest, as well as immune-histochemical analysis for apoptosis. ChemoIP treatment is able to trigger the disintegration of targeted tumor spheroids, and is able to inhibit the tumor growth of ex ovo-grown glioblastomas significantly. Furthermore, the proteomes of neurons and glioblastoma cells were recorded via proteomics, which showed that only GBM cells are harmed by the chemotherapeutic treatment, but not neurons. In parallel, can follow the pharmacokinetics of the chemoIP-mediated drug administration via drug quantification using mass spectrometry and compare it to computer simulations in different tumor models.

Conclusion

The here exemplified electrically-driven drug delivery via chemoIPs is a drug administration method that can serve as basis for further implant development, which has the potential to increase the efficacy of chemotherapy due to highly-targeted and locally-controlled drug delivery.
P10.04.A The development of a potent, tumour-specific heptamethine cyanine dye-palbociclib conjugate with novel mechanisms of action for the treatment of glioblastoma
Authors: Cooper E A , Choi P J , Schweder P , Correia J , Turner C , Faull R , Denny W A , Dragunow M , Jose J , Park T I
Published: September 2022

Background

Glioblastoma is the most common and aggressive primary brain tumour in adults. The development of anti-cancer agents for brain tumours is challenged by the blood-brain barrier and the resistance conferred by the local tumour microenvironment. Heptamethine cyanine dyes (HMCDs) are a class of near-infrared fluorescence compounds that have recently emerged as promising agents for drug delivery

Material and Methods

We conjugated palbociclib, a cyclin-dependent kinase 4/6 inhibitor to the HMCD, MHI 148 for the treatment of GBM. Patient-derived GBM cell lines were established from surgically resected biopsy GBM tissue.

Results

High-throughput drug screening revealed an almost 100-fold increase in cytotoxicity of the palbociclib-MHI 148 conjugate compared to palbociclib alone. Moreover, the palbociclib-MHI 148 conjugate was synergistic with radiation, but not with temozolomide. Further analysis revealed the palbociclib-MHI 148 conjugate was superior to other cyclin-dependent kinase inhibitors in vitro. The shift of palbociclib from cytostatic to cytotoxic when conjugated to MHI 148 prompted further investigation. We revealed that palbociclib-MHI 148-dependent inhibition of cell-cycle progression resulted in increased DNA damage. This preceded increased transcription of key extrinsic apoptosis genes and caused a time-dependent upregulation of TNFR1 endocytosis-dependent cell death signalling. Notably, inhibition of endocytosis and siRNA knockdown of TNFR1 prevented palbociclib-MHI 148-induced cell death.

Conclusion:

These results highlight a novel mechanism of action of palbociclib when conjugated to MHI-148 that induced autocrine-driven TNFR1-mediated apoptosis. In addition, we highlight the potential application of HMCDs in repurposing tyrosine kinase inhibitors, to overcome the current limitations preventing the expansion of second-line treatment options for GBM.
P10.05.B Platelet-derived growth factor signalling pathways in patient-derived glioblastoma cells
Authors: Li S Y , Schweder P , Correia J , Park T I , Dragunow M
Published: September 2022

Background

Platelet-derived growth factor (PDGF) signalling is essential in the development and maintenance of the neurovasculature. Of particular importance is PDGFRβ signalling for the recruitment and maintenance of the mural cell type pericytes, which occupy an important position in coordinating blood-brain barrier functions. The PDGF pathway is also implicated in glioblastoma, where overexpression of PDGFRα is a signature of the proneural subtype of the highly malignant and invasive tumour. The expression and signalling of both PDGFRα and β by tumour cells have been implicated in tumorigenesis and progression. Therefore, we sought to study PDGF receptor signalling in primary human-derived glioblastoma tumour cells to gain a better understanding of the signalling mechanisms driven by these receptors.

Material and Methods

Primary human epilepsy pericytes and glioblastoma tumour cells were isolated from surgical resections obtained from consenting patients at Auckland City Hospital. PDGF signalling pathways were investigated through treatment with exogenous PDGF ligands. Pathway activation was quantified using immunocytochemistry, human cytokine XL Proteome Profiler and cytometric bead arrays.

Results

PDGF-BB and PDGF-DD treatment led to the activation of PDGFRβ in pericyte cultures, which mediated the activation of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/Akt cascades, ultimately increasing pericyte proliferation and cytokine secretion. PDGF-AA treatment resulted in transient MAPK activation, but was not followed by increased proliferation in pericytes. In contrast, although PDGF-AA, -BB and -DD induced PDGFRα internalisation (and PDGF-BB and -DD induced PDGFRβ internalisation) in GBM tumour cells, this did not result in MAPK or PI3K/Akt activation or cell proliferation.

Conclusion

Despite PDGF receptor expression, the GBM tumour cells, in contrast to pericytes, surprisingly displayed a lack of responses to ligand stimulation through either PDGFRα or PDGFRβ. This warrants further investigation into the signalling mechanisms behind tumour cells to better understand tumour biology.