bluuebunny/crossref_metadata_2025 huggingface dataset:
P10.13.A AN ATRAUMATIC ACCESS TO HUMAN GLIOBLASTOMA IN A XENOGRAFT ANIMAL MODEL BY CEREBRAL OPEN FLOW MICROPERFUSION FOR THE ASSESSMENT OF BIOMARKER IN THE TUMOR MICROENVIRONMENT
Authors: Altendorfer-Kroath T , Asslaber M , Hummer J , Zügner E , Schimek D , Prugger E , Stanzer S , Prietl B , Pieber T R , Bernhart E , Magnes C , Birngruber T
Published: September 2023

BACKGROUND

Orthotopic xenograft studies strongly promote the development of targeted/personalized cancer therapies to improve the still poor life expectancy of glioblastoma patients. In recent years, the tumor microenvironment has increasingly become subject of investigations, as it could have an impact on the progression of the cancer. However, examination of the tumor microenvironment with currently available methods inevitably causes trauma that might compromise the reliability of the obtained data. We aimed to implement an atraumatic access to human glioblastoma with cerebral Open Flow Microperfusion (cOFM) by implantation of xenograft cells in rodent’s brain of different species (mouse and rat) with intact blood brain barrier (BBB) and subsequent development of a xenograft glioblastoma at the interface between the cOFM probe and the surrounding brain tissue. Thereafter, we used the cOFM probe to collect interstitial fluid (ISF) from the tumor microenvironment for metabolome and biomarker assessment.

MATERIAL AND METHODS

Human glioma cells were implanted at a well-defined position into immune-deficient rodent’s brain via cOFM or syringe. Characteristics of the mature tumors from both groups were assessed. ISF from tumor microenvironment was collected without further traumatization by using cOFM, and the collected tumor ISF samples were analyzed using a UHPLC-HRMS metabolomics platform. A targeted (Biocrates MxP®) and an untargeted (Metaboanalyst) approach were used to analyze the metabolomics data.

RESULTS

For the first time xenograft cells were successfully introduced into rodent brain with intact BBB using cOFM, and the tumor tissue that developed around the cOFM probe was unaffected by the presence of the probe. Thereby, an atraumatic access to the tumor was created. The mature cOFM-induced tumors resembled the syringe-induced ones and showed typical features of human glioblastoma. The cOFM sampling procedure did not alter tumor morphology.

CONCLUSION

This novel atraumatic access to human glioblastoma in a rodent brain was used to collect ISF from functional tumor microenvironment in vivo without trauma generation. The thereby generated reliable data are likely to promote drug research, biomarker identification, and enable investigation of the BBB of a functional tumor.
P10.15.A THE ROLE OF NONCODING RNAS IN THE PROGRESSION OF IDH-MUTANT ASTROCYTOMAS TO GRADE 4
Authors: Hartewig A , Jaatinen S , Annala M , Helén P , Haapasalo J , Zhang W , Haapasalo H , Nykter M , Rautajoki K J
Published: September 2023

BACKGROUND

Low grade IDHmutant astrocytomas are heterogeneous brain tumors that have a prognosis of 7-10 years. However, this prognosis is significantly worsened if the tumors progress to grade 4 astrocytomas. Noncoding RNAs, especially long noncoding RNAs and microRNAs, have been studied increasingly in the past years in various cancers including gliomas, and a general dysregulation was observed. The dysregulated RNAs were shown to regulate crucial disease processes, such as cell proliferation, apoptosis, and therapy resistance. Thus, several noncoding RNAs were identified as promising biomarkers and potential therapy targets, some of which are already being tested in clinical trials. Despite advances in the field, little is known about the role of noncoding RNAs in the progression of IDHmutant astrocytomas.

MATERIAL AND METHODS

We collected matched samples and clinical information from six IDHmutant astrocytoma patients before and after progression to grade 4 and subjected them to RNA- and small RNA-sequencing. We defined which microRNAs and long noncoding RNAs were significantly up- or downregulated upon progression. We also predicted the target genes of differentially expressed microRNAs utilizing machine learning algorithms and experimentally validated databases. The predicted targets were filtered for negative correlation in gene expression, and their biological relevance was assessed with gene set analysis and literature research.

RESULTS

We found 33 differentially expressed microRNAs upon progression, out of which 19 were up- and 14 were downregulated. A total of 443 negatively correlating targets were identified for the microRNAs (0-115 per microRNA). The target genes were associated with DNA repair, proliferation, and G-Protein coupled receptor signaling. Furthermore, we observed 19 up- and 14 downregulated lncRNAs within the differentially expressed genes. Six of them have been reported to be cancer-related, including known tumor-suppressors and lncRNAs known to promote cell proliferation, invasion and migration.

CONCLUSION

The study identified a number of noncoding RNAs associated with the progression of IDHmutant astrocytoma to grade 4. Further studies are needed to evaluate their potential to act as biomarkers or therapy targets.
P10.16.B ATR INHIBITION ENHANCES CELL DEATH AND INDUCES IMMUNE-RELATED GENE EXPRESSION IN COMBINATION WITH STANDARD TREATMENT IN PATIENT-DERIVED GLIOBLASTOMA CELLS
Authors: Lozinski M , Bowden N , Graves M , Fay M , Day B , Stringer B , Tooney P
Published: September 2023

BACKGROUND

Patients with glioblastoma are confronted with a high likelihood of recurrence and poor prognosis despite an aggressive treatment-regime involving surgery followed by radiation therapy (RT) and temozolomide (TMZ). RT and TMZ cause extensive DNA damage and replication stress, thus activating tumour cell death pathways. Upregulation of the DNA repair mechanisms significantly reduces effective treatment response and contributes to poor patient outcomes. We investigated the effect of inhibiting ATM- and Rad3-Related protein (ATR), a crucial sensor of replication stress and initiator of cell cycle arrest in tumour cells, using the potent and selective ATR inhibitor, gartisertib.

MATERIAL AND METHODS

Twelve patient-derived glioblastoma cell lines were grown as monolayer cultures in serum-free media and treated with TMZ, RT and/or gartisertib. Cell viability of treated cells was assessed after a 7-day incubation using the MTT method, while cell confluence, apoptosis and cell death were examined using the Incucyte S3 Live-Cell Analysis System (Sartorius, Germany). Gene expression of glioblastoma cell lines treated with TMZ+RT and/or gartisertib was assessed 4-days post-treatment.

RESULTS

As a single agent, gartisertib potently reduced glioblastoma cell viability, while 8-fold less potent in human astrocyte cells. Glioblastoma cell lines with mutated DNA damage response-related genes were more sensitive to gartisertib treatment. Live-cell imaging of glioblastoma cells treated with gartisertib (1 µM) plus TMZ (35µM) and RT (2Gy) showed a significant increase in cell death and apoptosis compared to gartisertib or TMZ+RT alone. ATR inhibition by gartisertib strongly synergised with TMZ, while moderately synergising with RT in reducing glioblastoma cell growth. Gartisertib, alone and in combination with TMZ+RT, increased gene expression in pro-inflammatory cytokines, antigen presentation, and pattern recognition pathways while decreasing genes involved in hypoxia and epithelial-mesenchymal transition pathways.

CONCLUSION

These data suggest the potential for ATR inhibition as an effective chemo- and radiosensitiser in glioblastoma tumours. Whether the change in gene expression induced by ATR inhibition reduces hypoxia within or provokes an immunogenic response directed at glioblastoma tumours, requires further investigation.
P10.20.B POSTOPERATIVE ISCHEMIA CAUSED BY MICROSURGICAL RESECTION PROMOTES PRONEURAL-TO-MESENCHYMAL TRANSITION IN GLIOBLASTOMA
Authors: Ballestín A , Pichol-Thievend C , Bourmeau G , Blanchard B , Pettiwala A , Reveilles J , Leboucher S , Anezo O , Seano G
Published: September 2023

BACKGROUND

Four glioblastoma (GB) cellular states drive the intratumoral heterogeneity of this lethal primary brain tumor and are influenced by genetics, the tumor microenvironment (TME), and response to treatment. The impact of microsurgical resection on the TME and plasticity of GB cells is unknown. Postoperative cerebral ischemic events have been described after these surgical resections, altering the proper distribution of subsequent chemo-radiotherapy treatment. Despite the aggressive standard of care, 90% of patients experience recurrence a few months after treatment and it usually begins with the regrowth of highly invasive cells that spread from the peritumoral brain resection zone. Therefore, the objective of this study was to perform morphological and transcriptomic phenotyping of residual tumor cells and TME after microsurgical resection.

MATERIAL AND METHODS

The GFP-transduced syngeneic GB IDH-wildtype cell lines CT2A and GL261 were orthotopically implanted in C57Bl6j mice brains. We developed a refined microsurgical resection protocol for GB in a size-matched study by carefully following the same surgical steps performed in patients. Mice were randomly divided into four groups: control (prior to surgery) and 1, 3, and 7 days post-surgery. Tumor tissues were harvested for time-resolved bulk and single-cell RNA sequencing as well as immunohistochemistry (IHC) studies.

RESULTS

According to our time-resolved transcriptomic and IHC analyses, microsurgical resection induced pronounced proneural-to-mesenchymal transition (PMT), chromatin remodeling, and stimulation of hypoxia-driven pathways in residual GB cells after surgery. Moreover, single-cell RNA-seq of post-resection tumors allowed us to observe significant changes in the TME relative to the immune response and vascular function in line with ischemia exposure.

CONCLUSION

The impact of microsurgical resection has important consequences on the phenotypic landscape of GB tumor cells and TME, which is characterized by a transient ischemic TME that induces PMT in GB cells. In addition, we developed a refined microsurgical resection model that can be useful in a wide variety of preclinical studies. Support/Disclosure: This study was supported by the Institut National du Cancer (INCa; 1154 INCa-2020-1-PLBIO-01-ICR-1) and by the Marie Skłodowska-Curie Postdoctoral Fellowship under the European Union’s programme Horizon2020 (HORIZON-MSCA-2021-PF-01, GlioSurg, Grant agreement ID: 101061921).
P10.30.B COMBINATION TREATMENT WITH ERIBULIN AND TTFIELDS INDUCES APOPTOSIS AND G2/M CELL CYCLE ARREST IN HUMAN GLIOBLASTOMA CELLS
Authors: Goett H , Schön C , Beusker P , Uhl E , Stein M
Published: September 2023

BACKGROUND

TTFields has emerged to a first line treatment in newly diagnosed glioblastoma (GBM) patients. Several preclinical studies showed that the alternating electric fields inhibit proliferation and survival of human glioblastoma cells by disruption of the spindle apparatus and impairment of mitotic segregation. Eribulin is an antimitotic drug, that is currently used in the third line treatment of breast cancer. As it is also able to inhibit the pro-mitotic function of TERT, which is mutated in 80% of human glioblastoma, the drug was also shown to have a radiosensitizing and antiproliferative effect on human glioblastoma and ovarian cancer cell lines. This study aims to evaluate the effect of the combination of Eribulin and TTFields on the survival and cell cycle of glioblastoma cells.

MATERIAL AND METHODS

U87, A172 and four patient derived glioblastoma cell lines were cultured and plated to 80% confluence. Cells were then treated with TTFields at a frequency of 200kHz for 24 hours and/or received the ED50 and 0.5-fold ED50 of Eribulin. Controls remained untreated respectively. After 24 hours cells were harvested and counted by automatic cell count. Survival and cell cycle status were evaluated by FACS analysis.

RESULTS

The rate of early apoptotic cells was 82.28% in the group treated with TTFields and Eribulin. With TTFields treatment only 50.99% and with Eribulin alone 14.38% of cells were in an early apoptotic state. Untreated control cells had an apoptosis rate of 4.25%. The combination of TTFields and Eribulin was significantly more effective than the single treatment modalities (p>0.05). Treatment with TTFields increased the rate of cells an G2/M status. This effect was even stronger in the group with combination treatment.

CONCLUSION

Combination treatment of the antimitotic drug Eribulin with TTFields is able to improve the inhibitory effect of the drugs on cell survival. Furthermore the combination therapy effects the cell cycle of glioblastoma cells inducing G2/M arrest. Future preclinical studies should focus on the antimitotic effect and the influence of the treatment on genome integrity for a more detailed insight into the mechanisms of action.
P11.03.A DOES REGULAR SURVEILLANCE IMAGING IMPROVE SURVIVAL IN GLIOBLASTOMA? RESULTS FROM A NATIONAL, MULTI-CENTRE COHORT STUDY (INTERVAL-GB)
Authors: Gillespie C S , Bligh E R , Poon M T C , Solomou G , Gough M , Islim A I , Millward C P , Rominiyi O , Zakaria R , Price S J , Watts C , Camp S , Booth T , Thompson G , Mills S J , Waldman A , Brennan P , Jenkinson M D ,   British Neurosurgical Trainee Research Collaborative, Neurology and Neurosurgery Interest Group, INTERVAL-GB Collaborative
Published: September 2023

BACKGROUND

Glioblastoma is the most common malignant primary brain tumour in adults and is usually incurable. Post-operative magnetic resonance imaging (MRI) is used to assess extent of resection, and subsequent follow-up MRI is used to monitor response to treatment and to detect progression. The benefit of regular, scheduled follow-up MRI on patient management and outcomes is unclear.

MATERIAL AND METHODS

In this multi-centre, retrospective observational cohort study we included patients with a histopathologically confirmed glioblastoma, operated between August 31, 2018 and February 1, 2019 who received any adjuvant oncological treatment. Follow-up MRI schedules, indications, and clinical outcomes were collected. The primary objective was to investigate the follow-up MRI surveillance practice after surgery for glioblastoma and assess compliance with recommendations from the National Institute for Health and Care Excellence (NICE) (Post-operative scan <72 hrs, MRI every 3-6 months). The secondary objectives were to determine indications for MRI scans and the association on overall survival (OS) and progression-free survival (PFS).

RESULTS

754 patients, with a median age of 63 years (range: 21-84) from 26 neuro-oncology centres were included. Most patients had post-operative MRI within 72 hours of surgery (88.1%, N=407/462). The median number of subsequent follow-up MRI was 1 (Interquartile range 0-4). 28.1% of patients had follow-up MRI in accordance with NICE recommendations (N=212/754). Patients in this group were more likely to receive second-line chemotherapy (28.6% vs 19.5%, P=0.009). The median follow-up period was 10.5 months (IQR 5.3-19.4 months). Median overall survival was 15.1 months (95% CI 12.9-17.3) in the scheduled MRI group and 9.1 months (95% CI 7.8-10.4) in the non-compliant group. On multivariable cox regression analysis, regular, scheduled MRI was independently associated with longer overall survival (HR 1.67, 95% CI 1.33-2.10, P<0.001), but not PFS (HR 1.20, 95% CI 0.98-1.47, P=0.074). Patients with progression first detected on scheduled imaging had a significantly longer OS (18.4 vs 15.6 months, P=0.013) and PFS (9.9 months vs 7.9 months, P=0.041).

CONCLUSION

Following regular scheduled surveillance follow-up MRI for glioblastoma is associated with longer overall survival. Prospective trials are needed to determine whether regular or symptom-directed MRI influences survival outcomes and quality of life.
P11.14.B PROGNOSTIC ASSOCIATIONS OF STEROID USE IN GLIOBLASTOMA: A POPULATION-BASED STUDY
Authors: Abdel Moneim Y , Weller M , Gramatzki D
Published: September 2023

BACKGROUND

Steroids are widely used in brain tumor patients to control symptoms related to tumor and cerebral edema. A possible detrimental effect of steroid treatment on prognosis in glioblastoma patients has been proposed. Whether this represents only a negative patient selection due to the potential confounding factor of steroid treatment or whether glucocorticoid use per se causes a worse prognosis remains a matter of debate.

MATERIAL AND METHODS

We reviewed retrospective data of 225 patients diagnosed with isocitrate dehydrogenase (IDH)-wildtype glioblastoma from 2010 to 2014 in the Canton of Zurich, Switzerland. We assessed clinical data and the use of steroids at different time points. Survival data were analyzed with the Kaplan-Meier method, and corrections for known prognostic or predictive factors were performed with Cox regression analyses. Correlations were determined with Spearman’s correlation coefficient.

RESULTS

Most patients (N=203, 95%) received steroids at least once in the first year after diagnosis, the majority (N=153, 69%) in the perioperative setting (defined at the time of hospitalisation for the surgery plus/minus seven days), and 94 patients (62%) in the first three months. Steroid use at three months after surgery was associated with with steroid treatment at six months, too (p<0.01). The latter was associated with inferior overall survival after correction for known prognostic factors (p=0.006).

CONCLUSION

Use of steroids at six months after diagnosis was associated with inferior survival in glioblastoma even when controlling for confounding factors. The precise mode of action of steroids in this setting remains to be identified, but cytoprotective effects of tumor cells versus radiotherapy and chemotherapy as well as decreased immune function of the host are potential mechanisms.
P11.16.B THE MAYO CLINIC MULTIDISCIPLINARY NF2 CLINIC EXPERIENCE OF BEVACIZUMAB IN NEUROFIBROMATOSIS TYPE 2-RELATED SCHWANNOMATOSIS PATIENTS WITH VESTIBULAR SCHWANNOMAS
Authors: Webb M J , Webb L M , Van Gompel J J , Link M J , Neff B A , Carlson M L , Driscoll C W , Ruff M W , Anderson K A , Neth B J , Kizilbash S H , Uhm J H , Lane J I , Benson J C , Blezek D J , Mehta P M , Bathla G , Sener U T
Published: September 2023

BACKGROUND

Neurofibromatosis type 2-related schwannomatosis (NF2) is an autosomal dominant tumor-predisposition syndrome characterized by bilateral vestibular schwannomas (VS) as well as other nervous system tumors. Management decisions for NF2-related VS are typically predicated on tumor size, associated symptoms, patient age, and comorbidities. Observation, surgical resection, and stereotactic radiosurgery can be viable options. In patients with VS associated with NF2, vascular endothelial growth factor A (VEGF-A) inhibitor, bevacizumab, is a systemic treatment option. In this single institution study, we review our clinical experience in patients with NF2 who received bevacizumab for VS and evaluate the effect of bevacizumab treatment on VS growth and symptom progression.

MATERIAL AND METHODS

This is a retrospective analysis of patients seen at the Mayo Clinic Rochester Multidisciplinary NF2 Clinic. Three-dimensional volumetric data for VS were measured using manual segmentation with Visage PACS software under the direct supervision of a board-certified neuroradiologist.

RESULTS

Out of 76 patients with NF2 evaluated in the past 3 years, we identified 19 that received treatment with bevacizumab. Median age of NF2 diagnosis was 19 years (range 0.5-61) with a median NF2 phenotype severity score of 2 (range 1-3). Thirteen of these patients have discontinued bevacizumab, accounting for a median duration of 12.2 months (range 3.3-88 months) of bevacizumab treatment. Bevacizumab was discontinued due to hypertension (n=5), proteinuria and renal dysfunction (n=3), tumor progression (n=2), fatigue or other intolerance (n=2), or non-compliance (n=1). The remaining 6 patients are currently receiving bevacizumab treatment for a median duration of 9.4 months as of March 2023 (range 3.7-48.3 months). Fifteen patients had brain MRI data available to evaluate VS change during bevacizumab treatment, with partial response observed in 5 patients, stable disease in 8, and progression in 2. Ten of the 13 patients who stopped bevacizumab had MRI data to evaluate VS change following treatment termination. Within 6 months of bevacizumab discontinuation, 6 patients had rebound growth of their VS between 21-95% from their previous tumor volume, while 4 did not. Three patients with rebound growth went on to have surgery or irradiation for VS management.

CONCLUSION

Our single institution experience confirms that bevacizumab can slow progression of VS and symptoms associated with VS growth. However, we note that there is the potential for rapid VS growth following bevacizumab discontinuation, for which we propose heightened surveillance imaging and symptom monitoring for at least 6 months upon stopping anti-VEGF therapy.
P11.19.A MACROPHAGES-BASED IMMUNOTHERAPY OF SOLID TUMORS MICROENVIRONMENT: THE TEM-GBM STUDY (NCT03866109)
Authors: Eoli M , Gentner B , Anghileri E , Farina F , Capotondo A , D'Alessandris G , Di Meco F , Ferla V , Franzin A , Ferroli P , Gagliardi F , Legnani F , Mazzoleni S , Mortini P , Olivi A , Pallini R , Saini M , Snider S , Naldini L , Russo C , Ciceri F , Finocchiaro G
Published: September 2023

BACKGROUND

We have developed an HSC-based platform to switch from pro-tumor to anti-tumor bone-marrow derived tumor-infiltrating macrophages. Specifically, Temferon cell therapy delivers IFN-a into the tumor microenvironment (TME) in a targeted manner via Tie-2 expressing monocytes, with transcriptional and post-transcriptional controls mediated by miRNA target sequences.

MATERIAL AND METHODS

TEM-GBM is an open-label, Phase 1/2a dose-escalation study evaluating the safety and efficacy of Temferon in up to 27 newly diagnosed, unmethylated MGMT glioblastoma (GBM) patients. Twenty-four patients are assigned to 8 cohorts and will receive a single increasing dose of Temferon, 3 additional patients will be further enrolled to confirm the safety profile of the chosen Temferon dose to be tested in a broader group of patients (Phase 2). Patients are followed up to 2 years after treatment with Temferon. Here we report the analysis on the biological activity of Temferon on patients who underwent a second surgery intervention.

RESULTS

As of 31st March 2023, 6 out of 19 Temferon treated patients underwent a second surgical intervention; of these, 4 belonged to low dose cohorts (C1-C2) and 2 to high dose cohorts (C4-C5). The second surgery occurred at a median of 11 months after 1st surgery (range 7-17 months). Where enough fresh material was collected to enrich for CD45+ cells within the tumor, a 3% to 5% of gene-marked tumor infiltrate was found (2/2 specimens) suggesting that Temferon-derived cells homed to the TME. To verify if the local delivery of IFN-a by TEMs was able to upregulate the Interferon Stimulated Genes (ISGs) in tumor tissue, the transcripts for IFIT1, IRF7, OAS1a genes were evaluated by RT-PCR in formalin-fixed paraffin sections obtained at first and second surgery. The analysis was performed on eighteen (18) 1st surgery samples (from C1 to C6), and on six (6) 2nd surgery specimens. At 1st surgery, transcripts were detected in 17 out of 17 specimens (one sample excluded since housekeeping genes did not amplify) and most of the patients showed a relatively low quantity of ISGs expression. The comparison of the overall ISGs expression at first surgery and second surgery highlighted the activation of IFN-responsive genes at second surgery suggesting the occurrence of the local delivery within the TME of biologically active IFN-a.

CONCLUSION

The results provide initial evidence of Temferon’s potential to modulate the TME of GBM patients.
P11.31.B LEPTOMENINGEAL SPREAD AFTER POSTOPERATIVE STEREOTACTIC RADIOTHERAPY FOR BRAIN METASTASES
Authors: Hakstege M P , Kiderlen M , Crouzen J , Hagenbeek R , Wiggenraad R , Nandoe Tewari R , Kerkhof M , Vos M , van der Voort van Zyp N , Mast M , Petoukhova A , Broekman M , Zindler J
Published: September 2023

BACKGROUND

Stereotactic radiotherapy (SRT) is the preferred treatment after surgical resection of brain metastases to improve local tumour control compared to observation. Some recent studies suggest that leptomeningeal metastases (LMM) occur more often after postoperative SRT compared to primary SRT with brain metastases in situ. This may be caused by tumour cells spillage during surgery. The aim of this study was to determine the incidence of LMM after postoperative SRT of brain metastases in our institution.

MATERIAL AND METHODS

All patients treated with postoperative SRT for brain metastases in our hospital between 2015 and 2020 were included in this retrospective analysis. LMM was diagnosed by a neuro-radiologist (RH) on a cerebral MRI. LMM, overall survival, and time to local recurrence (LR) were estimated from date of SRT, using the Kaplan-Meier method.

RESULTS

In total, 53 patients with 84 brain metastases were included in the analysis. Median age at SRT was 58 years (range 45 - 75 years). Median survival in this cohort was 16 months (IQR 9 - 26 months). Eight of 53 patients (15%) developed LMM at a median of 9 months after SRT. Using Kaplan-Meyer analysis, the incidence of LMM at 1 and 2 years was 15% and 19%, respectively. Twelve patients (23%) of 53 experienced LR at a median of 9 months. The 1 and 2-year actuarial incidence was 14% and 35%, respectively.

CONCLUSION

In our cohort, the incidence of LMM after postoperative SRT for brain metastases is comparable to other studies. Studies are needed to determine whether the incidence of LMM after postoperative SRT can be reduced.
P11.32.A GLIOBLASTOMA NOMOGRAM: PREDICTING THE LOCATION OF FIRST PROGRESSION AFTER LONG-COURSE CHEMORADIOTHERAPY BASED ON A NATIONAL COHORT
Authors: Clarke A M , Lukacova S , Dahlrot R H , Haslund C A , Muhic A , Bibby B M , Trip A K
Published: September 2023

BACKGROUND

Glioblastoma (GBM) is known for its high local failure rate, as well as its migration, leading to these possible locations of disease progression:

1. Local-only; lesion of progression is connected to the initial tumour location

2. Non-local; lesion of progression is not connected to the initial tumour location

3. Combined; both local-only and non-local progression lesions are present

An upfront prediction of progression location could potentially be used to select patients for differential treatment strategies. The aim of this retrospective national study was therefore to predict location of first progression using clinical variables.

MATERIAL AND METHODS

All adults with newly diagnosed GBM between 2014-2019 who started long-course (chemo)radiotherapy were included, if they had a radiotherapy-planning MRI made. The MRI of first progression was identified by retrospective review following RANO-criteria, and used to assess the location of contrast-enhancing progression. Median time to progression (TTP) and survival beyond progression were estimated using the Kaplan-Meier method (log rank test for comparison). To predict location of progression in subgroups of patients, we used a multivariable multinomial model (age, biological sex, performance status, tumour location & focality & laterality, MGMT-methylation status, and extent of surgery).

RESULTS

We included 940 patients (MGMT methylated n=376, unmethylated n=483, not reported n=81), of whom 760 had radiographic progression. Of those, progression location was local-only in 69%, non-local in 16%, and combined in 15%. Median (95% CI) TTP in months was shortest in the combined group (8.4, 7.3-9.4), followed by the local-only (9.2, 8.5-9.8) and non-local (13.9, 12.3-15.6) (p-value <.001). Survival beyond progression in months was shortest in the combined group (5.0, 3.8-6.2), followed by the non-local (6.0, 4.4-7.6) and local-only (9.0, 8.3-9.7) (p-value <.001). When comparing patients with MGMT-methylated and unmethylated tumours, the probability (95%CI) of local-only progression was .67 (.62-.73) vs. .73 (.69-.78), non-local was .21 (.17-.26) vs. .11 (.08-.14), and combined was .12 (.08-.15) vs. .16 (.12-.19). In the multivariable model, the probability (95%CI) of local-only progression varied from .49 (.29-.69) to .86 (.74-.97), of non-local from .04 (.00-.09) to .34 (.15-.53), and of combined from .05 (.01-.10) to .34 (.07-.60) between respective subgroups.

CONCLUSION

Location of progression was associated with time to progression and survival beyond progression. In our study population it was feasible to identify subgroups of patients with a high chance of local-only progression, who may potentially benefit most from radiation dose-escalation. Both patients with MGMT-methylated and unmethylated tumours had the highest chance for first progression located at the initial tumour site only.
P11.42.A LONG- AND SHORTIME SURVIVORS WITH GLIOBLASTOMA IDENTIFIED BY FLT PET/MR AND METABOLOMICS
Authors: Sandström M , Larhed S , Axelsson J , Björblom B , Asklund T
Published: September 2023

BACKGROUND

Patients with glioblastoma still have a dismal prognosis despite multimodal treatment with surgery and radiochemotherapy. Sometimes these patients also suffer from difficulties in the interpretation of outcome from treatment. Since most patients affected by glioblastoma have a short survival it is of outermost importance that ineffective treatment is discontinued in time to spare them from unwanted side effects.

MATERIAL AND METHODS

48 patients with suspected glioblastoma were included in a clinical study at Umeå University Hospital between the years 2015-2019. Patients were treated according to clinical routines with surgery and radiochemotherapy and within the framework of the study they performed up to four 18F-flourothymidine (FLT) PET/MR and serial blood-tests for metabolomics. Blood samples were analyzed at Metabolon, USA and the metabolomic pattern were compared with clinical and radiomic data.

RESULTS

The measures of standardized uptake values (SUV) and tumor volumes show a higher SUV for short-time survivals compared to long-time survivors but only a significant difference for the MR-measures Vtumor, Vtotal after 6 weeks of treatment. Regarding blood samples the metabolite patterns could separate patients living long (>3 years) and patients living short (<500 days) in blood samples taken both preoperatively and after six weeks of radiochemotherapy.

CONCLUSION

New methods are needed to accurate assess prognosis and outcome of treatment for patients with glioblastoma. This clinical study gives new insights in foreseeing prognosis for patients with glioblastoma by using 18F-flourothymidine (FLT) PET/MR and also by serial blood sampling during treatment. Both results of FLT PET/MR and the impact of metabolomics will be presented and discussed at the conference.
P11.43.B HIGH-RESOLUTION NERVE ULTRASOUND IN NEUROFIBROMATOSIS TYPE 1
Authors: Noordhoek D C , Mann E , Ennik T , van Dijk S A , Drenthen J , Taal W
Published: September 2023

BACKGROUND

Patients with neurofibromatosis type 1 (NF1) can develop plexiform neurofibromas (PN). PN are peripheral nerve sheath tumors that can cause pain, neurological deficit and can transform into malignant peripheral nerve sheath tumors (MPNST). High-resolution ultrasound (HRUS) is suggested as a quick and cost-effective technique, as compared to whole-body MRI, for screening NF1 patients for PN. Our aim is to describe the variety of HRUS nerve abnormalities in NF1 patients and to study the link between nerve morphology and nerve function.

MATERIAL AND METHODS

We selected patients with a clinical diagnosis of NF1, with or without symptoms related to the peripheral nervous system (PNS) such as pain, sensory disturbances or loss of strength. Patients were invited for a study visit including neurological examination, nerve conduction studies (NCS) and HRUS. One-sided NCS were performed of the median and ulnar nerve (motor and sensory), peroneal and tibial nerve (motor) and sural nerve according to standard protocol. We visualised the brachial plexus, median-, radial-, ulnar-, peroneal-, tibial-, and sural nerves on both sides using HRUS. The cross-sectional area (CSA) of the nerve was measured at predefined anatomical sites, and additional sites in case of focal nerve enlargement.

RESULTS

We enrolled 60 NF1 patients, of which 57% had PNS-related symptoms. One third of our patients had neurological deficits during physical examination. We found nerve enlargement with HRUS in 48 out of 60 patients (80%), this was not significantly different between patients with PNS symptoms or without PNS symptoms (82% vs 77% respectively, p=0.602). In 82% of the patients with PNS symptoms, their symptoms were likely to be related to one or more nerve enlargements. Nine of these patients had clinical and neurophysiological signs of carpal tunnel syndrome. Different patterns of nerve enlargement were identified. 46% had isolated nerve enlargements, 25% had diffusely enlarged nerves and 29% had a mixture of diffusely enlarged nerves with isolated nerve enlargements. The majority of the patients with nerve enlargement on HRUS had no abnormalities on NCS (65%).

CONCLUSION

The majority of NF1 patients have nerve enlargements as seen by HRUS, however we have shown that nerve enlargements can often be asymptomatic and do not always lead to impaired nerve function. To determine whether patients have PN cannot be based solely on clinical evaluation of symptoms. HRUS might have an application as a screening tool for NF1 patients in clinical practice. However, further research is needed to describe growth of nerve enlargements, the impact of intra- and interobserver variability on CSA measurements and to improve our knowledge on the link between nerve morphology and nerve function in NF1.
P11.60.A RACTAC TRIAL: PHASE II MULTICENTRIC ITALIAN TRIAL ON REPOSITIONING OF THE ANTIPSYCHOTIC DRUG CHLORPROMAZINE AND ITS COMBINATION WITH TEMOZOLOMIDE IN MGMT UNMETHYLATED GLIOBLASTOMA PATIENTS
Authors: Pace A , Lombardi G , Villani V , Benincasa D , Abruzzese C , Cestonaro I , Corrà M , Cerretti G , Caccese M , Silvani A , Gaviani P , Giannarelli D , Paggi M G
Published: September 2023

BACKGROUND

The poor prognosis of patients affected by glioblastoma (GBM) prompts the search for new and more effective therapies, particularly for GBMs with unmethylated MGMT. In this regard, drug repurposing, can represent a safe and inexpensive way to bring novel pharmacological approaches from bench to bedside. Chlorpromazine, a medication in use since six decades for the therapy of psychiatric disorders, shows in vitro features that make it eligible for repositioning in GBM therapy. In our experimentation on six GBM cell lines, chlorpromazine inhibited cell viability in an apoptosis-independent way, induced polyploidy, reduced cloning efficiency as well as neurosphere formation and downregulated the expression of stemness genes. Notably, we found that chlorpromazine synergized with temozolomide, in reducing cell viability and strongly cooperated in reducing cloning efficiency and inducing cell death in vitro for all the GBM cell lines assayed.

MATERIAL AND METHODS

With these assumptions, we started a multicentric Phase II clinical trial on newly diagnosed GBM patients with unmethylated MGMT by adding chlorpromazine to temozolomide in the adjuvant phase of the standard first-line therapeutic protocol. The experimental procedure involves the combination of CPZ with standard treatment with TMZ in the adjuvant phase of the Stupp protocol. CPZ was administered orally at a dose of 50 mg/day - GG 1-28 - of every cycle of the adjuvant treatment with TMZ. . Efficacy outcomes were evaluated using Kaplan-Meier methodology. OS was measured from diagnosis to death; PFS was determined from radiotherapy to the first sign of PD or death due to any cause.

RESULTS

The trial was closed on December 2022. 53 patients have been enrolled, 39 male, 14 female. 21 patients completed 6 cycles of treatment, without relevant toxicity.The results shows a median PFS of 7 months (St.Dev. 5,7) and a median OS of 15 months (St.Dev. 6,9). 23 patients are still alive (43%)

CONCLUSION

The addition of Chlorpromazine to the standard adjuvant chemotherapy with temozolomide was well tolerated in newly diagnosed Glioblastoma unmethylated patients, with promising impact on outcome measures. On the basis of the RACTAC trial

RESULTS

, a phase II multicentric trial evaluating Chlorpromazine added to standard treatment (RT+TMZ+adj TMZx 6 cycles plus CPZ) in newly diagnosed Glioblastoma patients is in preparation
P11.69.B INTRAVENOUS THROMBOLYSIS WITH OR WITHOUT ENDOVASCULAR TREATMENT FOR SUSPECTED ISCHEMIC STROKE IN PATIENTS WITH INTRACRANIAL TUMORS
Authors: Seystahl K , Martinez-Majander N , Salerno A , Beyeler M , Erdur H , Marto J P , Hametner C , Zedde M , Pezzini A , Leker R R , Altersberger V L , Costamagna G , Serôdio M , Migliaccio L , Pascarella R , Zini A , Razaqi L , Béjot Y , Jung S , Gensicke H , Padjen V , Ringleb P , Nolte C H , Heldner M R , Michel P , Engelter S T , Wegener S , Weller M
Published: September 2023

BACKGROUND: AND OBJECTIVES

Intravenous thrombolysis (IVT) for suspected ischemic stroke in patients with intracranial neoplasms is off-label. However, data on risks of intracranial hemorrhage (ICH) is scarce.

METHODS

In a multicenter registry-based analysis within the European Thrombolysis in Ischemic Stroke Patients (TRISP) collaboration, we assessed frequencies of symptomatic and fatal ICH after IVT for suspected ischemic stroke in patients with intracranial tumors by descriptive statistics and analyzed associations with clinical and imaging characteristics by binary logistic regression. Definition of symptomatic ICH was based on the clinical criteria of the European Cooperative Acute Stroke-II trial including hemorrhage at any site in cranial imaging and concurrent clinical deterioration.

RESULTS

Screening data of 21,289 patients from 14 centers, we identified 105 patients receiving IVT, among them 29 patients (28%) with additional endovascular treatment, with suspected, i.e. imaging-based, or histologically confirmed diagnosis of intracranial tumors. Among 104 patients with CT or MRI after IVT available, symptomatic and fatal ICH were observed in nine and four patients (9% and 4%). Among 82 patients with suspected or confirmed meningioma, symptomatic and fatal ICH occurred in six and three patients (7% and 4%). In 18 patients with intra-axial suspected or confirmed primary or secondary brain tumors, there was one symptomatic nonfatal ICH (6%). Out of four patients with tumors of the pituitary region, two patients (50%) had symptomatic ICH including one fatal ICH (25%). Tumor size was not associated with occurrence of symptomatic ICH (Odds ratio 2.8, 95% CI 0.3-24.8, p=0.34).

CONCLUSION

In our dataset from routine clinical care, we provide insights on the safety of IVT for suspected ischemic stroke in patients with intracranial tumors, a population that is commonly withheld thrombolysis in clinical practice and prospective trials. Except for a potential high risk of symptomatic ICH after IVT in patients with tumors of the pituitary region, frequencies of symptomatic ICH in patients with intracranial tumors in our cohort appear to be in the upper range of rates observed in previous studies within the TRISP cooperation. These results may guide individual treatment decisions in patients with acute stroke and intracranial tumors with potential benefit of IVT.
P11.70.A EQUITY IN GENOMIC TESTING: LESSONS LEARNT FOLLOWING THE ROLLOUT OF AN AMBITIOUS GENOMIC TESTING STRATEGY FOR NEUROLOGICAL TUMOUR PATIENTS IN THE UNITED KINGDOM
Authors: Huskens N , Aitken C , Watts C , Kurian K
Published: September 2023

BACKGROUND

The NHS England Genomic Test Directory now offers extensive genomic testing to brain tumour patients including whole genome sequencing (WGS), methylation arrays, gene panels, and other targeted mutation tests. Comprehensive genomic testing enables precise diagnosis and prognosis, tailoring of treatment, and research into new actionable targets. Despite the ambitious plans and potential for significant patient benefits, the Tessa Jowell Brain Cancer Mission (TJBCM) identified variation in deployment of these tests across Neuro-Oncology Centres in the UK. Based on these findings, we aimed to further understand the variation. We aimed to uncover drivers to delivering a successful genomic testing programme and identify local and national barriers to rolling out extensive genomic testing.

MATERIAL AND METHODS

As part of the TJBCM Centre of Excellence Programme, 90% of Neuro-Oncology Centres in the UK provided self-reported data on volumes of genomic testing for brain tumour patients. Subsequently, structured interviews were conducted with neuro-oncologists, neuropathologists, neurosurgeons, clinical scientists and other stakeholders from these Centres to further evaluate the state of genomic testing.

RESULTS

Accessibility to WGS varied from no access, to Centres where WGS was available in a limited capacity, to Centres where WGS was accessible but not scalable or timely. Bottlenecks were identified throughout the WGS pathway including inadequate tumour tissue, sample processing and transport delays, and insufficient clinical scientists to interpret results. As such, no UK Centre interviewed had sufficient capacity to offer WGS to all neurological tumour patients in a timely manner using NHS-accredited pathways. Interviews showed geographic variability in access to basic molecular tests such as methylation array and CDKN2A/B which are required for diagnostics and prognostics. There was also a strong reliance on a small number of laboratories to provide methylation array, resulting in backlogs. Common drivers to effective delivery of genomic testing included funded posts for research nurses, innovative systems for delivery of tumour samples from surgery to the laboratory, dedicated staff who advocated for genomic testing, and well-established Genomic Tumour Advisory Boards for test interpretation.

CONCLUSION

Impressive progress has been made in the last two years yet there remains a mismatch between what the National Genomic Test Directory dictates, and what can currently be delivered in a manageable timeframe. Inconsistencies in infrastructure, funding and training are preventing UK Centres from delivering the intended world-leading genomic testing. Barriers to address vary from simple changes at a local level, to national coordination and funding so that genomic testing will be equally accessible to all brain tumour patients in the UK.
P11.73.B COMPARING GAMMA KNIFE RADIOSURGERY WITH MICROSURGERY AND THEIR RISK-BENEFIT-RATIO OF TUMOR CONTROL AND FACIAL DETERIORATION IN LARGE VESTIBULAR SCHWANNOMAS (KOOS III-IV)
Authors: Wang S , Ebner F , Rizk A , van Eck A , Horstmann G , Tatagiba M , Naros G
Published: September 2023

BACKGROUND

The level of evidence to provide treatment recommendations for vestibular schwannoma (VS) is low. Both stereotactic radiosurgery (SRS) and microsurgical resection (SURGERY) are available as treatment options for VS. If treated with monotherapy alone, SRS has shown to be inferior in tumor control, but superior in facial nerve preservation compared to SURGERY. The aim of this study was to analyze the risk-benefit-ratio in the treatment of large VS (Koos III-IV) comparing SRS and SURGERY.

MATERIAL AND METHODS

This is a retrospective dual-center cohort study enrolling consecutive patients with solitaryVS between 2005 und 2011 to enable follow-up of up to 10 years. Tumor size was classified by Koos Classification. Clinical state was reported by House and Brackmann (H&B) and Gardner-Robertson (G&R) scale (with H&B and G&R 1-2 considered as good outcome), and Recurrence-free-survival (RFS) was assessed radiographically by contrast-enhanced MR imaging. As an expression of success/harm, the absolute risk reduction (ARR) and risk increase (ARI) were calculated as the difference between incidence of recurrences and facial deterioration rates in patients treated with SRS and SURGERY, respectively. ARR and ARI were used to derive additional estimates of treatment effectiveness (in SURGERY), i.e. the number-to-operate (NNO) and the number-to-harm (NNH), respectively.

RESULTS

The study population included N=901 patients, who were treated in both centers. N=492 (55%) were large VS (Koos III-IV). Of them N=260 (53%) were treated with SRS and N=232 (47%) with SURG. The SRS treatment arm presented with a recurrence rate of 14.2%, and SURGERY with 3.0%. Therefore, ARR for recurrence was 11.21% (95% CI: 6.4%-16.0%) with a NNO of 9 (95% CI: 6.3-15.6) in SURGERY meaning that one in every 9 patients will benefit from SURGERY treatment. When analyzing facial nerve deterioration (facial paresis HB>2 and facial spasm) in large VS, SRS presented with 6.9%, and SURGERY with 12.5% adverse facial nerve outcome resulting in an ARI of 5.6% (95%CI: 0.3%-10.8%) and a NNH of 18 (95%CI:9.2-312.1).

CONCLUSION

The analysis of the different proportion in success/harm in the management of large VS (SRS vs. SURGERY) in this cohort yielded in a low NNO, combined with a high NNH. This shows that SURGERY was superior to SRS considering tumor control in large VS (Koos III-IV). Still, the direct translation of these results into treatment recommendations is not self-evident, but multi-faceted: This analysis is a vivid representation of a dilemma well-known to neuro-oncological surgeons - the negotiation between tumor control and functional outcome. Large VS should be treated in specialized centers, which have enough experience to ensure a high-rate of facial preservation in large VS (Koos III-IV).