bluuebunny/crossref_metadata_2025 huggingface dataset:
P11.77.B PREDICTING SURVIVAL IN GLIOBLASTOMA PATIENTS WHO DON’T UNDERGO NEUROSURGERY
Authors: de Haan Y , de Roover M , Duijnkerke D , Colmer N , Smits M , Dirven C M F , Vincent A J P E
Published: September 2023

BACKGROUND

Patients with glioblastoma have poor overall survival (OS), even with surgical treatment and adjuvant therapy. However, up to a quarter of patients with presumed glioblastoma does not receive any form of treatment and not much is known in the literature about this population. Their OS is estimated to be around 1.2 months. Generally, patients with presumed glioblastoma that don’t receive any form of treatment do so either because of their poor physical condition or because of their own preference. Receiving a terminal diagnosis comes with psychological and existential distress and providing a more personalized prognosis of survival may be beneficial in acceptance and end-of-life decision-making. We aimed to evaluate overall survival in a large cohort and analyze which clinical and radiological factors predict overall survival in this population.

METHODS

Patients in this retrospective cohort were included in a tertiary hospital in the Netherlands. Patients were eligible if they were aged above 18 years old and didn’t receive any treatment for their presumed glioblastoma. We used a log-rank test to analyze the differences in the survival between the groups are not fit enough for surgery and the group that prefers to not undergo any treatment. We performed Cox regression to analyze the predictive value of clinical and radiological factors on survival.

RESULTS

Between January 1st, 2010 and 31st December 2022 212 patients were included. The median OS of the entire cohort was 2.68 months. In the group with poor physical condition as reason for not undergoing surgery, the median OS was 1.92 months versus an OS of 2.73 months in the group that didn’t want to undergo treatment (p=0.0174). In univariate Cox regression analysis, location in the right hemisphere, not receiving any treatment because of poor physical condition, tumor crossing the midline, Karnofsky Performance Scale lower than 70, a multifocal lesion in the contralateral hemisphere and NIHSS of 5 or higher had a statistically significant increased Hazard Ratio for OS.Additional analysis of the statistical significance in a multivariable model is still ongoing.

CONCLUSION

This large retrospective cohort of patients with presumed glioblastoma that don’t receive any treatment provides more robust information about expected median overall survival and gives physicians better tools in conversations about end-of life care based on factors that influence survival.
P11.80.A DOUBLE BLIND RANDOMISED TRIAL WITH ADD-ON OF VALGANCICLOVIR OR PLACEBO TO STANDARD THERAPY OF NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Stragliotto G , Pantalone M , Brandas P , Sagerup-Bjorland L , Söderberg-Naucler C
Published: September 2023

BACKGROUND

The origin of glioblastoma is not known. Our earlier and other groups research have shown the presence of cytomegalovirus in glioblastoma, but not in adjacent tumor-free tissue. Furthermore there is a significant correlation between the amount of virus proteins in the tumor and prognosis, patients with low tumoral load have longer survival compared to patient with hogh tumoral viral load. In a retrospective study with 100 newly diagnosed patients with glioblastoma we showed tha the addition of valganciclovir yielded a median survival of 25 months as compared to 13 months for contemporary controls from the same institution. In the case of maximal surgical resection, the median survival reached 29 months. We therefore aimed to run a randomised doule blind study in newly diagnosed glioblastoma.

MATERIAL AND METHODS

The study started in September 2019, and has the goal to recruit 220 patients, 110 in the valganciclovir group and 110 in the placebo. A macroscopic surgery (at least 90% resection of contrast enhancing tumor on post op MRI), followed by radiation and chemotherapy with temozolomide. Patients receive the study drug, 900mg twice daily during the first 6 weeks, followed by maintenance 450mg twice daily for 2 years. There is no cross-over. The use of Optune is allowed. There is a stratification for MGMT methylation status. Only IDH1 wt tumors can be included, and the randomization has to take place within 10 weeks from surgery. The primary outcome is overall survival, secondary endpoints are the proportion surviving at 2 years and quality of life. 20 patients who fullfilled inclusions criteria have not been randomised.

RESULTS

since September 2019, 120 patients have been included at Karolinska Hospital in Stockholm. The oncology clinics in Oslo and Stavanger started including patients in September 2022, and have so far included 20 patients. At Karolinska there are 47 MGMT methylated and 73 unmethylated. Nineteen deceased patients and 45 deceased respectively. The median survival is 22 and 14 months respectively. Forteen patients with MGMT methyl completed the study (24 months and 6 months follow-up) versus 8 in the unmethylated. The survival of 20 patients not randomised was 18 months. Five patients showed reversibel hematological side effects grade 3-4, always with the initial high dose and concomittant to radiochemotherapy. No patient stopped the study due to side effects.

CONCLUSION

the is an ongoing trial, that has recruited about 35 patients per year at the main center, even during the 2 years of pandemics. about half of newly diagnosed patients are eligible for this study, and more than 80% of eligible patients are randomized which is remarkable for this category of patients. There may be a trend as a group for positive survival results, but we need to wait the final results, which may be available in 2-3 years. The study wil recruit until December 2024.
P12.03.A MULTIMODAL ANALYSIS OF GLIOBLASTOMA REVEALS THE POTENTIAL OF CXCR7-CXCL12 IN GBM CELLS SENSITIZES GBM TO IMMUNE CHECKPOINT BLOCKADE THERAPY
Authors: Liu C , Chien C , Yang W , Chuang J , Chang K
Published: September 2023

BACKGROUND

Glioblastoma (GBM), a WHO Grade IV glioma, is one of the most lethal brain tumors. In spite of the standard of care and currently developed advanced treatment, the prognosis of GBM patients is still poor. In addition to the understanding of GBM cells, the microenvironment plays a critical role in regulating GBM progression. Also, more and more information indicates the interaction of GBM-associated macrophages (GAMs) and GBM cells facilitates GBM progression via sculpturing immunosurveillance, cancer stemness, and cancer resistance. And thus, we hypothesized that GBM cells sculptured the microenvironment via macrophage alternation of which interventions may potentialize immune checkpoint blockade therapy.

MATERIAL AND METHODS

The bulk RNA sequencing (seq.) of the paired primary-recurrent GBM specimens, single-cell RNA seq., in vitro (including mRNA, protein, and cell behavior tests), and in vivo validation, were integrated to explore our hypothesis.

RESULTS

The bulk RNA seq. of the paired primary-recurrent GBM specimens showed recurrent GBM enhanced the neuroinflammation pathway. Among the secretory components, CXCL12, also known as stromal cell-derived factor 1 was accumulated during GBM progression and upregulated in temozolomide (TMZ)-resistant GBM cells compared with parental GBM cell lines. In addition, the newly CXCL12 receptor CXCR7 may act as a scavenger to breakdown CXCL12-CXCR4 positive feedback in GBM resistance. Moreover, the bulk RNA sequencing seq. showed that recurrent GBM reduced CXCR7 expression. Single-cell RNA seq. of GBM patients’ specimens suggested that CXCR7 was majorly expressed in GBM cells than in normal neural and immune cells. Developing TMZ resistance in GBM cell lines also down-regulated CXCR7 expression. Furthermore, silencing CXCR7 attenuated TMZ cytotoxicity while silencing CXCR7 and CXCL12 simultaneously reversed the effects. In contrast, combining CXCR7 agonists and TMZ enhanced TMZ cytotoxicity Otherwise, the GBM-associated CXCL12 activated M0 macrophages into GAMs by facilitating macrophage proliferation and inducing pro-tumor factors, including IL-1β and its receptors, IL-6, MMP9, and immune checkpoint PD-L1. Mechanistically, GBM-associated CXCL12 upregulated PD-L1 in GAMs via NF-κB. Also, in the orthotopic GBM mouse model, CXCR7 knockdown in GBM cells led to poor survival and increased PD-L1 expression in GAMs. Finally, we combined CXCR7 agonist and anti-PD-L1 to show prolonged survival, in contrast, anti-PD-L1 did not show this effect.

CONCLUSION

In accordance with the multimodal analysis, GBM regulated the accumulation of CXCL12 via silencing CXCR7 in GBM cells. The CXCR7-CXCL12 axis confers the immunosuppression by up-regulating PD-L1 in GAMs. Our study suggested that CXCR7 activation treatment alone or combined with an immune checkpoint inhibitor may be a potential strategy for the treatment of GBM.
P12.07.B THE POST-SURGICAL MICROENVIRONMENT OF GLIOBLASTOMA AS THERAPEUTIC TARGET TO AVOID RECURRENCES
Authors: TCHOGHANDJIAN A
Published: September 2023

BACKGROUND

Glioblastoma (GBM) is an incurable primary brain tumour. Most GBM patients undergo surgery prior to chemoradiation, but recurrences inevitably lead to patient death. The brain physiological regenerative responses following tumor debulking have a beneficial role in the healing process. However, they also evoke characteristic time-dependent peritumoral immune responses which can promote the formation of recurrences. The crosstalk between glial, immune and GBM cells at the surgical borders and their impact on recurrences still lacks appropriate characterization. This project aims at dissecting the GBM post-surgical microenvironment (SMe) over time and space to identify therapeutic targets and develop tailored GBM therapies to avoid the onset of recurrences.

MATERIAL AND METHODS

We developed a tumor resection model in transgenic mice bearing GL261 tumors and established a chronic intracranial window post-surgery by biphotonic imaging. Nuclear imaging was performed at defined time points using 99mTc-DTPA, 68Ga-RGD and 18F-FDG to evaluate neuroinflammation, neoangiogenesis, infiltrating tumor cells metabolism and BBB permeability. The dynamics of the inflammatory landscape following surgery was characterized by blood sampling and post-mortem analysis on brain samples (peripheral and local immunophenotyping by multiparametric flow cytometry; brain clearing and ultramicroscopy).

RESULTS

We analyzed the dynamics of recruitment and localization of immune cells coming to the resection site from the brain parenchyma or from the periphery from surgery to recurrence. BBB disruption was observed post-surgery followed by a recovery within three days. Based on the results obtained we finally tested a therapeutic approach combining the local administration of lauroyl-gemcitabine lipid nanocapsules hydrogel with the repeated systemic administration of a SMAC-mimetic drug showing an increase in survival of GBM-bearing mice.

CONCLUSION

This comprehensive study expands the knowledge on the SMe by analyzing the impact of BBB disruption on immune cells recruitment and the role of lymphoid and myeloid populations - as well as macrophages and microglia - on the onset of tumor recurrences. Moreover, it proposes a rationally designed combinatory treatment able to target the identified cellular targets to delay or inhibit the onset of recurrences.
P12.15.A THE IMPACT OF MICROGLIA MODULATION ON THE IMMUNE TUMOR MICROENVIRONMENT IN SYNGENEIC GLIOBLASTOMA MOUSE MODELS
Authors: Kaymak D , Shekarian T , Ritz M , Ferrari N , Kälin R , Glass R , Hutter G
Published: September 2023

BACKGROUND

Glioblastoma is exceptionally resistant to T-cell targeting immunotherapies for which the immunosuppressive myeloid compartment is held responsible. As influencer and instructor of antitumoral T-cell-immunity this compartment mainly consists of Monocyte-derived Cells (MdCs) and tissue-resident (TR) macrophages called microglia (MG). Since the response to immunotherapies depend on antigen presenting cells at the tumor site, we aim to investigate this compartment and its individual role in tumor progression by genetically depleting/activating the TR MG.

METHODS

We made use of two MG-specific and tamoxifen inducible knockout mouse models in which 1) we activate MG by excision of the activation-repressing transcription factor Sall1 (Sall1CreERT2/wt x Sall1fl/wt) and 2) deplete MG by deleting the “survival-receptor” Csf1r on MG (Sall1CreERT2/wt x Csf1rfl/fl). To investigate the effect of MG activation and depletion on the immune tumor microenvironment (iTME), immunocompetent mice were engrafted with syngeneic glioma cells (CT-2A, GL261) and the iTME subsequently characterized by scRNAseq, spectral flow cytometry and immunofluorescence imaging.

RESULTS

Upon Sall1-KO MG demonstrate a morphologically reactive phenotype reminiscent of activated MG. The MG-specific deletion of Csf1r effectively depletes the brain parenchyma of TR MG which rapidly gets repopulated by a morphologically distinct microglia-(like) population. Genetic activation of MG leads to a survival benefit in Gl261-engrafted mice compared to Cre-negative littermates. In contrast, depletion of MG significantly reduces the survival in Gl261 and CT-2A engrafted mice. ScRNAseq confirms the effective depletion of MG and the subsequent emergence of a microglia-like cell population that despite microscopical resemblance to MG, transcriptionally remains distinct. The iTME in MG-depleted mice is characterized by a decreased abundance of exhausted and naïve CD8-Tcells and an increased infiltration of MdCs. Gene set enrichment analysis demonstrate a dampened inflammatory immune profile of infiltrating MdCs highlighted by a downregulation of hallmark gene sets of “interferon-α and γ response” and “TNFα-signaling via NF-κB”.

CONCLUSION

The presence of MG orchestrate the development towards a more antitumorigenic iTME by shaping the antitumoral response of incoming myeloid cells and furthermore directly or indirectly influencing T-cell immunity. Understanding this interplay of MG and MdCs in cancer and its impact on instruction of antitumoral T-cell immunity could help guiding the development of novel immunotherapeutic strategies in GBM.
P13.02.A APPLICATION OF NOVEL PACS-BASED INFORMATICS PLATFORM TO IDENTIFY IMAGING BASED PREDICTORS OF CDKN2A ALLELIC STATUS IN GLIOBLASTOMAS
Authors: Tillmanns N J , Lost J , Tabor J , Vasandani S , Vetsa S , Marianayagam N , Yalcin K , Erson-Omay Z , von Reppert M , Jekel L , Merkaj S , Ramakrishnan D , Avesta A , Dixe de Oliveira Santo I , Jin L , Huttner A , Bousabarah K , Ikuta I , Lin M , Aneja S , Turowski B , Aboian M , Moliterno J
Published: September 2023

BACKGROUND

Gliomas with CDKN2A mutations are known to have worse prognosis but imaging features of these gliomas are unknown. Our goal is to identify CDKN2A specific qualitative imaging biomarkers in glioblastomas using a new informatics workflow that enables rapid analysis of qualitative imaging features with Visually AcceSAble Rembrandtr Images (VASARI) for large datasets in PACS. Gliomas with CDKN2A mutations are known to have worse prognosis but imaging features of these gliomas are unknown. Our goal is to identify CDKN2A specific qualitative imaging biomarkers in glioblastomas using a new informatics workflow that enables rapid analysis of qualitative imaging features withVisually AcceSAble Rembrandtr Images (VASARI) for large datasets in PACS.

MATERIAL AND METHODS

Sixty nine patients undergoing GBM resection with CDKN2A status determined by whole-exome sequencing were included. GBMs on magnetic resonance images were automatically 3D segmented using deep learning algorithmsincorporated within PACS. VASARI features were assessed using FHIR forms integrated within PACS.

RESULTS

GBMs without CDKN2A alterations were significantly larger (64% vs. 30%, p=0.007) compared to tumors with homozygous deletion (HOMDEL) and heterozygous loss (HETLOSS). Lesions larger than 8 cm were four times more likely to have no CDKN2A alteration (OR: 4.3; 95% CI:1.5-12.1; p<0.001). The pial invasion was predictive of HOMDEL (OR: 8.1, 95% CI: 1.8-53.2; p<0.012) as tumors with pial invasion were eight times more likely to be HOMDEL, even after adjusting for deep white matter and subependymal invasion.

CONCLUSION

We developed a novel integrated PACS informatics platform for the assessment of GBM molecular subtypes and show that tumors with HOMDEL are more likely to have radiographic evidence of pial invasion and less likely to have deep white matter invasion or subependymal invasion. These imaging features may allow noninvasive identification of CDKN2A allele status.
P13.05.B INCORPORATION OF AI-BASED AUTOSEGMENTATION AND CLASSIFICATION INTO NEURORADIOLOGY WORKFLOW: PACS-BASED AI TO BUILD YALE GLIOMA DATASET
Authors: Tillmanns N , Lost J , Merkaj S , von Reppert M , Chadha S , Lin M , Bousabarah K , Huttner A , Aneja S , Avesta A , Omuro A , Aboian M
Published: September 2023

BACKGROUND

Translation of AI algorithms into clinical practice is significantly limited by lack of large individual hospital-based datasets with expert annotations. Current methods for generation of annotated imaging data are significantly limited due to inefficient imaging data transfer, complicated annotation software, and time required for experts to generate ground truth information. We incorporated AI tools for auto-segmentation of gliomas into PACS that is used at our institution for reading clinical studies and developed a workflow for annotation of images and development of volumetric segmentations in neuroradiology clinical workflow.

MATERIAL AND METHODS

1990 patients from Yale Radiation Oncology Registry (2012-2019) were screened. Segmentations were performed using a UNETR algorithm trained on BRaTS 2021 and an internal dataset of manually segmented tumors. AI generated segmentation can be revised and confirmed in PACS. Segmentations were validated by a board-certified neuro-radiologist, after which natively embedded PyRadiomics in PACS was used for direct feature extraction.

RESULTS

In 7 Months (05/2021 - 08/2021, 03/2022 - 05/2022) segmentations and annotations were performed in 1033 patients (429 female, 604 male, mean age 53 yrs). Dataset includes 595 Grade 4 Gliomas (96 Grade 3, 105 Grade 2, 45 Grade 1, 192 unknown). Molecular subtypes include IDH (129 mutated, 651 wildtype, 253 unknown), 1p/19q (94 deleted or co-deleted, 135 intact, 804 unknown), MGMT promotor (216 methylated, 110 partially methylated, 321 unmethylated, 383 unknown), EGFR (125 amplified, 248 not amplified, 660 unknown), ATRX (41 mutated, 238 retained, 754 unknown), Ki-67 (726 known, 307 unknown) and p53 (639 known, 394 unknown). Classification of gliomas between grade 3/4 and grade 1/2, yielded AUC of 0.85.

CONCLUSION

We developed a method for incorporation of volumetric segmentation, feature extraction, and classification that is easily incorporated into neuroradiology workflow. These tools allowed us to annotate over 100 gliomas per month, thus establishing a proof of concept for rapid development of annotated imaging database for AI applications.
P13.09.B FULLY AUTOMATED BRAIN METASTASES SEGMENTATION USING T1-WEIGHTED CONTRAST-ENHANCED MR IMAGES BEFORE AND AFTER STEREOTACTIC RADIOSURGERY
Authors: Kanakarajan H , De Baene W , Verhaak E , Hanssens P , Sitskoorn M
Published: September 2023

BACKGROUND

Brain metastases (BM) represent the most common intracranial tumor in adults. An estimated 20% of all patients with cancer will develop BM. Stereotactic Radiosurgery (SRS) is a major treatment option for BM. For SRS treatment planning and outcome evaluation, magnetic resonance images (MRI) are acquired before and at multiple stages during the follow-up. Accurate segmentation of brain tumors on MRI is crucial for treatment planning and response evaluation. Detection and segmentation of BM which is a tedious and time-consuming task for many radiologists could be optimized with machine learning

METHODS

. The accuracy of the auto-segmentation, however, is influenced by the presence of false-positive and false-negative segmentation. There are studies which evaluated the segmentation performance of several deep learning algorithms, these were mainly focused on training and testing the models on either the pre-treatment or post-treatment images. The purpose of this study was to investigate a well-known deep learning approach (nnU-Net) for BM segmentation and to evaluate its performance on both pre-treatment and post-treatment images to assess if it could be a handy tool for the clinicians.

METHODS

Pre-treatment T1-weighted brain MRIs which were contrast-enhanced with triple-dose gadolinium were collected retrospectively for 266 patients with BM. Scans were made as part of clinical care at the Gamma Knife Center of the Elisabeth-TweeSteden Hospital (Tilburg, the Netherlands). All patients underwent Gamma Knife Radiosurgery, a form of SRS. This total of 266 patients were randomly split into 210 patients for model training/validation and 56 patients for testing. For these 56 patients used for testing, the post treatment follow-up T1-weighted brain MRI scans which were contrast-enhanced with single-dose gadolinium were also retrospectively collected. The nnU-Net model was trained with the pre-treatment training data, and then tested separately against the pre-treatment and follow-up data.

RESULTS

The model obtained a Dice score of 0.91 when tested with the pre-treatment images and a Dice score of 0.80 when tested with the follow-up after treatment T3 images. The False Negative Rate (FNR) when tested with the pre-treatment images was 0.07 and 0.24 when tested with post-treatment T3 images.

CONCLUSION

The model achieved a good performance score for pre-treatment images. The nnU-Net model can automatically detect and segment brain metastases with high sensitivity, and low FNR for treatment planning. This could be a beneficial tool for clinicians and assist SRS management for diagnosis and treatment planning. Though there is a decline in the Dice score and an increase in the FNR of the model for the post-treatment images, the performance still remained higher than in other similar studies.
P13.11.B CLINICAL-RADIOMICS MODEL FOR LOW-GRADE GLIOMA SURVIVAL PREDICTION
Authors: Neimantaite A , Carstam L , Gómez Vecchio T , Dunås T , Häggström I , Smits A , Jakola A S
Published: September 2023

BACKGROUND

Low-grade gliomas are by the latest WHO classification exclusively IDH-mutated tumors, and are further divided into astrocytomas (1p19q non co-deleted) and oligodendrogliomas (1p19q co-deleted). Radiomics, that is extraction of mathematical features of images, has prognostic potential and the method is able to capture properties of whole tumors, in contrast to typical biological samples. Our aim was to investigate how a radiomics prognostication model performs in relation to a clinical prognostication model for IDH-mutated tumors.

MATERIAL AND METHODS

143 cases (71 astrocytomas and 72 oligodendrogliomas) were included in the analysis. Median follow-up time was 75 months. The data was divided in training and test set with 70:30 ratio. Four different radiomics models were investigated including image features extracted from tumor and peritumor zones respectively.

RESULTS

Preliminary results have shown best radiomics model performance for prognostication purposes in IDH-mutated tumors were based on the peritumoral zone 0-10 mm around the segmented tumor. This model resulted in a c-index of 0.88 on training set and 0.76 on test set in explaining the overall survival when the cohort of IDH-mutated tumors were analyzed together. The model will also be evaluated in the molecular subgroups and on an external test set, and finally compared to a clinical model.

CONCLUSION

Our findings will identify the top features in radiomics prognostication of IDH-mutated tumors, and also provide important data on the best area for radiomics extraction in these cases. The clinical implications of our findings will show whether radiomics adds additional value to the clinical model of low-grade glioma prognostication.
P14.06.A GLIOMA ESPIONAGE: UTILIZING CSF PROTEOMICS FOR PHARMACODYNAMIC BIOMARKER DISCOVERY
Authors: Riviere-Cazaux C , Carlstrom L , Munoz-Casabella A , Andersen K , Ikram S , Warrington A , Burns T
Published: September 2023

BACKGROUND

Cerebrospinal fluid (CSF) is emerging as an abundant source of candidate biomarkers, including proteins, for gliomas. Longitudinal CSF access may enable insights into treatment response and resistance. To that end, we have established a growing biobank of CSF samples, many of which have been obtained longitudinally via CSF access devices, such as Ommaya reservoirs, through our ongoing biomarker discovery clinical trials (NCT04692337, 04692324). We have previously presented our initial data demonstrating a conserved proteomic signature of HGG that decreased with resection and increased with recurrence. Since then, samples have been acquired throughout individual patients’ treatments toward our goal of identifying CSF-derived biomarkers of treatment response.

MATERIAL AND METHODS

CSF samples obtained prior to, during, and throughout treatment underwent global proteomics analysis via the SomaScan® assay by Somalogic, which uses slow off-rate modified aptamers to sensitively detect over 7,000 proteins. Fold-changes for each protein were calculated between different timepoints for each patient and ranked based on the comparison of interest. Comparisons included prior to versus after resection, chemoradiation or adjuvant temozolomide (each with or without pembrolizumab), bevacizumab, and low versus high blood contamination.

RESULTS

Treatment with pembrolizumab alone resulted in increased IL-23 (5.01x), IL-12 (4.25x), lymphocyte activation gene 3 protein (LAG3) (3.26x), and granzyme A (2.93x). Chemoradiation, with or without pembrolizumab, consistently downregulated NAD kinase, acetyl CoA transferase, and Bcl-2 and upregulated proteins related to neuronal signaling, such as neurexins and cerebellins, in addition to LAG-3, suggesting potential for synergy between chemoradiation and anti-LAG-3 antibodies currently in clinical trials. Interestingly, pembrolizumab and chemoradiation decreased MMP-12 and MMP-9 abundance as compared to chemoradiation alone (0.25x vs. 18.5x; 0.54x vs. 4.99x). Finally, bevacizumab treatment consistently increased VEGF (7.32x), GFAP (3.38x), and MMP-3 (2.99x) abundance, while decreasing the presence of our previously reported plasma-associated protein signature in CSF, suggesting decreased blood-brain barrier disruption.

CONCLUSION

The global CSF proteome can be longitudinally accessed to evaluate response to standard-of-care and experimental therapies. Further studies are ongoing to identify signatures of therapeutic resistance and to assess the impact of novel immunotherapeutic combinations on the CSF proteome.
P15.11.B POSTOPERATIVE68GA-DOTATATE/PET-CT IMAGING IS PROGNOSTIC FOR PROGRESSION-FREE SURVIVAL IN MENINGIOMA WHO GRADE 1: A PROSPECTIVE SINGLE-CENTER STUDY
Authors: Teske N , Biczok A , Quach S , Dekorsy F J , Forbrig R , Bodensohn R , Niyazi M , Tonn J , Albert N L , Schichor C , Ueberschaer M
Published: September 2023

BACKGROUND

Microsurgical tumor resection represents the first-line treatment for symptomatic meningiomas, and extent of resection has been shown to be of prognostic importance. Assessment of tumor remnants with somatostatin receptor PET proves to be superior to intraoperative estimation with Simpson grading or MRI. However, prognostic relevance of postoperative PET for progression-free survival in meningiomas remains unclear.

METHODS

We conducted a prospective study including patients with surgically removed meningioma WHO grade 1 and collected clinical and imaging data. All patients received postoperative MRI and 68Gallium-DOTATATE/PET, and were followed regularly with MRI surveillance scans for detection of tumor recurrence/progression.

RESULTS

We included 46 patients with 49 tumors. Mean age at diagnosis was 57.8 ± 1.7 years with a male-to-female ratio of 1:1.7. Local tumor progression occurred in 7/49 patients (14%) after a median follow-up of 52 months. Positive PET was associated with an increased risk for progression (*p = 0.015) and a lower progression-free survival (*p = 0.029) whereas MRI was not. 20/20 patients (100%) with negative PET findings remained recurrence-free. Location of recurrence/progression on MRI was adjacent to regions where postoperative PET indicated tumor remnants in all cases. Gross tumor volumes were higher on PET compared to MRI (*p = 0.032).

CONCLUSION

Our data show that 68Ga-DOTATATE/PET is highly sensitive in revealing tumor remnants in patients with meningioma WHO grade 1. Negative PET findings were associated with a higher progression-free survival, thus improving surveillance. In patients with tumor remnants, additional PET can optimize adjuvant radiotherapy target planning of surgically resected meningiomas.
P15.12.A BIUX2X2
Authors: Gromova E , Smirnova A , Kataeva G , Plakhotina N
Published: September 2023

BACKGROUND

Brain metastases occur in 20-40% of cancer patients. In connection with the development of radiosurgical treatment, the problem of differential diagnosis of continued tumor growth and post-radiation changes becomes relevant. The main method of radiosurgical treatment of secondary lesions is the Gamma-Knife. Positron emission tomography with 11C-Meth and 18F-FET is an important method in monitoring the treatment of patients with secondary brain tumors.

MATERIAL AND METHODS

We examined 73 patients with brain metastases. Of these, 36.36% were patients with breast cancer, 39.39% were patients with lung cancer, 9.00% were patients with melanoma, 6.06% were patients with kidney cancer, 9.09% were other nosology, which corresponds to the data on the frequency of metastasis to the brain of various types of cancers. All patients underwent MRI with standard sequences (T1, T2, FLAIR, T1+C) and PET-CT with 18F-FET. PET-CT was performed according to the standard protocol: scanning 20 minutes after the

INTRODUCTION

of the radiopharmaceutical, scanning time 20 minutes. The evaluation of PET images was carried out by a semi-quantitative method - TBR max.

RESULTS

The mean age of patients with breast cancer was 54.5 ± 10.4, which significantly differs from the mean age of patients with lung cancer (65.9 ± 8.7) and the mean age of patients with other primary cancers (62.8 ± 8, 8) (Kruskal-Wallis test: H(2, N=66)=13.99052 p=.0009). Differences in TBR max and the number of metastases in these groups are not significant, as well as, according to the Kaplan-Meier analysis, differences in the duration of the relapse-free period. However, differences in the duration of the relapse-free period in the groups after a single ( Median, Q1; Q3) (12.9, 10.5; 24.4) or multiple (7.5, 3.5; 10.5) radiosurgical treatment are significant ( Gehan's Wilcoxon Test, Test statistic = 2.063905 p = .03903). Based on the analysis of the data obtained, it was found that the threshold value TBR max >=2.8 in 100% of cases indicates progression, TBR max <=1.7 indicates a stable course. Whereas TBR max in the range from 1.7 to 2.8 (in 33 people from the examined group, i.e. in 50% of all cases) may indicate both progression and post-radiation changes, as well as confirmed positive dynamics.

CONCLUSION

Thus, we confirmed that the numerical value of TBR max is a relative indicator. And when interpreting PET data, we cannot rely only on the TBR max value in the range from 1.7 to 2.8 for a confident judgment about the genesis of increased RP uptake in tumors. In the absence of other markers of the development of progression (for example, the appearance of new pathological foci), to assess the dynamics and confidently identify post-radiation changes, a repeat PET study should be prescribed after 2-3 months with a preliminary MRI with contrast enhancement.
P15.14.A DIFFERENTIATE TREATMENT EFFECTS FROM DISEASE PROGRESSION IN TREATED BRAIN TUMOR: PROMISING RESULTS USING DELAYED CONTRAST MRI
Authors: Navarria P , Pessina F , Bellu L , Politi S , Savini G , Clerici E , Marini B , Scorsetti M
Published: September 2023

BACKGROUND

Treatment effects are reported in about 30% of treated glioma and brain metastases (BMs) characterized by increasing volume of contrast enhancing regions on MRI, similarly to tumor progression. Data interpretation are often difficult. The most methodology used to distinguish this 2 conditions is perfusion MRI; treatment effects are characterized by a decreased relative cerebral blood volume (rCBV) while persistent or progressive tumors by high rCBV. Limits of perfusion MRI are represented by overlap between two conditions, low spatial resolution, and presence of susceptibility artifacts. To overcome this crucial issue, encouraging results have been obtained using delayed contrast MRI that through contrast clearance analysis (CCA) allows to calculate high resolution maps called “treatment response assessment maps” (TRAMs). We prospectively evaluated patients with doubtful framework between treatment effects (TE) and tumor progression (TP) aiming to assess the ability of CCA in differentiate this two conditions in a cohort of treated brain tumor patients.

MATERIAL AND METHODS

Maps (TRAMS) were calculated through contrast clearance analysis (CCA) by subtracting ceT1MRI images acquired 5 minutes after contrast injection from images acquired at least 60-105 minutes after. Diagnosis of persistent tumors or disease progression was based on presence of contrast clearance (CC) region in blue, and treatment effects on contrast accumulation (CA) region in red. Data of CCA were compared to perfusion MRI. All images were uploaded, co-registered and elaborate into the image workstation of Brainlab. Whole tumor and enhancing tumor volumes were segmented and perfusion measures in area of signal alteration. TRAMs were generated and at last the calculation of effective volume of viable tumor tissue (CC region) and treatment-induced tissue changes within each lesion (CA region) have been calculated.

RESULTS

From February 2021 and November 2022, 62 patient (96 delayed-contrast-MRI) with doubtful framework between TE and TP underwent CCA and perfusion-MRI. Twenty-five treated for newly diagnosed glioma, 13 for recurrence, and 37 for BMs. Significantly increased rCBV value in CC regions compared to CA was observed (p=0.01). Patients with TP showed significantly greater CC that subjects with stable disease/partial response 33% vs 78% (p=0.01). TRAMs metric were in agreement with perfusion results. Greater accuracy of TRAMs compared to perfusion-MRI in discriminate TE from TP 81% vs 69% has been observed.

CONCLUSION

In our experience CCA tool compared to perfusion MRI had a greater accuracy in discriminating true tumor progression from treatment induced tissue changes, and can be of improvement in patient management.
P16.01.A THE CASE OF AGGRESSIVE DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMOR IN ADULT TREATED WITH CRANIOSPINAL IRRADIATION AND TEMOZOLOMIDE
Authors: Hwang J , Lee C , Yoon S , Kim M , Park K , Park S
Published: September 2023

BACKGROUND

Diffuse leptomeningeal glioneuronal tumor (DLGNT) is a rare tumor, which was introduced as a separate entity in the 2016 World Health Organization classification of central nervous system tumors. It is most common in pediatric age, but very rare in adults. Literature demonstrates limited reports regarding treatment strategy in adult. We present a case of young female affected by DLGNT with aggressive behavior.

MATERIAL AND METHODS

A 28-year-old woman presented with severe headache and vomiting. Brain MRI showed diffuse leptomeningeal enhancement with hydrocephalus. At first, she was under suspicion of tuberculosis meningitis with mild increased protein level in CSF study. Her symptom rapidly improved after ventriculoperitoneal shunt and she started anti-tuberculosis medication. Despite 8-month of medication, her neurological status gradually deteriorated with paraparesis and follow-up MR images showed progression of disease. She underwent open biopsy of superficial brain lesions.

RESULTS

Intraoperatively, multiple nodular masses were attached inner side of dura mater and diffuse adhesion on subarachnoid space of brain surface. Histological examination revealed small round cells with oligodendroglial-like aspects. Immunohistochemistry showed positivity for Olig2, synaptophysin and S100. Chromosome 1p deletion was confirmed by FISH. Next-generation sequencing profile disclosed mutation of H3K28M, FGFR1 and ATRX. Diagnosis was consistent with DLGNT. She received craniospinal irradiation of 36 Gy in 20 fractions, then started chemotherapy with temozolomide (TMZ) at a dose 200mg/m2/day for 5 days in 4 weeks. After 4 cycles of TMZ, MR images demonstrated stable disease.

CONCLUSION

DLGNT is a very rare tumor in adult. Diagnosis needed high level of suspicion and histological confirmation. We present a very rare adult DLGNT patient with aggressive clinical features who showed stable state treated with craniospinal irradiation and TMZ chemotherapy.
P16.03.A DEVELOPMENT OF INTRATHECAL DRUG DELIVERY PLATFORM TO CURE BREAST CANCER LEPTOMENINGEAL DISEASE BY DENDRITIC CELL VACCINE IN PRECLINICAL MODEL
Authors: Law V , Snyder C , Macaisa L , Garg S , Czerniecki B , Forsyth P A
Published: September 2023

BACKGROUND

Leptomeningeal disease (LMD) is a rare form of metastasis in the meninges, a membrane surrounding the brain and spinal cord. Approximately 5% of advanced stage breast cancer (BC) will develop LMD and currently there is no cure. One reason for poor prognosis is the issue of drug accessibility to tumor sites due to the blood brain barrier (BBB) and blood-cerebral spinal fluid (CSF)-barrier. While the Ommaya reservoir is used clinically to overcome this challenge, there has not been an optimized preclinical model that allows researchers to adequately test novel therapies in the CSF space.

MATERIAL AND METHODS

The Forsyth lab have recently developed an MRI-compatible device called the “murine Ommaya” which mimics the Ommaya reservoir and allows repeated intrathecal (IT) administration of drugs in 3-7μl volume directly into CSF, bypassing BBB. In a joint effort with Dr. Czerniecki, whose lab have developed a pipeline for screening immunogenic MHC class II peptides from tumor-associated oncodrivers and subsequently generating tumor-targeting dendritic cells (DC), we have created a platform to IT deliver peptide-pulsed DCs directly targeting BC-LMD.

RESULTS

Currently, we have tested the efficacy of treatment in HER2+ LMD and triple negative breast cancer (TNBC) LMD models and found a very favorable response; LMD mice that received IT DC therapy exhibited reduced tumor burden and prolonged survival, and is more superior than systemic therapy. About 70% of mice from HER2+ LMD and 30% from TNBC LMD were cured of disease. Cured mice also exhibited resistance against LMD recurrence.

CONCLUSION

Our preliminary data suggest IT DC immunotherapy is effective against the incurable BC-LMD. We are currently investigating the mechanism(s) by which IT DC-initiated CD4 Th1 adaptive immune response against LMD. By using single-cell RNA-sequencing technique, we are analyzing the immune landscape in CSF tumor microenvironment in response to IT DC. FDA-approved phase I clinical trial has been funded by the US Department Of Defense. Future approach includes employing our IT DC vaccine platform in other cancer types, such as LMD from melanoma.
P17.03.A MAGIC-G1: A PHASE 1 DOSE-ESCALATION TRIAL OF WEEKLY INTRATUMORAL ADMINISTRATION OF THE SOLUBILISED FORMULATION OF PANOBINOSTAT (MTX110) IN PATIENTS WITH RECURRENT GLIOBLASTOMA (RGBM)
Authors: Desjardins A , Barnes H , Davies R , Grant G , Cavaliere R , Sauvageau E , Zamoryakhin D
Published: September 2023

BACKGROUND

One of the biggest challenges in treating rGBM is achieving high local drug concentration. Convection enhanced delivery (CED) is a ‘direct-to-brain’ drug delivery method that previously demonstrated its usefulness in overcoming the blood-brain barrier, while also limiting systemic toxicity. MTX110 (Midatech Ltd), a water-soluble formulation of panobinostat, has demonstrated cytotoxic activity in GBM cell lines, as well as safety and efficacy in two pediatric diffuse pontine glioma trials. Delivery of MTX110 via an implanted pump and CED catheter system in patients with GBM appears to be an attractive treatment option, that allows for therapeutic doses of the drug to be delivered weekly directly to the tumor, thus avoiding systemic administration and therefore toxicity.

MATERIAL AND METHODS

Eligibility includes adult rGBM patients with a single enhancing lesion ≤3cm in maximal diameter; ≥4 weeks after chemotherapy, bevacizumab, or study drug; adequate organ function; and KPS ≥60%. MTX110 is continuously infused over 48hrs weekly at a rate of 0.5mL/h, via a CED catheter implanted into the enhancing disease recurrence connected to a fully internalized pump system. After safety of a single patient treated at 60μM has been established, 3-6 patients will be treated with MTX110 at 90μM as a single agent (Cohort 1). Patients in cohort 2 will receive MTX110 in combination with lomustine at a starting MTX110 dose of 60 μM and following the same dose-escalation approach.

RESULTS

As of March 30, 2023, the 1st patient was treated in monotherapy at 60μM and has received 12 weekly infusions of MTX110. No dose-limiting toxicities were observed. Observed study related adverse events (AEs) included: grade 1 cognitive disturbance, headache, and seizure; grade 2 candida wound infection, erythema of the scalp, bruising, and hemiparesis; and grade 3 abdominal seroma at pump insertion site. Enrolment is ongoing and the next patient will receive the 90 μM dose.

CONCLUSION

Weekly intratumoral administration of MTX110 via a fully internally implanted CED pump system is feasible. Updated results will be presented.
P17.07.A REGORAFENIB IN RECURRENT GLIOBLASTOMA PATIENTS: AN ITALIAN OBSERVATIONAL, MULTICENTRIC AND PROSPECTIVE TRIAL (REGOMA-OSS)
Authors: Caccese M , Padovan M , Desideri I , Villani V , Simonelli M , Buglione M , Chiesa S , Franceschi E , Gaviani P , Stasi I , Caserta C , Brugnara S , Lolli I , Bennicelli E , Bini P , Cuccu A , Cerretti G , De Salvo G , Lombardi G
Published: September 2023

BACKGROUND

In the randomized phase 2 REGOMA trial, regorafenib has shown promising activity in recurrent glioblastoma patients with a significantly longer survival compared to the standard lomustine therapy. Subsequently, in Italy regorafenib was approved as second-line therapy by the Italian Medicines Agency. We performed a large multicenter, prospective and observational study to confirm REGOMA data in the real-world setting.

METHODS

Based on the REGOMA results, at least 150 patients had to be enrolled to estimate a 1-year survival rate with a precision of 7.8% and a confidence interval of 95%. Major inclusion criteria were: histologically confirmed diagnosis of glioblastoma according to WHO 2016, radiologically documented first relapse/progression after Stupp treatment, good performance status (ECOG PS 0-1), adequate hepatic and hematological function, stable or decreasing corticosteroid use within 7 days before starting regorafenib.Regorafenib has been administered at the standard dose of 160 mg/die for 3 weeks on/1 week off, until disease progression or unacceptable toxicity. Brain MRI has been performed within 14 days before starting regorafenib and then every 8-12 weeks. Primary endpoint is overall survival. Secondary endpoints include: progression-free survival, objective response rate, toxicity and quality of life. RANO criteria is used for response evaluation, CTCAE v. 5.0 for adverse events, EORTC QLQ-C30 and brain module BN20 for quality of life. Recruitment started in September 2020 and finished in October 2022. 191 recurrent glioblastoma patients were prospectively enrolled from 29 cancer centers in Italy: median age was 59 years (IQR 52.6-66.9), 68% male and 32% female, ECOG PS was 0 in 84 (44%), 115 pts (60%) undertook steroids at baseline. MGMT was methylated in 43% and IDH1/2 was wild-type in 92% of patients. The results from this large multicenter Italian study are expected in the second half of 2023.
P17.10.B VOLUMETRIC DIFFERENCES IN TARGET DEFINITON OF RECURRENT HIGH-GRADE GLIOMAS USING CONTRAST ENHANCED MRI VS.[18F] FDOPA PET IN RADIOSURGICAL PLANNING
Authors: Obad N , Tveiten Ø , Biermann M , Brekke J
Published: September 2023

BACKGROUND

Radiosurgical treatment of high-grade gliomas usually bases target definition on contrast-enhanced T1-weighted MRI images. Despite advances in several MRI techniques, a number of limitations exist, primarily due to the disruption of the blood-brain barrier, making the target delineation less accurate, particularly when treating recurrences. Several studies support the use of amino acid PET/MRI in distinguishing progression from post-operative/post-radiation inflammation. However, no established guidelines define the biological target volume when using amino acid PET/MRI in radiosurgical treatment planning. We aimed to explore the volumetric differences in target volumes obtained with standard contrast-enhanced MRI versus [18F]FDOPA PET in patients with recurrent high-grade gliomas (rHGG).

MATERIAL AND METHODS

Ten patients obtained [18F]FDOPA PET/MRI within 1 week before radiosurgical treatment. We co-registered these images with the 3D MPRAGE-MRI typically used for stereotactic target definition and performed a follow-up PET/MRI scan 4-6 weeks after treatment. We reviewed and compared the method of tumor delineation, target volumes, and stereotactic accuracy in both modalities.

RESULTS

Radiosurgical treatment delivers high radiation doses to defined targets. The target volume and the proximity to eloquent structures limit the dose, thus depending on high-accuracy imaging. The invasive nature of malignant brain tumors makes anatomical delineation insufficient, particularly when treating recurrences. In such cases, amino acid PET supplies additional information. However, the spatial resolution afforded by [18F]FDOPA uptake alone is insufficient for stereotactic definition, which to a large degree is based on contrast-enhanced T1-weighted MRI images in order to achieve the sub-millimeter resolution needed for radiosurgical planning. Hybrid PET/MRI allows the combination of metabolic information of [18F]FDOPA-PET with the anatomical precision of stereotactic MRI. In the recurrent setting, [18F]FDOPA-PET supplies the necessary information for targeting the biologically active tumour, differentiating it from radiation necrosis, thus limiting the target volumes. This enables us to treat the recurrent tumours more efficiently.

CONCLUSION

[18F]FDOPA-PET is a useful supplement in radiosurgical planning and treatment of rHGG. It is helpful in the delineation of the biologically active tumor, thus limiting the target volume significantly. This enables higher radiation doses and potentially more efficient treatment. Further results will be presented.