bluuebunny/crossref_metadata_2025 huggingface dataset:
DDDR-32. A NEW IMMUNOMODULATORY FUNCTION OF PYRIDO-PYRIMIDINE DERIVATIVES TO IMPAIR METASTATIC GROUP 3 MEDULLOBLASTOMA IN VIVO
Authors: Zollo Massimo , Asadzadeh Fatemeh , Ferrucci Veronica , De Antonellis Pasqualino , Bibbò Francesca , Siciliano Roberto , Sorice Carmen , Criscuolo Giuseppina , Filiz Dalim Kardelen , Tecik Melisa , Amente Stefano , Saccà Carmen Daniela , Gorini Francesca , Pedone Emilia , Diana Donatella , Pirone Luciano , Fattorusso Roberto , Navas Luigi , Donofrio Vittoria , Errico Maria Elena , Spennato Pietro , De Martino Lucia , Quaglietta Lucia , Tirone Felice , Cinalli Giuseppe
Published: November 2022

Medulloblastoma (MB) is an embryonal tumor of the cerebellum constituting ~ 20% of pediatric brain tumors. To date, four MB molecular groups (further stratified in twelve subtypes) have been described. Among them, Groups 3 and Group 4 MB have the poorest prognosis due to their high metastatic potential. Recently, we have reported a metastatic axis driven by Prune1 overexpression in MB Group3 characterized by canonical TGF-β signaling enhancement and epithelial-mesenchymal transition. Here, we have developed a new not toxic pyrido-pyrimidine derivative with the ability to impair Prune-1-driven-axis, thus ameliorating the survival rate of a murine model of metastatic MB Group3 characterized by overexpression of human Prune1 gene in the cerebellum (under the control of MATH1 promoter). Of importance, this small molecule also is showing immunomodulatory functions thus inhibiting the conversion of tumor-infiltrating T lymphocytes (TILs) to immunosuppressive regulatory T cells (Tregs) in vivo via impairing the secretion of inflammatory cytokines from MB cells. Furthermore, this molecule can also act synergistically with the currently used modified-intensity chemotherapy (e.g. in PNET5 use of Vincristine) or potential in the combination with epigenetics drugs (e.g., LSD1/KDM1A inhibitors). Altogether these results are of importance for future targeted therapies of high-risk metastatic MB. Acknowledgments: We thank for funding support: the Italian Association for Cancer Research (AIRC) Grant IG no. 22129 (M.Z.) and Lazio Innova Grant n. 85-2017-14785 (FT; MZ)
EPID-10. SEIZURE CONTROL BY BEVACIZUMAB IN GLIOBLASTOMA PATIENTS
Authors: Hertler Caroline , Seystahl Katharina , Le Rhun Emilie , Wirsching Georg , Roth Patrick , Weller Michael , Gramatzki Dorothee
Published: November 2022

Seizures are a frequent symptom in patients with glioblastoma and bear a relevant impact on quality of life. Likewise, anti-epileptic treatment may affect patients’ well-being due to side effects. Here, we assessed whether owing to relieve from edema and intracranial pressure, treatment with bevacizumab for recurrent glioblastoma might contribute to seizure control.We retrospectively analyzed clinical data of adult patients with glioblastoma who were treated with bevacizumab versus a non-bevacizumab-containing regimen for first recurrence of glioblastoma in the Canton of Zurich between 2010 and 2014 and assessed occurrence and dynamics of seizures before and after first recurrence. Categorical and continuous variables were compared by the Chi-square and the Mann-Whitney U test, respectively. Associations of clinical parameters and seizures were analyzed by binary logistic regression.We identified 55 patients with glioblastoma who had received bevacizumab and 61 patients that received a non-bevacizumab-containing regimen at first recurrence. Seizures were noted in 42 of 111 patients (37.8%) during the 12 weeks preceding tumor recurrence. In the non-bevacizumab group, 23 patients (39.0%) still suffered from seizures 3 months after recurrence whereas only 4 patients (7.7%) in the bevacizumab group experienced seizures (p < 0.001). Multivariable binary logistic regression analyses, including sex, age, performance status, extent of resection, O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status and first-line treatment confirmed bevacizumab to be inversely associated with seizures in the 12 weeks after first recurrence (odds ratio (OR) 0.23, 95% confidence interval (CI) 0.06-0.94, p = 0.009).Bevacizumab may contribute to a reduction in seizure frequency in patients with recurrent glioblastoma.
EPCO-18. UNSUPERVISED MACHINE LEARNING ON TUMOR IMMUNE TRANSCRIPTOMIC DATA REVEALS DISTINCT IMMUNOLOGIC SUBTYPES OF GLIOBLASTOMA
Authors: Haddad Alexander F , Chen Jia Shu , Perera Sudheesha , Reddy Anvith , Ambati Vardhaan , Aghi Manish
Published: November 2022

Glioblastoma (GBM) has demonstrated a limited therapeutic response to single-agent immunotherapies, highlighting the need for a better understanding of GBM tumor immune phenotypes to inform targeted immunologic treatments. To elucidate GBM immunologic phenotypes we performed unsupervised machine learning on microarray transcriptomic data from 815 newly diagnosed GBM patients. We utilized immune genes only and performed k-means clustering for k=2-10 with within-cluster sum of squares and silhouette methods used to identify the optimal number of clusters. Identified subtypes were further characterized using xCell to estimate the tumor infiltration of 64 immune and stromal cell types. Two primary immunologic subtypes were identified: subtype 1 (423 patients) and subtype 2 (392 patients). There was no difference in patient age (mean age 58 years) or gender between subtypes. Subtype 1 was primarily classical subtype GBMs (50.5%, p< 0.001), while subtype 2 was composed of primarily mesenchymal subtype GBMs (74.2%). Relative to subtype 1, subtype 2 was characterized by high expression of immune checkpoint and co-stimulatory proteins, including CD86, OX40L, IDO1, and LAG3. Subtype 2 also had increased activation of immune genes associated with cytolytic activity and antigen processing. In addition, subtype 2 had increased infiltration of M2 macrophages, monocytes, dendritic cells, and neutrophils while subtype 1 had higher infiltration of CD8 naïve T cells. Multivariate logistic regression confirmed that subtype 2 was characterized by monocytes, M1 and M2 macrophages, neutrophils, and dendritic cells while subtype 1 was characterized by CD8 naïve T cells, regulatory T cells, and naive B cells. Subtype 2 had reduced progression-free survival, but there was no difference in overall survival between the two subtypes. In summary, unsupervised machine learning of GBM immune transcriptomic data identified two immune phenotypes, one of which was more immunologically active than the other, potentially informing future personalized immunotherapy treatments.
IMMU-02. STANDARDIZATION OF THERAPY AND MANUFACTURING USING TUMOR-ASSOCIATED ANTIGEN-STIMULATED AUTOLOGOUS DENDRITIC CELLS CO-CULTURED WITH CYTOKINE-INDUCED KILLER CELLS IN CANCER IMMUNOTHERAPY
Authors: Yen Chun-Ming , Fu Yun-Yen
Published: November 2022

BACKGROUND

The application of DC-CIK in the field of cancer immunotherapy has been shown to be an effective treatment. However, the cost of DC-CIK treatment is prohibitive for many patients, and the lack of standard manufacturing processes and treatment strategies are the main limitations.

METHODS

Our experiments used tumor lysate instead of tumor cell line as tumor-associated antigen source with DCs co-culture. We provide the most efficient method for obtaining autologous DC-CIK cells from peripheral blood. Flow cytometry was used to evaluate DCs activation, CBA assay was used to quantify cytokines secreted by CIK cells, and the antitumor activity of DC-CIK was evaluated in vitro by K562 cell line.

RESULTS

We demonstrate that the manufacturing process of employing frozen Peripheral Blood Mononuclear Cells (PBMCs) can balance patient’s comfort and economic benefits. DC-CIK can effectively upgrade the immunological specificity of CIK cells to tumors in the presence of tumor-associated antigen. In vitro experiments showed that when the number of DC: CIK cells was co-cultured in 1:20 ratio on the 14th day, the amount of cytokine secreted by CIK cells was the largest, and the anti-tumor immune effect was the most potent. When the number of CIK: K562 cells was in 25:1 ratio, the cytotoxic activity of CIK on K562 cells was the highest.

CONCLUSION

We developed an efficient activated fashion of DC:CIK, established the optimal ratio of DC-CIK immunologic activity and the best cytotoxic model of CIK to K562 cells.
IMMU-23. ELIMINATING MONOCYTE CHEMOATTRACTION INVOKES COMPENSATORY NEUTROPHIL INFLUX AND PRONEURAL TO MESENCHYMAL TRANSITION IN GLIOBLASTOMA
Authors: Chen Zhihong , Soni Nishant , Pinero Gonzalo , Giotti Bruno , Eddins Devon , Lindblad Katherine , Ross James , Tsankova Nadejda , Gutmann David , Lira Sergio , Lujambio Amaia , Ghosn Eliver , Tsankov Alexander , Hambardzumyan Dolores
Published: November 2022

Myeloid cells comprise the majority of immune cells in tumors, where their content and composition is determined by tumor type and driver mutation. While these cells are essential for shaping the tumor microenvironment, promoting tumor growth, and contributing to therapeutic resistance, targeting tumor-associated myeloid cells, including bone-marrow-derived monocytes and neutrophils, has not been successful in the clinics. Monocyte chemoattractant protein (MCP) family, comprising of Ccl2, Ccl7, Ccl8, Ccl12, are essential for monocytes trafficking to the tumor sites. To eliminate monocyte recruitment, we leveraged CRISPR/Cas-9 based gene editing tool to generate a mouse strain that is devoid of all MCP genes, which we termed quadruple MCP knockout (qMCP-/-). Using these mice in combination with genetically engineered mouse models (GEMM) of glioblastoma (GBM), we abolished tumor monocyte infiltration. Due to the functional redundancy of MCP family members, we show that targeting individual MCP genes leads to compensation by other MCPs. In contrast, when all MCPs are genetically deleted and monocyte recruitment is abolished, neutrophil infiltration ensues. Single-cell RNA sequencing revealed that intratumoral neutrophils promoted proneural-to-mesenchymal transition in GBM, and supported tumor aggression by facilitating hypoxia response via TNF production. Remarkably, pharmacologic or genetic interventions that suppress both monocytes and neutrophil infiltration improve the survival of GBM-bearing mice. Taken together, our findings establish that specific subsets of myeloid cells can influence the dynamism of tumor microenvironment, and they emphasize the importance of targeting both monocytes and neutrophils simultaneously for effective GBM immunotherapy.
IMMU-41. VERSATILE MRNA-NANOPARTICLE PLATFORM TO REPROGRAM THE BRAIN TUMOR MICROENVIRONMENT AND PREDICT TREATMENT OUTCOME
Authors: Grippin Adam , Mendez-Gomez Hector , Wummer Brandon , Weidert Frances , Wildes Tyler , Dyson Kyle , Dobson Jon , Mitchell Duane , Sayour Elias
Published: November 2022

RNA vaccines have shown great promise as activators of immune responses against viral pathogens but their efficacy in cancer is unclear. Here, we describe a versatile, personalized mRNA-nanoparticle (RNA-NP) platform that can be customized to produce powerful anti-tumor immune activation, reprogram the brain tumor microenvironment, and predict vaccine efficacy just two days after treatment. Lipid mixtures (i.e. DOTAP, Cholesterol) with or without iron oxide nanoparticle-cores were complexed with mRNA encoding tumor antigens. Intravenous administration of RNA-NPs induced robust activation of innate immune cells resulting in prolonged survival in murine models of subcutaneous and intracranial melanoma. Inclusion of cholesterol in the lipid backbone enabled delivery of nucleic acids across the blood brain barrier and into tumor-associated myeloid cells in intracranial GL261 and KR158b tumors. These cholesterol-bearing liposomes not only activated innate immune cells in the tumor microenvironment (i.e. increased expression of CD80 and MHCII), but also enabled further manipulation of this compartment. Use of RNA-NPs to deliver siRNA targeting PD-L1 resulted in significant reduction in PD-L1 expression among tumor associated myeloid cells, leading to 37% long term survivorship in combination with systemic checkpoint blockade in an otherwise fatal model of GL261. We have also shown that IONPs incorporated into the cores of these particles enable non-invasive tracking of dendritic cells by MRI, enabling creation of a theranostic approach to: 1) enhance immunologic effects; 2) facilitate translocation across the blood-brain barrier; and 3) enable non-invasive imaging to predict response to RNA-NPs.
INNV-16. SPINAL POST-TREATMENT SURVEILLANCE IN MEDULLOBLASTOMA – A SYSTEMATIC REVIEW OF THE LITERATURE AND CLINICAL TRIALS
Authors: Park Christopher , Packer Roger , Rood Brian , Kilburn Lindsay , Bornhorst Miriam , Rossi Christopher , Fonseca Adriana , Hwang Eugene
Published: November 2022

BACKGROUND

Monitoring for dissemination in medulloblastoma involves spinal MRIs (sMRIs) and lumbar punctures (LPs). The frequency and duration of these studies vary depending on risk of dissemination; general practice varies between and within institutions. Our goal is to review the current practice in post-treatment monitoring via examination of published data, clinical trial standards, and expert practice.

METHODS

We reviewed the available literature and accessible clinical trial protocols. Using PRISMA guidelines, we conducted searches of Ovid MEDLINE, Embase, and PubMed to identify studies which detailed relapse rates and patterns, and recommended practice for patients with medulloblastoma aged 3-21 years. Eligible studies from 1990 to present were included.

RESULTS

Thirteen multi-institutional clinical trials from North America and Europe were analyzed for frequency of post-therapy surveillance with LPs/sMRIs. Several studies (n=8) recommend LPs/sMRIs every 3-6 months in standard risk and every 3 months in high risk disease for two years when initially completing therapy, and then often diverge in frequency after 2 years. Some studies (n=5) did not include post-treatment recommendations. Cumulative data on relapse from available clinical trial reports and single institution studies (n=673 relapses) demonstrated local failure rate of 18.4%, distant failure of 49.1%, and combined distant and local failure of 32.5%. Spine-only relapses were reported to occur in approximately 13-20%, with one small study reporting spine-only relapse rate of 37.5%.

DISCUSSION

Patterns of recurrence in medulloblastoma have shifted over time as therapeutic approaches have evolved, including more spinal-only recurrences. Standardized guidance regarding surveillance could have significant impact on clinical detection and streamline management to minimize unnecessary examinations. Early detection of recurrent disease could optimize treatment options for providers and families, whether focusing on curative approaches or quality of life.
INNV-22. A CASE REPORT OF MULTIPLE LESIONS DISAPPEARING AFTER TMZ+TTFIELDS+ DARAFENIB AND TRAMETINIB IN A PATIENT WITH GBM
Authors: Cai Boning , Ma Xiaodong , Qu Baoling
Published: November 2022

A 44-year-old female patient developed the disease with left visual field defect in both eyes. Brain MRI on September 13, 2021, showed irregular masses in the right basal ganglia, thalamus, and hippocampus of temporal lobe, with the lesion extending to the right midbrain and right optic tract. On September 28, 2021, intraoperative total resection of lesions in right gyrus, hippocampus, thalamus and cingulate herniawas performed under nuclear magnetic navigation and electrophysiological detection. The pathological integration diagnosis result was glioblastoma, IDH wild type with TERT C228T mutation, chromosome 7 amplification and BRAF V600E mutation, WHO grade 4, MGMT non-methylation, postoperative visual acuity same as before. Based on the protocols and data of the clinical trials that have been conducted, and the safety of simultaneous use of TTFields during radiotherapy is controllable and patients can benefit, we started the follow-up treatment: standard TMZ (75mg/m2/d), combined with TTFields and retaining the transducer arrays placed on the shaved scalp. The dose of 60/54Gy, 30 times was selected. The application time of TTFields was relatively long throughout the radiotherapy period, and patient compliance was good, with treatment duration of about 20 hours per day. One month after conventional radiotherapy, reexamination indicated that local T1 enhanced hypersignal and PWI showed hyperperfusion. The methionine PET suggested that tumor activity might still exist. We found that the BRAF V600E mutation may provide therapeutic benefit, so this patient was treated with TMZ (standard 5/28 regimen) +TTFields+ Darafenib and Trametinib. Nearly two months after the follow-up treatment, a re-examination found a remarkable phenomenon, the multiple lesions disappeared. At present, the patient continues to be treated with TTFields for a relatively long time, and the skin side effects are only grade ONE. The combination of TTFields with targeted agents and chemotherapy brought clinical benefit to the patient with manageable adverse reactions.
INNV-29. MULTISPECTRAL ANALYSIS FOR INTRA-OPERATIVE CHARACTERIZATION OF BRAIN TUMOURS, MARGINS OF RESECTION, AND ELOQUENT AREAS ACTIVATION – PRELIMINARY RESULTS
Authors: Anichini Giulio , Zepeng Hu , Leiloglu Maria , Gayo Iani , Patel Neekhil , Syed Nelofer , Nandi Dipankar , O’Neill Kevin , Elson Dan
Published: November 2022

BACKGROUND

The identification of intrinsic brain tumours’ boundaries and their anatomical relationship with eloquent connectomes is one of the main challenges in neurosurgery. Several new intra-operative spectroscopic technologies have been recently investigated for this purpose. Multispectral imaging (MSI) analysis is based on analysis of reflected light, divided in specific wavelengths ranges across the electromagnetic spectrum. By doing so, it can identify wavelengths invisible to the naked eye, and make them visible by applying specific filters.

METHODS

We have used MSI to acquire intraoperative images during brain tumours surgeries. The MSI camera has been adapted to be connected to the intra-operative microscope and acquire a stack of images of different spectra to be analysed on a separate time. The focus of the images acquisition includes tumour structure, its margins, and eloquent connectomes during awake surgery or neurostimulation to analyse the possibility of different perfusion signal during activation. Image segmentation using K-mean clustering has been used to detect structural information and identify tumour’s area and tumour’s margins, while oxygen maps have been created using linear least squares regression to detect areas of metabolic activity.

RESULTS

Twenty-three patients have been enrolled in the current study at the time of this submission. We have analysed the intra-operative acquisition using intra-operative microscope picture, pre- and post-operative MRI scan, and neurophysiological findings as ground truth. Our preliminary results show that MSI is a potential additional technology to visually show tumour core, margins, and different degree of perfusions on the tissues analysed during tumour surgery. Although on a very limited subgroup of patients, MSI seems to be reliable in identify eloquent areas activation during awake surgery. These results are promising and warrant more data acquisition to be confirmed.
INNV-31. PROTECT: PROCARBAZINE, LOMUSTINE, AND VINCRISTINE VERSUS TEMOZOLAMIDE IN HIGH-RISK, LOW-GRADE GLIOMAS: A RETROSPECTIVE COHORT STUDY
Authors: Jia Jason , Alshamsan Bader , Andronic Cristina , Fazzari Francesco , Leigh Jennifer , Shah Hely , Ng Terry
Published: November 2022

INTRODUCTION

Low-grade gliomas (LGG), specifically WHO grade 2 diffuse astrocytoma and oligodendroglioma, are increasingly considered for adjuvant chemotherapy with high-risk features (age ≥ 40y or subtotal resection). This is based on prospective studies showing improvement in survival with adjuvant procarbazine, CCNU, vincristine (PCV) or temozolomide (TMZ) in this cohort. Use of PCV or TMZ is variable without published head-to-head comparison. PROTECT is a Canadian multicentre retrospective study aiming to compare overall survival (OS) in high-risk LGGs receiving PCV or TMZ. We are presenting results from The Ottawa Hospital Cancer Centre (TOHCC).

METHODS

Patients age ≥ 18y with LGG that received PCV or TMZ within 6 months of primary brain tumor resection at TOHCC from 2005 to 2019 were included. The primary outcome is OS. Secondary outcomes include 1)time to progression (TTP), 2)rate of completion of 6 cycles of PCV or TMZ, and 3)rate of hospitalization or death due to chemotherapy-related complications.

RESULTS

Of 250 cases, 20 patients (11 diffuse astrocytoma, 9 oligodendroglioma) were eligible. IDH status was mutated in 11, wild-type in 1, and unknown in 5 cases. 1p/19q co-deletion was present in 6, non-co-deleted in 1, and unknown in 13 cases. Six patients received PCV, and 14 received TMZ. Hematologic toxicity (CTCAE Grade 1-2) occurred in 3 PCV patients and 0 of 11 of assessable TMZ patients; no severe toxicity was observed. Median follow-up was 64.5 (IQR 42.5–88) months. The median OS and TTP for PCV and TMZ groups were not reached. The 5-year OS and TTP were 75% vs. 100 % (p=0.08) and 83.3% vs 81.3% (p=0.7) respectively.

CONCLUSIONS

There are insufficient cases and follow-up time to determine OS and TTP amongst patients treated with PCV or TMZ. Hematologic toxicity appears to be more common with PCV. Patient screening and data collection is ongoing at 8 other cancer centres.
PATH-33. “GENETIC AND EPIGENETIC PROFILING IDENTIFIES TWO DISTINCT CLASSES OF SPINAL MENINGIOMAS”
Authors: Ricklefs Franz , Fita Krystian , Mohme Malte , Westphal Manfred , Lamszus Katrin , Mawrin Christian , Schüller Ulrich , Eicker Sven
Published: November 2022

BACKGROUND

Spinal meningiomas account for 1.2-12 % of all meningiomas and 25-45 % of all spinal tumours. 20 % of intracranial, but only 4.6 % of spinal meningiomas recur requiring additional treatment. Whereas the classification of intracranial meningiomas has evolved considerably in recent years and uses genetic and epigenetic parameters, the classification of spinal meningiomas is based solely on histopathological findings. By embedding epi-/genetic features, the prognosis of intracranial meningiomas could be significantly improved, which is still lacking for spinal meningiomas. In our work, we integrated genetic and epigenetic parameters into the classification of spinal meningiomas.

METHODS

We performed epi-/genetic profiling of 50 spinal meningiomas. 497 intracranial meningiomas served as a reference cohort. Copy number variations (CNV) were inferred from the methylation data. Principal component (PCA) and t-SNE analysis were conducted. Clinical and histopathological parameters (location, size, recurrence, WHO°, pathological subtype) were correlated with methylation signatures using the DKFZ brain tumour classifier.

RESULTS

The methylation signature of spinal meningiomas matched to that of intracranial meningiomas (50/50), although meningioma subgroup assignment was achieved in only 13/50 cases. PCA and t-SNE analysis showed that most spinal meningiomas separate from cranial meningiomas and form two distinct clusters. Cluster 1 matched the methylation class ben-2, while cases in cluster 2 were heterogenous and had a low MSC score. Cases of cluster 1 were located in the upper spine, are more common in males and had an AKT1E17K mutation. NF2 mutations were found mainly in the second cluster, in line with a chr.22 q loss. Interestingly 4 tumors did not associate with the two spinal meningioma clusters and had a particular higher recurrence rate.

CONCLUSION

Genetic and epigenetic profiling of spinal meningiomas identifies two distinct classes of spinal meningiomas, which may allow an improved prognosis that could lead to a better guidance for adjuvant therapy.
PATH-34. SOLITARY FIBROUS TUMOR: NATURAL HISTORY AND PROGNOSIS IN ACCORDANCE WITH THE WHO 2021 CLASSIFICATION OF CNS TUMORS
Authors: Eschbacher Kathryn , Jenkins Sarah , Fritchie Karen , Moskalev Evgeny , Caron Alissa , Link Michael , Brown Paul , Guajardo Andrew , Brat Daniel , Wu Ashely , Santagata Sandro , Louis David , Brastianos Priscilla , Kaplan Alexander , Alexander Brian , Rossi Sabrina , Ferrarese Fabio , Raleigh David , Nguyen Minh , Gross John , Vega Jose Velazquez , Rodriguez Fausto , Perry Arie , Alverez Maria Martinez-Lage , Haller Florian , Giannini Caterina
Published: November 2022

Meningeal solitary fibrous tumor (SFT) is a rare tumor with high propensity to recur and metastasize, even late in the course of disease. The WHO 2021 classification of CNS tumors divides SFT in 3 grades, based on mitotic index and necrosis. We re-examined our cohort of 126 patients (57 F, 69 M; mean age 53.0 years) with SFT, confirmed by STAT6 nuclear positivity and/or NAB2::STAT6 fusion, with extended follow-up (median 7.6 years; range 4 days-26.6 years). Tumors included 76 grade 1, 36 grade 2 and 14 grade 3 according to 2021 WHO criteria, evaluated at primary resection (n=90), recurrence (n=35), or metastasis (n=1). Fifty-six patients had one or more post-surgical events, the earliest event being local recurrence (n=41) or metastasis (n=15). Forty patients died (29 of disease; 9 of other causes; 2 unknown). Overall survival (OS), and progression-free survival (PFS, recurrence and/or metastasis) from time of primary resection (n=90) were not significantly associated with grade; however, risk of metastasis differed significantly (5-year estimates: 4.1%, 15.3%, and 37.8% for grades 1, 2, and 3 SFT, respectively; p=0.005). NAB2::STAT6 fusion status was known in 101 cases (51 = ex5-7-ex16-17, 26 = ex4_ex2-3; 12 = ex2-3_exANY/other and 12 =no fusion). Disease specific 5-year survival in primary tumors with molecular data (n = 75) was 80.0% in patients whose tumors harbored ex5-7_ex16-17 compared to 93.3% in all others combined (p=0.014). Targeted TERT promoter mutation testing was performed in 98 patients, revealing patients with tumors lacking TERT promoter mutation (n = 88) were younger at time of surgery than those harboring a mutation (n=10; p = 0.022), and none with a mutation harboring concurrent ex5-7_ex16-17 fusion (p = 0.0009). In summary, WHO 2021 grade is associated with risk of metastasis. Patients whose tumors harbor ex5-7_ex16-17 fusion have a higher risk of dying from the disease.
PATH-40. A GIANT CELL LESION RESEMBLING REPARATIVE GIANT CELL GRANULOMA WITH FN1-TEK FUSION, IN THE SPECTRUM OF CALCIFIED CHONDROID MESENCHYMAL NEOPLASM?
Authors: Kong Xiao-Tang , Movassaghi Mehrnaz , Perez-Rosendahl Mari , Choi Yoon , Yong William
Published: November 2022

A newly described entity called “calcified chondroid mesenchymal neoplasms” includes chondroid neoplasms with variable amounts of calcification and FN1 fusions [Liu et al, Mod Pathol 2021]. We report a case of a left temporal bone giant cell granuloma-like lesion that also shows an FN1-TEK fusion. Close monitoring with MRI images after surgery has showed no recurrence. Case report: a 33-year-old male developed left jaw pain and he was diagnosed with a temporomandibular joint disorder. He felt left ear fullness and 2 years later experienced severe pain and swelling in the left temporal region. Imaging showed an expansile osseous lesion with multi-cystic components involving the left sphenoid bone as well as all portions of the temporal bone including the mastoid, middle ear cavity, and glenoid fossa. Pathology showed a hemorrhagic giant cell lesion that was negative for H3G34W mutation and USP6 rearrangement, suggesting a reparative giant cell granuloma. A subsequent NGS with the Tempus 648 gene panel did not identify somatic or germline mutations, but an additional Tempus RNA fusion test found a FN1-TEK fusion suggesting the possibility of neoplasia. Close monitoring with brain MRI over past 9 months has shown no signs of recurrence.

DISCUSSION

A recent small series describes a novel entity called calcified chondroid mesenchymal neoplasm that has FN-1 fusions including a FN1-TEK fusion in one case. The case in that series with FIN1-TEK fusion also showed prominent giant cells. It is unclear whether giant cell granuloma-like lesions with FN1-TEK fusion belong in the calcified chondroid mesenchymal neoplasm spectrum or are a separate non-neoplasm entity that shares the same alteration. More studies are warranted.
PATH-47. THE CHALLENGE AND THERAPEUTIC RELEVANCE OF A NON-MATCHING CLASSIFIER OUTPUT USING GENOME-WIDE DNA METHYLATION FOR CLINICAL ROUTINE
Authors: Drexler Richard , Eckhardt Alicia , Bode Helena , Fita Krystian , Lamszus Katrin , Westphal Manfred , Dührsen Lasse , Schüller Ulrich , Mohme Malte
Published: November 2022

DNA methylation-based classification of central nervous system tumours has been increasing in importance for routine clinical workups and offers novel opportunities in discriminating subtypes which could lead to a more customized therapy. However, there are still unclassifiable entities for which defining an effective therapeutic regimen is challenging. The aim of our study was to gain further insight in these challenging cases. We included 81 patients with a calibrated score below 0.9 in the classifier output, who underwent surgery for a tumour of the central nervous system (CNS). 47 patients had a different output using the classifier version v11b4 when compared to their histological diagnosis. Of these, 41 patients (87.2 %) did not have any diagnosis from the methylation classifier (“no matching methylation class”). Surgical and clinicopathological features as well as DNA input had no impact on the calibrated score. Cases with non-classifiable tumors had a significantly longer time until a decision for adjuvant therapy and these cases were presented more often in neurooncological tumor boards (p< 0.01). Further analyses in 23 glioblastoma patients revealed comparable results for the overall survival, but a significantly shorter progression-free survival in cases with a discrepancy between the histological and classifier diagnosis. Application of the latest classifier version v12.5 enabled classification in 67.9% of cases, resulting in re-classification with a high calibrated score (> 0.9) in 25.7% of the tumors. Taken together, our study presents unclassifiable cases and the possible clinical impact when waiting for the accurate diagnosis in these challenging cases. Even though DNA methylation profiling significantly contributes to advanced CNS tumour diagnostics, clinicians should be aware of a prolonged interval to treatment initiation, especially for highly malignant brain tumours. Therefore, we would recommend to schedule adjuvant treatment as early as possible if surgical and histological results are suspicious for this disease.
NIMG-13. DEEP LEARNING-BASED AUTOMATIC DETECTION AND SEGMENTATION OF BRAIN METASTASES FOR STEREOTACTIC ABLATIVE RADIOTHERAPY USING BLACK-BLOOD MAGNETIC RESONANCE IMAGING
Authors: Kim Tae Hyung , Yoo Sang Kyun , Kim Hojin , Kim Jin Sung , Yoon Hong In
Published: November 2022

PURPOSE/OBJECTIVES

Stereotactic ablative radiotherapy (SABR) is becoming popular in the treatment of Brain metastases (BM). However, detection and manual delineation of BM are labor-intense processes, and normal blood vessels are occasionally mistaken for metastatic lesions. In this study, we investigated the efficacy and accuracy of a deep learning (DL) model for the detection and segmentation of BM using black-blood (BB) magnetic resonance imaging (MRI).

MATERIALS/METHODS

The BB MRI data of 48 patients with 806 BMs were collected to train and validate the DL model. Since MRI data have an inconsistent intensity scale across the patients, we applied piecewise linear histogram matching algorithm, also called the Nyul normalization. To deal with bias corruption in the patient, N4 bias field correction was applied. The modified U-Net was implemented to automatically detect and segment BMs. The detection performance was measured with sensitivity and average false positives and the segmentation performance was measured with the dice score (DSC).

RESULTS

Twelve patients with 132 BMs were randomly selected as the test-set for evaluating our trained model. In the test-set, 19.2% BMs had a volume of < 0.02 cc, max volume of 16.642 cc, min volume of 0.009 cc, median volume of 0.071 cc, and mean volume of 1.158 cc. The sensitivity was 96.87% and average false positives were 0.2. We consider < 0.02 cc volume as the small volume. 100% sensitivity for BMs with volumes ≥ 0.02 cc, and 84.6% sensitivity for BMs with volumes < 0.02 cc volume. The DSC was 86.27 (range, 77-91.2).

CONCLUSIONS

Our model can detect and segment BMs on BB MRI data with good detection and segmentation performance. Further study is on a way to generate a synthetic BB image from the T1-Gd image by applying this model.
NIMG-17. A DEEP LEARNING MODEL FOR DISCRIMINATING TRUE PROGRESSION FROM PSEUDOPROGRESSION IN GLIOBLASTOMA PATIENTS
Authors: Moassefi Mana , Faghani Shahriar , Conte Gian Marco , Kowalchuk Roman , Vahdati Sanaz , Crompton David , Vega Carlos Perez , Cabreja Ricardo Domingo , Vora Sujay , Quiñones-Hinojosa Alfredo , Parney Ian , Trifiletti Daniel , Erickson Bradley
Published: November 2022

INTRODUCTION

Glioblastomas (GBMs) are highly aggressive tumors. A common clinical challenge after standard of care treatment is differentiating tumor progression from treatment-related changes, also known as pseudoprogression (PsP). Usually, PsP resolves or stabilizes without further treatment or a course of steroids, whereas true progression (TP) requires more aggressive management. Differentiating PsP from TP will affect the patient's outcome. This study investigated using deep learning to distinguish PsP MRI features from progressive disease.

METHOD

We included newly diagnosed GBM patients who met the inclusion criteria, including a new or increasing enhancing lesion size within the original radiation field and who had clinical, medication, and any histopathology available. The interpretation of the MR images at the image inclusion time point had to be indeterminate. We labeled those who subsequently were stable or improved on imaging and clinically as PSP and those with clinical and imaging deterioration as TP. A subset of subjects underwent a second resection. We labeled these subjects as PSP or TP based on the histological diagnosis. We performed skull stripping, coregistered contrast-enhanced T1 MRIs with T2-weighted images for each patient and used them as input to a 3-D Densenet121 model. We used several augmentation techniques and five-fold cross-validation to achieve more robust predictions.

RESULT

We included 124 patients who met the criteria, and of those, 63 were PsP and 61 were TP. We trained a deep learning model that achieved 76.4% (ranged 70%-84%, SD 5.122) mean accuracy over the 5 folds, 0.7560(ranged 0.6553-0.8535, SD 0.069) mean AUROCC, 88.72% (SD 6.86) mean sensitivity, and 62.05%(SD 9.11) mean specificity.

CONCLUSION

We report the development of a deep learning model that distinguishes PsP from TP in GBM patients treated per the Stupp protocol. Further refinement and external validation are required prior to widespread adoption in clinical practice.
NIMG-20. INCORPORATION OF AI-BASED AUTOSEGMENTATION AND CLASSIFICATION INTO NEURORADIOLOGY WORKFLOW: PACS-BASED AI TO BUILD YALE GLIOMA DATASET
Authors: Lost Jan , Tillmans Niklas , Merkaj Sara , von Reppert Marc , Lin MingDe , Bousabarah Khaled , Huttner Anita , Aneja Sanjay , Omuro Antonio , Aboian Mariam , Avesta Arman
Published: November 2022

PURPOSE

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: 1990 patients from Yale Radiation Oncology Registry (2012-2019) were identified. Segmentations were performed using a UNETR algorithm trained on BRaTS 2021 and an internal dataset of manually segmented tumors. Segmentations were validated by a board-certified neuro-radiologist and natively embedded PyRadiomics in PACS was used for feature extraction.

RESULTS

In 7 Months (05/2021 - 08/2021, 03/2022 - 05/2022) segmentations and annotations were performed in 835 patients (322 female, 467 male, 46 unknown, mean age 53 yrs). Dataset includes 275 Grade 4 Gliomas (54 Grade 3, 100 Grade 2, 31 Grade 1, 375 unknown). Molecular subtypes include IDH (113 mutated, 498 wildtype, 2 Equivocal, 222 unknown), 1p/19q (87 deleted or co-deleted, 122 intact, 626 unknown), MGMT promotor (182 methylated, 95 partially methylated, 275 unmethylated, 283 unknown), EGFR (76 amplified, 177 not amplified, 582 unknown), ATRX (40 mutated, 157 retained, 638 unknown), Ki-67 (616 known, 219 unknown) and p53 (549 known, 286 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.
NIMG-69. MRI T2 RELAXIVITY IN THE PREDICTION OF PROGRESSION-FREE SURVIVAL IN NEWLY-DIAGNOSED GLIOBLASTOMA: WHOLE BRAIN MEASUREMENTS AND DEEP LEARNING
Authors: Rulseh Aaron , Vymazal Josef
Published: November 2022

Glioblastoma (GBM) is the most common and aggressive primary brain tumour; we aimed to evaluate T2 relaxivity in their follow. Fifty-one newly diagnosed GBM followed at our department after surgery and combined chemo-radiotherapy were included (> 180 days progression-free survival [PFS] as determined by RANO, ≥ 3 MRI examinations in the PFS interval). All data used were prior to progression. T2 relaxation rates (1/T2f) were calculated voxel-wise assuming mono-exponential decay. Whole-brain (WB) values were extracted including skewness, kurtosis, mean, median, 15 and 85 percentile histogram values and variance. We additionally segmented the 1/T2f volumes using a 5 compartment Gaussian mixture model, producing mean, variance and percent per component. To evaluate predictive potential with respect to PFS, we used a deep long short-term memory (LSTM) model in tensorflow (4 timesteps). Twenty subjects were included in the predictive model, as inclusion criteria differed (progression, ≤ 120 days between all MRIs [mean 44.3 days], ≥ 4 PFS MRIs). Two models were tested: a regression model (days to progression) and a classification model (±18 months PFS; models differed in output layer). Both models were run 10 times; mean results are presented. We found WB median 1/T2f correlated with PFS, as values decreased prior to progression. WB median 1/T2f linear regression slopes also differed in progression vs. pseudo-progression. The deep LSTM regression model achieved an R2 of 86%. The deep LSTM classification model achieved a mean macro precision of 85%, recall 84% and F1 accuracy of 84% in classifying progression/no progression at an 18 month cutoff. We found very intriguing results with WB median 1/T2f measurements in distinguishing progression from pseudo-progression, and in suggesting progression despite otherwise unremarkable imaging. A more complex predictive model, using a fully-automated segmentation method followed by deep learning, was very promising. Our results may find utility in the monitoring of GBM patients.
NIMG-70. MAGNETIC RESONANCE HYPOXIA IMAGING FOR RADIATION TREATMENT GUIDANCE IN GLIOBLASTOMA MULTIFORME - A DIAGNOSTIC/PROGNOSTIC CLINICAL IMAGING STUDY
Authors: Brighi Caterina , Waddington David , Keall Paul , Booth Jeremy , O'Brien Kieran , Parkinson Jonathon , Yim Jackie , Bailey Dale , Back Michael , Drummond James
Published: November 2022

Local recurrence in glioblastoma (GBM) patients is caused by the ability of tumour cells to develop treatment resistance mechanisms. Hypoxia, which is present in subregions of GBM tumours, is the leading cause of resistance to radiotherapy and is associated with worse clinical outcomes in GBM. Current standard of care treatment does not account for tumour hypoxia. The ability to image tumour hypoxia at various stages of treatment offers opportunities to personalise and improve treatment for GBM patients. Preoperative imaging of tumour hypoxia offers the opportunity for supramarginal resections in surgical planning beyond current neurosurgical standard of care guidelines. Imaging hypoxia prior to radiotherapy enables selective dose escalation strategies to radioresistant tumour regions, increasing the likelihood of local control. Identifying hypoxic tumour regions harbouring progression at follow up is key to intervening at an early stage of tumour recurrence and personalising therapy tailored to the tumour response to treatment. Imaging of tumour hypoxia in routine clinical practice is challenging, as it requires 18FMISO PET, which is not available in most clinical centres. In this clinical imaging study, we aim to investigate the role of oxygen enhanced (OE) and blood-oxygen level dependent (BOLD) MRI as imaging biomarkers of hypoxia in GBM. Aiming to recruit 20 GBM patients, this study involves the addition of OE/BOLD MRI and 18FMISO PET imaging at several timepoints during the course of treatment. The primary objective is to investigate the ability of OE/BOLD MRI to map tumour hypoxia on preoperative scans using 18FMISO PET as the ground truth. Secondary objectives include evaluating the role of hypoxia imaging biomarkers for dose-painting radiotherapy planning and treatment response assessment in GBM. Overall, by validating the role of MRI biomarkers of hypoxia we ought to provide a non-invasive and more accessible means to more effective, personalised treatment to GBM patients.
NIMG-76. MORPHOLOGIC CHANGES TO THE HIPPOCAMPI FOLLOWING SURGICAL RESECTION AND ADJUVANT CHEMORADIATION IN PATIENTS WITH HIGH GRADE TEMPORAL GLIOMAS
Authors: Fernandez Luis , Oyon Daniel , Gibson William , Behbahani Mandana , Khan Osaama , Sharma Shelly
Published: November 2022

BACKGROUND

The hippocampus is known to remodel in pathologic conditions including epilepsy and Alzheimer’s disease. Literature investigating the effect of high-grade gliomas (HGGs) on the hippocampus following resection and adjuvant chemoradiation are limited; no study has evaluated these effects in tumors exclusively in the temporal lobe.

METHODS

A retrospective chart review was conducted on 30 patients with temporal HGGs who underwent craniotomy for resection with adjuvant RT and TMZ. Brainlab Elements was used to manually contour bilateral hippocampal gray matter volumes in the subgranular zone using T1-precontrast MRI sequences (1.5 mm thickness or less) pre-resection and at time of most recent follow up. These volumes were compared using a student’s t-test with significance set at p< 0.05.

RESULTS

Average follow up time was 23.5 months from initial resection. Average pre-treatment hippocampal volumes in this temporal glioma cohort compared to healthy controls from prior studies were 2.93 vs 2.83 cm3 (right, p=0.31) and 2.78 vs 2.76 cm3 (left, p=0.39) respectively. Pre vs post resection right hippocampal volumes in patients with right sided lesions were 2.59 vs 1.75 cm3 (p=.002). Left hippocampal volumes in patients with left sided tumors were 2.99 vs 1.64 cm3 pre and post resection respectively(p=0.0009). No significant differences in hippocampal volumes contralateral to the tumor side were found following treatment (p=0.31 and 0.07 for right and left hippocampi respectively).

CONCLUSIONS

Temporal gliomas are in close anatomic proximity to the hippocampi also may invade and/or disrupt local circuits which output to the hippocampi. Resection and chemoradiation are correlated with decreased hippocampal volumes ipsilateral to the primary locus of disease. Further characterization of hippocampal subregions, particularly the dentate gyrus, in addition to results of neuropsychiatric testing pre and post treatment are necessary to better elucidate the clinical implications of these morphologic changes and the putative functional networks which underlie them.
NIMG-93. CORRELATING RELATIVE LEVEL OF IMMUNOCOMPETENCE FOR CNS LYMPHOMA BY RADIOLOGIC CHARACTERISTICS: A CASE SERIES
Authors: Koduri Laila , Gupta Kanika , Katz Makenna , Trevino Christopher
Published: November 2022

Radiologically, central nervous system lymphoma (CNSL) presents differently in immunocompetent versus immunosuppressed states. Most patients with immunocompetent CNS lymphoma present with a solitary, deep, homogeneously enhancing lesion while patients with immunocompromised CNS lymphoma frequently have multifocal, centrally necrotic enhancing brain lesions. To date, there have been no radiologic features described along a spectrum of relative levels of immunocompetence. A single institution review on twelve patients with primary and secondary CNSL included clinical factors at diagnosis that are associated with varying levels of relative immunocompromised state. We collected qualitative data on age, prior cancer, radiation, chemotherapy, HIV, diabetes mellitus, steroid/immunosuppressant use, and quantifiable data including white blood cell, neutrophil, and lymphocyte counts. These factors were stratified for severity and correlated with findings on imaging. Our study identified patients with a minor level of immunocompromised state were more likely to develop multifocal disease, while patients with more severe immunocompromised states were likely to develop necrosis. Although our study is limited as a retrospective analysis, these findings suggest that the radiographic findings can present as a spectrum which can reflect a relative level of immunocompetence. This study warrants further evaluation in a larger and prospective cohort for validation.