bluuebunny/crossref_metadata_2025 huggingface dataset:
IMMU-62. INVIGORATING EFFECTOR IMMUNE CELLS WITH HIGHLY SELECTIVE IL-2R AGONISTS AND POTENTIAL SYNERGY WITH TUMOR TARGETING THERAPEUTICS FOR TREATMENT OF GLIOBLASTOMAS
Authors: To Minh D , Sharma Aanchal , Merchant Nina , Liu Jiali , Chamberlain Christopher A , Morris Yasmin , Anantharam Varshaa , Sheraz Shahida , Shah Mansi , Mastrokalos Gerasimos , Pollard Steve , Thorne Lewis , Brennan Paul , Merchant Fahar , Galvez-Cancino Felipe , Quezada Sergio A
Published: November 2024

Glioblastoma (GBM) is an aggressive brain tumor with a median overall survival (mOS) of 14 months. Treatment options are limited with no new approved therapies over the past 3 decades and no standard of care for a majority of patients (> 90%) who experience recurrence. GBM has a highly immune suppressive tumor microenvironment (TME) comprising of myeloid derived suppressor cells (MDSCs) and tumor associated macrophages (TAMs) that are capable of suppressing the activity of anti-cancer CD8+ T and NK cells. We have engineered highly selective IL-2 superkines (IL-2SK) that preferentially expand and activate CD8+ T and NK cells with limited effects on immune suppressive regulatory T cells (i.e., Tregs). MDNA11 is an IL-2SK -albumin fusion protein designed to increase half-life and promote tumor accumulation. MDNA223 is a bi-functional anti-PD1-IL-2SK designed to stimulate effector immune cells while preventing immune exhaustion. MDNA11 and MDNA223 extended survival of mice harboring orthotopic GBM tumors with accompanying increase in CD8+ T and NK cells within the TME. When patient-derived GBM tumor explants were treated with MDNA11 and MDNA223 ex vivo, there was clear evidence of activation among resident CD8+ T cells characterized by increased levels of intra-cellular Granzyme B responsible for tumor cell killing. There was also increased release of soluble Fas ligand and granulysin, consistent with an activated anti-tumor immune response within the TME. Ongoing studies include in depth immune profiling to further understand the mechanism of MDNA11 and MDNA223 in GBM as well as to test potential synergy with tumor targeting therapeutics and other treatment modalities capable of eliciting immunogenic cell death.
IMMU-65. TARGETING AXONAL GUIDANCE DEPENDENCIES IN GLIOBLASTOMA WITH ROBO1 CAR T CELLS
Authors: Chokshi Chirayu , Brakel Benjamin , Shaikh Muhammad Vaseem , Rossotti Martin A , Venugopal Chitra , Brown Kevin R , Henry Kevin A , Moffat Jason , Singh Sheila K
Published: November 2024

Resistance to genotoxic therapies and subsequent disease recurrence are hallmarks of aggressive cancers, including glioblastoma (GBM). Here, we uncover functional drivers of post-treatment recurrent GBM using genome scale CRISPR-Cas9 screens accompanied by integrative genomic analysis. Using patient-matched pre- and post-treatment GBM models, our findings uncover large-scale reorganization of functional dependencies at tumor recurrence and implicate protein tyrosine phosphatases 4A2 (PTP4A2) as a novel driver of tumorigenicity in recurrent GBM. Small molecule inhibition and phospho-proteomic analyses reveal a novel PTP4A-ROBO1 signaling axis that modulates tumor invasion, self-renewal and proliferation in recurrent GBM. Since a pan-PTP4A targeting small molecule suffers from poor blood-brain-barrier penetrance, we engineered a novel second generation chimeric antigen receptor (CAR) targeting human ROBO1, a cell surface receptor enriched across GBM specimens. Not only do ROBO1 CAR T cells exhibit a potent and specific anti-tumor effect in vitro, a single dose of ROBO1 CAR T cells doubles median survival in a patient-derived xenograft (PDX) model of recurrent GBM. Expansion of ROBO1 CAR T cells to other invasive brain cancers leads to tumor eradication in ~50% of mice in PDX models of pediatric medulloblastoma and adult lung-to-brain metastases. Together, we provide insights into functional remodeling of GBM at recurrence and present a multi-targetable PTP4A-ROBO1 signaling axis with potential across multiple malignant brain tumors.
INNV-01. METASTATIC GLIOBLASTOMA TO THE LUNG TREATED WITH LENVATINIB
Authors: Yuen Carlen , Pekmezci Melike , Bao Silin , Kong Xiao-Tang
Published: November 2024

Glioblastoma is the most common malignant brain tumor. Despite its invasive nature, extra-cranial glioblastoma metastases are rare. We present a case of a 63 year-old woman with metastatic glioblastoma to the lung. Sarcomatous histology, a reported risk factor for disseminated disease, was found. Genomic alterations of TP53 mutation, TERT mutation, PTEN mutation, and +7/-10 were also uncovered. Early evidence suggests these molecular aberrations are common in metastatic glioblastoma. Treatment with third-line lenvatinib resulted in a mixed response. This case contributes to the growing body of evidence for the role of genomic alterations for predictive risk in metastatic glioblastoma. There remains an unmet need for treatment of metastatic glioblastoma.
INNV-02. BRAINMETS: A CLINICIAN-FRIENDLY SOFTWARE TO MANUALLY SEGMENT BRAIN METASTASES AND DETECT PRIMARY TUMOR ORIGIN USING DEEP LEARNING
Authors: Panchawagh Suhrud
Published: November 2024

Estimates suggest that around 20%-40% of cancer patients are affected by brain metastases. A subset of these patients first present with central nervous system manifestations with an unknown primary. The issue then arises regarding which region of the body should be imaged, if not the entire body, exposing the patient to more radiation. To address this issue, streamline workflows, and save precious time, we developed a software clinicians can use to identify primary tumor locus. “BrainMets” is a user-friendly software that handles a DICOM input, allows the user to segment the region(s) of interest manually, and uses a deep learning model to predict the most likely tumor origin. The model is a mixed-effects neural network pre-trained on radiomic features from open-source data by Ocaña-Tienda et al. (2023) using 637 high-resolution imaging studies from 10 different medical centers with an accuracy of 90.5%, precision of 92.7%, recall of 87.8%, and F1 score of 90.2%. The software leverages the open-source software 3D-Slicer to help segment regions of interest, extract radiomic features, and make predictions. It is built using Flask, a Python package for backend development. The frontend user interface is created using HTML/CSS and Bootstrap. The “BrainMets” software thus strives to enhance diagnostic workflow significantly, reduce appointment times for scans, and improve patient experience. Future enhancements include integrating more AI models, improving healthcare IT system compatibility, and updating datasets to boost predictive accuracy and generalizability. This tool sets a new standard in personalized medicine, optimizing treatment strategies for cancer patients with brain metastases. As adoption increases, it could substantially improve patient outcomes and reduce healthcare costs associated with misdiagnosis and overtreatment. Further research and development will focus on expanding its applicability across various types of cancers.
INNV-03. BEYOND ANALGESICS: PHOTOBIOMODULATION THERAPY AS A PARADIGM SHIFT IN PAIN MANAGEMENT
Authors: UWISHEMA Olivier
Published: November 2024

BACKGROUND

Pain constitutes a primary cause of medical care demand and disability among patients. The predominant method employed for pain management entails analgesic administration. Nonetheless, prolonged use of analgesics may lead to adverse effects, including cardiovascular and gastrointestinal complications. Photobiomodulation therapy (PBMT) emerges as a novel approach to pain treatment, demonstrating effective pain reduction and anti-inflammatory properties. This systematic review aims to elucidate the impacts of PBMT on pain modulation and assess its potential for widespread application.

METHODS

A systematic review was conducted utilizing Boolean operators combining terms such as “Photobiomodulation” AND “Pain Management”; “Photobiomodulation therapy” AND “pain”; “PBMT” AND “Pain”. Electronic databases including Cochrane Library, PubMed, and Scopus were searched. The review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 Statement.

RESULTS

The systematic review revealed that PBMT is a non-invasive, safe, and cost-effective technique for pain management. It has demonstrated efficacy across various conditions, encompassing neurological and musculoskeletal disorders. PBMT can complement existing interventions such as exercise programs, transcutaneous electrical nerve stimulation (TENS), or surgical procedures. However, further research with long-term follow-up is warranted to validate these findings.

CONCLUSIONS

PBMT emerges as a promising modality for pain management, offering a non-invasive alternative with favorable safety profiles. Its efficacy in diverse conditions underscores its potential utility as an adjunctive or standalone treatment option. Nonetheless, additional studies with extended follow-up periods are necessary to confirm and further elucidate its therapeutic benefits.
INNV-07. IVOSIDENIB AND BEVACIZUMAB IN HEAVILY PRETREATED PATIENTS WITH IDH1 MUTANT GLIOMAS
Authors: Patel Mallika P , Ziv Michal Nisnboym , Minor Maria , Johnson Margaret O , Batich Kristen , Low Justin , Shoaf Madison L , Khasraw Mustafa , Friedman Henry S , Ashley David M , Desjardins Annick , Peters Katherine B
Published: November 2024

Isocitrate dehydrogenase 1 (IDH1) inhibitors are transforming the treatment of patients with non-enhancing IDH1 mutant gliomas that have only undergone surgical resection. Questions remain on the utility of IDH1 inhibitors in patients that have received prior therapies such as radiation therapy (RT) and chemotherapy (e.g. temozolomide (TMZ)) and have progressive disease. We evaluated the safety and efficacy of ivosidenib, an oral IDH1 inhibitor, in combination with bevacizumab (BEV), a monoclonal antibody targeting VEGF-A, in IDH1 mutant glioma patients that were heavily pretreated. Fourteen patients received combination ivosidenib and bevacizumab starting between February 2021 to July 2023. In our small cohort, patient age range was 26 to 73 years with seven female patients and seven male patients. Diagnoses represented were astrocytoma, IDH1 mutant (n=10) and oligodendroglioma, IDH1 mutant (n=4). At the time of IDH1 therapy initiation, the majority of patients (n=10) had a grade 3 tumor. All patients (n=14) had canonical IDH1 mutation (p.Arg132His) and had enhancing disease. Therapies initiated prior to ivosidenib therapy included: prior RT (n=12), prior TMZ (n=14) and prior BEV (n=10). The median number of progressions prior to initiation of ivosidenib combination therapy was 3 (range 2 to 6). All patients received ivosidenib dosed at 500 mg daily with bevacizumab doses varying from 5 to 15 mg/kg IV dosed every 2 to 3 weeks. Combination therapy was well tolerated with minimal patients experiencing toxicities requiring dose interruptions; diarrhea (n=2), creatine phosphokinase elevations (n=1), QTc prolongation (n=1), and thrombocytopenia (n=1). The median treatment duration on ivosidenib combination therapy was 4.42 months (range 0.69 to 11.4 months). In this cohort, the combination of ivosidenib and bevacizumab was well tolerated. More information is needed on the benefit of ivosidenib in combination with other therapies and in heavily pretreated patients with IDH1 mutant gliomas.
INNV-15. A PIVOTAL, MULTICENTER TRIAL OF FOCUSED ULTRASOUND FOR BLOOD-BRAIN BARRIER DISRUPTION FOR PLASMA-BASED LIQUID BIOPSY IN PATIENTS WITH GLIOBLASTOMA (LIBERATE)
Authors: Ahluwalia Manmeet , Ozair Ahmad , Burns Terence , McDermott Michael , Sahgal Arjun , DeGroot John , Mogilner Alon , Hibert Matthew , Zhu Julia , Shah Bhavya , Patel Toral , Rincon-Torroella Jordina , Mishra Mark , Everson Richard , Sporrer Justin , Hilliard Justin , Bezchlibnyk Yarema , Weinberg Jeffrey , Cifarelli Christopher , Rezai Ali , Lipsman Nir , Woodworth Graeme
Published: November 2024

BACKGROUND

Liquid biopsy in glioblastoma (GBM) is hindered by insufficient requisite circulating-tumor (ct) and cell-free (cf) DNA in blood due to blood-brain barrier (BBB). This limits the identification of blood-based tumor biomarkers along with biomarker-driven systemic therapies. Real-time image-guided low-intensity focused ultrasound (LIFU) plus IV microbubble oscillators, leads to non-invasive BBB disruption.

METHODS

LIBERATE is an ongoing, prospective, multi-center, self-controlled, pivotal trial investigating safety and technical efficacy of LIFU-based BBB disruption for increasing blood ctDNA and cfDNA levels in adult GBM patients (aged 18-80 years). Patients with suspected GBM planned for biopsy/resection at ten US centers are being enrolled. Patients with multifocal tumors or tumors arising from deep midline, thalamus, cerebellum, or brainstem are excluded. Patients are administered IV microbubbles for enhanced sonication effects, after which MR-guided BBB disruption using 220kHz LIFU device is performed with real-time acoustic-feedback-control for effective microbubble activation. Pre- and post-LIFU, phlebotomy and MRI brain are performed. Primary study endpoint is defined, per subject, as ratio between their blood cfDNA level 1-hour post-LIFU procedure compared to blood cfDNA pre-procedure. Primary study hypothesis is that BBB disruption leads to ≥2-fold rise in blood cfDNA. Secondary hypothesis is that there exists ≥75% agreement between biomarker pattern in blood cfDNA sample obtained 1-hour post-LIFU and biomarker pattern in tumor tissue obtained later. Trial is powered to evaluate both primary and secondary hypotheses. Based on assumed true agreement rate of 91% and one-sided alpha=0.025, an exact test for binomial proportions provides N=50 with 84% power for secondary hypothesis. Exploratory endpoints include (1) sensitivity of detection of specific somatic mutations in ctDNA from blood collected pre- and post-LIFU, (2) ctDNA estimation in samples collected at 30-minutes, 1-hour, 2-hour, and 3-hour post-LIFU to determine time of greatest yield, (3) correlation of MRI parameters related to grading of BBB disruption and ctDNA-based biomarkers from post-LIFU blood samples. Patient enrollment commenced in 2022 and remains ongoing (NCT05383872).
INNV-18. FOCUS ON CURRENT AND EMERGING TREATMENT OPTIONS FOR GLIOMA: A COMPREHENSIVE REVIEW
Authors: Lucke-Wold Brandon , Shafique Muhammad Ashir , Mustafa Muhammad Saqlain , Haseeb Abdul
Published: November 2024

This comprehensive review delves into the current updates and challenges associated with the management of low-grade gliomas (LGG), the predominant primary tumors in the central nervous system. With a general incidence rate of 5.81 per 100000, gliomas pose a significant global concern, necessitating advancements in treatment techniques to reduce mortality and morbidity. This review places a particular focus on immunotherapies, discussing promising agents such as Zotiraciclib and Lerapolturev. Zotiraciclib, a CDK9 inhibitor, has demonstrated efficacy in glioblastoma treatment in preclinical and clinical studies, showing its potential as a therapeutic breakthrough. Lerapolturev, a viral immunotherapy, induces inflammation in glioblastoma and displays positive outcomes in both adult and pediatric patients. Exploration of immunotherapy extends to Pembrolizumab, Nivolumab, and Entrectinib, revealing the challenges and variabilities in patient responses. Despite promising preclinical data, the monoclonal antibody Depatuxizumab has proven ineffective in glioblastoma treatment, emphasizing the critical need to understand resistance mechanisms. The review also covers the success of radiation therapy in pediatric LGG, with evolving techniques, such as proton therapy, showing potential improvements in patient quality of life. Surgical treatment is discussed in the context of achieving a balance between preserving the patient’s quality of life and attaining gross total resection, with the extent of surgical resection significantly influencing the survival outcomes. In addition to advancements in cancer vaccine development, this review highlights the evolving landscape of LGG treatment, emphasizing a shift toward personalized and targeted therapies. Ongoing research is essential for refining strategies and enhancing outcomes in the management of LGG.
INNV-23. UNDERSTANDING THE BURDEN OF MIDH1/2 DIFFUSE GLIOMA AND THE COMPLEXITY OF NAVIGATING THE PATIENT PATHWAY: INSIGHTS FROM PATIENTS AND CAREGIVERS
Authors: Oliver Kathy , Burton Mary , Cardinal Craig , LaHay Shannon , Leon Bernard , Mallett Rebecca , Rogers Sarah , Tse Chris
Published: November 2024

Diffuse gliomas with mutations in isocitrate dehydrogenase 1 or 2 (mIDH1/2) are characterized by a slow-progressing yet life-limiting disease predominantly in young people. We report interim findings from a qualitative study to describe the mIDH1/2 diffuse glioma patient pathway, experience of the disease, and treatment approaches. Patients, caregivers, and patient-association group (PAG) representatives undertook individual interviews, with patients also completing standardized exercises as pre-work. Materials were developed in collaboration with the International Brain Tumour Alliance. Patients were aged ≥12 years with mIDH1/2 glioma and last resection ≥6 months before enrollment, either undergoing active observation or receiving chemotherapy/radiotherapy. Caregivers were living with the patient. PAG representatives were active members of a brain tumor PAG. From November 2023 to March 2024, 30 patients (Australia: n=10; China: n=6; France, UK: n=5 each; Canada, Japan: n=2 each), two caregivers (China, Australia: n=1 each) and one PAG (UK) participated. Median age of patients was 41.5 years, with 17 astrocytoma and 13 oligodendroglioma diagnoses. Presentation symptoms, circumstances of diagnosis and treatment, access to care, and navigation in the healthcare system differed per patient and within countries. Surgical resection was perceived as a crucial stage, both feared and desired. A second opinion was more often sought for surgery than for subsequent treatment approaches. Patients undergoing chemotherapy/radiotherapy (n=17) or active observation (n=13) expressed substantial physical, socioeconomic, financial, and psychological burden. Patients receiving active observation experienced strong and ongoing anxiety, as the uncertainty of tumor recurrence took a toll on their emotional wellbeing in the long term. The experience of people living with mIDH1/2 diffuse glioma is heterogeneous regarding their pathway and complexity navigating the healthcare system, with a substantial psychological and socioeconomic impact. Improved education, as well as facilitating early navigation and prioritizing shared decision-making along the disease pathway, will better support people living with mIDH1/2 diffuse glioma.
PATH-01. SELLAR SOLITARY FIBROUS TUMORS WHO GRADE II AND III: MIMICS OF NON-FUNCTIONING PITUITARY ADENOMAS
Authors: Persico Michele , Weinberg Brent , Shu Hui-Kuo , Zhong Jim
Published: November 2024

Solitary fibrous tumors WHO grade II and III (SFTs II/III) are rare mesenchymal neoplasia accounting for 0.4% of primary central nervous system tumors. SFTs II/III located in the sella turcica region are even rarer and, since the first case described in 1983, only 21 case reports of sellar/suprasellar SFTs II/III (ssSFTs II/III) have been described to this day. We aim to analyze ssSFTs II/III and to demonstrate that can be differentiated from non-functioning pituitary adenomas through pathological examination alone. We analyzed 20 case reports of ssSFTs II/III identified through PubMed and Google searches and a new unpublished case presented at Emory University. ssSFTs II/III are equally represented in both sexes, with 11 cases over 21 occurring in females and the mean age of onset at 46 years old. Clinically, ssSFTs II/III present with compression symptoms related to the tumor location. Headache, visual field defects, and anterior hypopituitarism-related symptoms are frequent chief complaints. As such, almost all cases of ssSFTs II/III had a pre-biopsy working diagnosis of non-functioning pituitary adenomas. The differentiation between SFTs II/III and pituitary adenomas based on imaging findings remains challenging, and surgical biopsies are necessary for a definitive diagnosis. ssSFTs II/III surgical reports describe a unifying trait of a highly vascular tumor adherent to the dura that bleeds profusely after resection. These characteristics are less consistent with a pituitary adenoma. The genetic hallmark of SFTs at all anatomical sites is paracentric inversions at 12q13, fusing the NAB2 and STAT6 genes, with consequent overexpression of STAT6. Pituitary adenomas lack this genetic signature. ssSFTs II/III have an overlapping presentation and similar imaging findings of pituitary adenomas, but different management and prognosis. Hence, it is crucial to include ssSFTs II/III among the pre-biopsy differential of sellar/suprasellar masses identified on imaging. Pathology confirmation is required to guide therapy.
PATH-06. TRANSLATION INTO CLINICAL PRACTICE OF THE G1-G7 MOLECULAR SUBGROUP CLASSIFICATION OF GLIOBLASTOMA
Authors: Georgescu Maria-Magdalena
Published: November 2024

Glioblastoma is the most frequent and malignant primary brain neoplasm. Glioblastoma growth is promoted by alterations in mediators from five major pathways: MAPK and PI3K canonical growth pathways, telomere elongation/TERT, cell cycle G1-phase and the p53 pathway. In a recent breakthrough study on a prospective Discovery cohort, I proposed the first all-inclusive molecular classification of glioblastoma into seven subgroups, G1-G7, based on MAPK pathway activation. New data from a subsequent, prospective Validation cohort validated the G1-G7 molecular subgroup classification, showing significant demographic and molecular differences between subgroups. Beside the initial histologic diagnosis, the G1-G7 classification requires next generation sequencing (NGS) of formalin-fixed paraffin-embeded (FFPE) samples and genomic-transcriptomic correlations between DNA mutations, copy number variations (CNVs) and RNA expression. Thus, in the Combined cohort containing tumors from over 220 glioblastoma patients, aproximately 75% of cases fell into three major subgroups, G1/EGFR, G3/NF1 and G7/Other, whereas the rest of 25% cases made up the four minor subgroups, G2/FGFR3, G4/RAF, G5/PDGFRA and G6/Multi-RTK. The name of the mutated most upstream, non-redundant, MAPK pathway effector corresponds to each subgroup, except for the G7/Other subgroup in which MAPK activation is minimal and PI3K pathway activation is dominant. The effectors of the other four pathways may be redundant; however, genomic-transcriptomic correlations showed subgroup specificity, with opposing trends for the G1/EGFR and G7/Other molecular subgroups. This first, all-inclusive, molecular subgroup classification of glioblastoma in a large prospective patient cohort allowed integrated pathway analysis, risk stratification and demographic comparison between Caucasian/White and African-American/Black patients. Most importantly, its implementation into clinical practice opened the avenue to controlled therapeutic approaches.
PATH-07. CLINICAL AND RADIOGRAPHIC FEATURES OF DIFFUSE GLIOMA MOLECULAR SUBTYPES IN ACCORDANCE WITH THE 2021 CNS5 WHO CLASSIFICATION
Authors: Jo Jasmin , Mondia Mark , Arewa Josephine , How Andrew , Patrie James , Dueck Nicholas , Gilbow Reed , Goschka Andrew , Joyner David , Patel Sohil H , Lopes M Beatriz , Schiff David
Published: November 2024

BACKGROUND

The incorporation of molecular parameters into WHO CNS5 has led to reclassification of many gliomas. We undertook to describe presenting clinical and radiographic features of diffuse adult gliomas according to CNS5 category.

METHODS

We reviewed pathology reports, clinical and MRI data at presentation of 972 adult patients with glioma diagnosed between 1/2010-2/2022. Continuous variables were presented as median; categorical variables as numbers and percentages, and comparison were performed using chi-square test.

RESULTS

736 patients had sufficient data for CNS5 re-classification and were included in the analysis: Grade 2 IDH-mutant (IDHmut) astrocytoma (A2) n=69, grade 3 IDHmut astrocytoma (A3) n=37, grade 4 IDHmut astrocytoma (A4), n=32, grade 2 oligodendroglioma (O2) n=60, grade 3 oligodendroglioma (O3) n=23, and grade 4 IDH-wildtype glioblastoma (GBM) n=515. Age at presentation significantly differed between grade 2&3 gliomas and grade 4 (mean age:39 versus 61.7; p<0.001); A4 were also younger than GBM (39.8 versus 63.1). A majority in all categories except grade 2 gliomas were male. Seizure was more common in IDHmut gliomas than GBM (58.4% versus 31.8%;p<0.001), while cognitive impairment was more common in GBM than in IDHmut gliomas (64.4% versus 34.4%;p<0.001) and in A4 (64% versus 40.6%;p=0.013). Focal deficits at presentation were more frequent in GBM than in IDHmut gliomas (74.2% versus 30.5%;p<0.001), but not significantly different compared to A4 (74.2% versus 58.1%;p=0.06). Contrast enhancement on MRI was more frequent in GBM compared to IDHmut gliomas (93% versus 48%;p<0.001), but similar frequency with A4 (93% versus 96%;p=1.00). The minimum ADC was significantly higher in IDHmut glioma including A4 than GBM(p<0.001). Calcification was more common in oligodendroglioma than astrocytoma and GBM (p<0.001), and more frequent in A4 than GBM(p=0.016).

CONCLUSION

Significant differences in the clinical presentation and radiologic features exist among CNS5 glioma subtypes, informing potential diagnosis, management and prognosis at initial presentation.
PATH-48. IMPACT OF DEPRESSION AND ITS TREATMENT ON SURVIVAL AND TUMOR PROGRESSION IN RTK2 GLIOBLASTOMAS: IDENTIFICATION OF A HIGH-RISK SUBGROUP
Authors: Zghaibeh Yahya , Brembach Florian , Silverbush Dana , Gempt Jens , Schüller Ulrich , Monje Michelle , Heiland Dieter Henrik , Drexler Richard , Ricklefs Franz
Published: November 2024

INTRODUCTION

Depressive symptoms are prevalent among glioma patients while the impact on survival is not fully clear and underlying mechanisms remain poorly understood. Here, we investigated the impact of glioblastoma-associated depression as the disease-presenting symptom and the influence of antidepressant pharmacotherapy on glioblastoma progression.

METHODS

We performed a retrospective cohort study on glioblastoma patients treated at our institution. Patients with a new depression as presenting symptom were compared to non-depressive glioblastoma patients employing propensity-matched survival analysis. Additionally, tumor tissues were subjected to DNA methylation analysis (EPIC 850k array). In vitro proliferation assays were performed to investigate the effect of antidepressants on glioma cell growth.

RESULTS

Of 298 glioblastoma patients, 23 patients suffered from a tumor-associated depression and received antidepressants at time of diagnosis (14 SSRI, 3 NaSSA, 4 TCA and 2 unknown). Propensity-matched survival analysis revealed a shorter OS in the depression group (median OS: 8 vs. 14; HR = 2.247; 95% CI: 1 - 5.051; p < 0.05). Methylation subclass analysis indicated a predominance of RTK2 glioblastoma within the depression group (n = 14; 63.6%). Tumors of the depression group originated more likely in the frontal lobe (43.5% vs. 29.2%) and in the midbrain (13% vs. 2.43%). No significant differences in epigenetic neural signatures were found. Treatment with either citalopram or sertraline – the most frequently used antidepressants - significantly increased the proliferation index in RTK2 glioblastoma cultures but not RTK1 glioblastoma cultures.

CONCLUSION

Our study reveals a strong correlation between glioblastoma-associated depression with antidepressant treatment and worse outcome in glioblastoma of the DNA methylation subclass RTK2. These findings may reveal a potential causal link, raising awareness of the increased likelihood of depression and glioblastoma progression in a methylation-dependent manner, which could guide antidepressant treatment for improving patients’ quality of life.
PATH-49. INTRA-OPERATIVE GENETIC ANALYSES FOR DECISION-MAKING DURING TUMOR REMOVAL OF ADULT-TYPE DIFFUSE GLIOMA USING RAPID QUANTITATIVE PCR DEVICE
Authors: Ohka Fumiharu , Maeda Sachi , Shimizu Hiroki , Motomura Kazuya , Takeuchi Kazuhito , Nagata Yuichi , Deguchi Shoichi , Shiba Yoshiki , Yamaguchi Junya , Takido Yuhei , Nakamura Akihiro , Ito Shohei , Saito Ryuta
Published: November 2024

BACKGROUND

Recent comprehensive molecular analyses of central nervous system (CNS) tumors identified several diagnostic or prognostic markers. Especially, for adult-type diffuse glioma, IDH mutation, TERT promoter (pTERT) mutation and CDKN2A homozygous deletion are quite important markers for diagnosis and prognosis of this type of glioma. Intra-operative identification of these molecular alterations could be effective for decision-making of tumor removal strategy.

METHODS

In this study, we established intra-operative gene analysis method using rapid quantitative PCR device, GeneSoC, by which we could obtain genotype of these important genes for 20 minutes in an operating room. Using GeneSoC, we could perform 50 cycles of quantitative PCR for approximately 12 minutes. Results; We established rapid gene analyses of mutations of IDH1 R132H, pTERT C225T, pTERT C250T and homozygous deletion of CDKN2A for adult-type diffuse gliomas. For elution of DNA, we incubated at least 1mg of tumor tissue at 95°for 5 minutes. Combined this boiling method with GeneSoC, we could obtain those genetic alterations for 20 minutes after collection of tumor tissue. In analyses of 111 adult-type diffuse glioma cases, sensitivity and specificity for detection of IDH1 p.R132H are 98% and 98%, respectively, and those of pTERT (C225T or C250T) are 100% and 100%, respectively. In analyses of 50 cases, sensitivity and specificity for detection of CDKN2A homozygous deletion are 100% and 83%, respectively. Conclusion; In this study, we could obtain the genotype of important molecular markers intra-operatively, not only during tumor removal but even during tumor biopsy, using GeneSoC device. This rapid genetic analysis might be effective not only for intra-operative diagnosis but also for detection of boundary between tumor and normal tissue.
PATH-58. SEQUENCING OF DNA RECOVERED FROM BRAIN TUMOR BIOPSY SURGICAL WASTE IMPROVES SENSITIVITY OF RAPID IDH/TP53-MUTANT TUMOR DIAGNOSES
Authors: Wadden Jack , Adam Tiffany , Cartaxo Rodrigo , Niculcea Michael , Kong Seongbae , John Vishal , Tripathy Arushi , Bird Cylaina , Nazarian Javad , Heth Jason , Muraszko Karin , Marupudi Neena , Magge Suresh , Garton Hugh , Al-Holou Wajd , Koschmann Carl
Published: November 2024

BACKGROUND

TP53 and IDH mutations are common in brain tumors and are highly relevant biomarkers for diagnosis and treatment. Thus, biopsy tissue is commonly tested for these mutations via immunohistochemistry (IHC), which is rapid and generally considered highly sensitive. However, IHC only tests for IDH1R132H (80%-90% of IDH mutant disease) and rarer IDH mutations are not covered. p53 nuclear staining is used to identify non-specific p53 upregulation and loss of function but does not test for specific mutations and has a relatively lower overall sensitivity/specificity of ~80%/80-97%. Sequencing can resolve all mutations and improve over IHC, but long turnaround time and high cost prevents this. New advances in rapid sequencing technologies allow same-day, low-cost panel sequencing. However, access to biopsy tissue is zero-sum and obtaining additional tissue for molecular diagnostics confers increased morbidity. We investigate whether tumor DNA recovered from surgical waste (specifically core biopsy needle fluid and non-adherent gauze) is sufficient to diagnose IDH/p53 status of tumors.

METHODS

Surgeons were instructed to save biopsy needle rinse saline, and/or to recover any non-adherent gauze used in specimen handling. Cell-free DNA was extracted and sequenced using a same-day targeted panel protocol and/or TruSight Oncology 500 panel sequencing.

RESULTS

100% of recovered samples yielded enough DNA for targeted sequencing (17/17). In all IDH1R132H IHC positive cases, waste sequencing recapitulated the mutation (4/4). In 7/9 p53 positive cases via IHC (>10% staining), waste sequencing of common hotspot loci was able to identify a specific TP53 mutation. Importantly, sequencing identified alternate IDH mutations in three IHC negative cases (3/13), discovered a rarer TP53 mutation (E286K) in one IHC negative case, and confirmed TP53 negative status in one indeterminate p53 report.

CONCLUSIONS

Surgical waste is an important diagnostic resource that should be leveraged for rapid diagnostic sequencing. Sufficient DNA can be easily recovered from surgical waste and sequenced within the same time-frame–but with increased sensitivity–to IHC.
PATH-66. MOLECULAR FEATURES RELATED TO LONG-TERM SURVIVAL IN GLIOBLASTOMA
Authors: Nisnboym Ziv Michal , Raphael Itay , Drappatz Jan , Marker Daniel F
Published: November 2024

Glioblastoma Multiforme (GBM) remains the most common malignant primary brain tumor in adults, with a dismal prognosis that rarely exceeds beyond 2 years of survival despite multimodal treatment. While small fractions of GBM patients seem to display extended survival, the underlying mechanisms for this peculiarity remain largely unknown. Previously published investigations of long-term survivors (LTS) usually incorporate small numbers of patients, non-uniform definition of LTS and rarely provide a comprehensive molecular analysis. With advances in multi-omics technologies and their integration with disease diagnostics, numerous prognostic molecular markers have been proposed. So far, only O6-methylguanine-DNA-methyltransferase (MGMT) gene promotor hypermethylation was linked to outcome and therapy response. We aim to investigate omics characteristics associated with LTS. Molecularly confirmed Isocitrate Dehydrogenase (IDH) wildtype GBM patients, >18 years old, operated and treated at our institution between 2013 and 2020 and living ≥5 years post-diagnosis (LTS = 62) or 1-2 years (STS = 62) were identified. Clinical and demographic characteristics were matched. Tumor tissues was analyzed with targeted next generation sequencing (NGS) and compared between LTS and STS. In addition, methylation analysis was done for all LTS. Results will be presented. We hope to shed a broader light on the molecular drivers behind the LTS in GBM patients, that will provide prognostic markers and potential targets for novel treatments.
NIMG-15. RAPID EARLY PROGRESSION AFTER SURGERY ON PRE-RADIATION PLANNING MRI FOR IDH-WILDTYPE GLIOBLASTOMA
Authors: Sackett Jonathan , Ahmed Khadija , Struve Tim , Pater Luke , Andaluz Norberto , Forbes Jonathan , Chaudhary Rekha , Yogendran Lalanthica , Sengupta Soma , Breneman John , Udstuen Gavin , Wang Kyle
Published: November 2024

BACKGROUND

Use of pre-RT planning MRI for glioblastoma (GBM) is inconsistent and not required by many clinical protocols. We performed a detailed volumetric analysis of rapid early progression (REP) on pre-RT planning MRI’s, hypothesizing that REP is associated with worse survival and more accurately risk stratifies than extent of resection.

METHODS

Patients with IDHwt GBM who had resection (biopsy-only patients excluded) and pre-RT planning MRI ≥2 weeks after postop MRI were included. MRI’s were reviewed by a neuroradiology fellow and attending who measured in 3 dimensions new/increased contrast-enhancing disease between postop and pre-RT MRI. REP was defined as disease ≥1cm in 2 dimensions or ≥0.5cc. Extent of resection was scored 1: gross total (GTR, >95%); 2:near total (NTR, 90-95%); 3:subtotal (STR). The primary endpoint was survival (OS). Cox proportional hazards model analyzed association with age, resection extent, MGMT+ status, short course RT (a surrogate for performance status), and REP.

RESULTS

The final cohort included 77 patients (median age 63), with 9 (12%) receiving short course RT. Surgical extent was GTR in 42 (55%), NTR in 16 (21%), and STR in 19 (25%). REP occurred in 41 patients (53%), with a rate of 29% after GTR, 75% after NTR, and 90% after STR. Age (p=0.24, HR 1.02/yr), short course RT (p=0.64, HR 1.2), and surgical extent (p=0.49, HR 1.1) were not significantly associated with OS on univariate analysis. MGMT+ and REP were associated with survival on both univariate and multivariate (MGMT+ p=0.002, HR 0.4; REP p=0.005, HR 2.3) analyses. Median OS was 1.3 years vs. 1.9 years with vs without REP.

CONCLUSIONS

REP occurs frequently, adds a “growth rate” variable, and is a better prognostic factor than extent of resection. These data have implications for clinical trial design and support pre-RT planning MRI’s as standard of care.
NIMG-16. ASSESSMENT OF RESPONSE TO LOMUSTINE-TEMOZOLOMIDE CHEMOTHERAPY IN ADDITION TO RADIOTHERAPY IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA USING FET PET
Authors: Werner Jan-Michael , Wollring Michael M , Tscherpel Caroline , Rosen Elena K , Ceccon Garry , Stetter Isabelle , Lohmann Philipp , Weller Johannes , Stoffels Gabriele , Baues Christian , Celik Eren , Mottaghy Felix M , Goldbrunner Roland , Herrlinger Ulrich , Fink Gereon R , Langen Karl-Josef , Galldiks Norbert
Published: November 2024

BACKGROUND

We examined the value of O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET for early response assessment in patients with newly diagnosed glioblastoma and methylated O6-methylguanine-DNA methyltransferase promoter treated with lomustine-temozolomide chemotherapy in addition to radiotherapy.

METHODS

Thirty-one patients (29-74 years) were treated according to the CeTeG/NOA-09 phase-3 trial. FET PET and anatomical MRI were performed at baseline and follow-up after the third cycle. We obtained mean and maximum tumor-to-brain ratios (TBR) and metabolic tumor volumes (MTV). Thresholds derived from FET PET were defined using receiver operating characteristic analyses to predict progression-free survival (PFS) of ≥12 months. The predictive value of FET PET parameters was subsequently evaluated using univariate and multivariate survival estimates. MRI response assessment was based on the RANO 1.0 criteria. FET PET data were also used to estimate response according to the PET RANO 1.0 criteria.

RESULTS

Patients received a median number of 6 cycles of lomustine-temozolomide chemotherapy (3-6 cycles). After treatment initiation, the median follow-up was 17.2 months (7.2-59.4 months). As of April 2024, we confirmed tumor progression according to the RANO 1.0 criteria in 24 patients (77%). After three cycles of lomustine-temozolomide chemotherapy, a reduced mean TBR value by ≥10% predicted a significantly longer PFS (31.0 vs. 10.4 months; P=0.039). In contrast, changes in maximum TBR values, MTV, the RANO 1.0 criteria, and the PET RANO 1.0 criteria were not predictive for response (P>0.05). Multivariate survival analysis revealed that changes in mean TBR values predicted a significantly prolonged PFS independent of age, the extent of resection, and the Karnofsky Performance Status (P=0.036; HR, 3.892; 95% CI, 1.242-17.230).

CONCLUSION

Our results suggest that FET PET is clinically valuable for identifying responders to lomustine-temozolomide chemotherapy in addition to radiotherapy early after treatment initiation. The evaluation of FET PET’s value in predicting a significantly longer overall survival is ongoing.
NIMG-18. RAPID INTRAOPERATIVE DIFFERENTIATION OF PRIMARY CNS LYMPHOMA FROM COMMON CNS TUMORS USING STIMULATED RAMAN HISTOLOGY AND DEEP LEARNING
Authors: Reinecke David , Maroouf Nader , Alber Daniel , Smith Andrew , Hollon Todd C , Neuschmelting Volker , Golfinos John G , Orringer Daniel A
Published: November 2024

Accurate intraoperative diagnosis is crucial for decision-making during tumor surgery and stereotactic-guided biopsies. Differentiating between primary CNS lymphoma (PCNSL) and non-PCNSL entities such as gliomas and metastatic cancers presents significant challenges due to overlapping histomorphological features, time constraints, and the differing further therapy strategies required. Our study utilized deep learning and stimulated Raman histology (SRH) to address this challenge. We imaged unprocessed, label-free tissue samples intraoperatively using a portable Raman scattering microscope, generating virtual H&E-like images within less than five minutes. Our training set comprised over 54,000 SRH tumor patch images, including various brain tumors. We developed a deep learning pipeline utilizing a ResNet-50 feature extractor and the BYOL (Bootstrap Your Own Latent) self-supervised learning algorithm. We trained a binary linear classifier to distinguish between PCNSL and non-PCNSL entities. Data were collected from New York University (NYU), the University of Cologne (UKK), and the University of Michigan (UM), including 263 SRH whole slide images from 177 patients sourced from surgical resections and stereotactic-guided biopsies. In an international bicentric test cohort (N = 100, NYU and UKK), the model achieved an overall accuracy of 91.1%, an area under the receiver operating characteristic curve (AUROC) of 0.983, a sensitivity of 89.3%, and a specificity of 100% compared to the final formalin-fixed, paraffin-embedded-based diagnosis. Our algorithm can accurately extract typical histomorphological features to help differentiate between PCNSL and non-PCNSL tumors. These results underscore the potential of deep learning models to enhance the accuracy of intraoperative diagnoses for PCNSL and non-PCNSL entities, thereby improving intraoperative decision-making and further treatment strategies by supporting neuropathologists and surgeons.
NIMG-29. EARLY REDUCTION IN MRI DIFFUSION APPARENT DIFFUSION COEFFICIENT (ADC) STRONGLY PREDICTS LONG TERM RESPONSE TO ONC201 THERAPY IN PATIENTS WITH H3K27M-DMG
Authors: Lau Benison , Ajaero Diala , Hoff Benjamin , Galban Craig , Parmar Hemant , Ibrahim Mohannad , Koschmann Carl
Published: November 2024

ONC201 is the first monotherapy to improve outcomes in H3K27M- diffuse midline glioma (DMG) beyond radiation. Despite impressive early efficacy in H3K27M-DMG, individual response to ONC201 is variable and no radiographic biomarkers predict long term response. Previous studies demonstrated baseline MRI diffusion apparent diffusion coefficient (ADC) is lower in DMG with H3K27M compared to wildtype but change after radiation therapy was not correlated with improved OS or PFS. We hypothesize ADC will enable stratification of patients more likely to respond to ONC201. Imaging and clinical data were abstracted from chart review of patients treated with ONC201 at University of Michigan. Two neuroradiologists performed centralized review for RAPNO measurements and mean ADC was assessed using ROI measured in consistent anatomic locations, with areas of cystic degeneration or necrosis excluded. Sixty-one patients were identified for review. Preliminary analysis was performed on twenty-three patients, with upfront ONC201 therapy, median age 14.8 years old (5-25yo), primary site includes pontine (n=15), thalamic (n=7). Baseline characteristics of age, ADC and size at diagnosis or follow-up RAPNO scored size were not statistically significant. Patients with longer than median survival (334 days) demonstrated increased ADC (+58.25x10-6mm2/s) from baseline to cycle 2 whereas patients with shorter than median survival demonstrated decreased ADC (-174.8x10-6mm2/s) (p = 0.0076). Further, patients with decreased ADC demonstrated mean OS of 302.8 days and patients with increased ADC had mean OS of 588.0 (p = 0.0054). In H3K27M-DMG patients treated with ONC201, increased ADC after two cycles of ONC201 was strongly predictive of longer overall survival. Our recent work demonstrated that ONC201 disrupts metabolic and epigenetic pathways to restore pathognomonic H3K27me3 reduction, which may underline greater change in ADC. Ongoing work will validate these findings in an independent external cohort and integrate histogram analysis, parametric assessments, MRI perfusion and liquid biopsy biomarkers (cf-tDNA and metabolomics).
NIMG-44. ELEVATED TRANSLOCATOR PROTEIN 18KDA BINDING IN LOW MEAN DIFFUSIVITY CLUSTERS IS A FEATURE OF THE TRANSFORMING GLIOMA AND IDH MUTANT GLIOMA MICROENVIRONMENT
Authors: Breese James , Agushi Erjon , Lewis Daniel , Hinz Rainer , Alfaifi Bandar , Jackson Alan , Waqar Mueez , Coope David
Published: November 2024

Around 95% of low-grade gliomas undergo anaplastic de-differentiation into high-grade gliomas, a process only partially understood from in vivo clinical imaging. 11 patients with suspected transforming gliomas underwent a combined magnetic resonance imaging (MRI) and positron emission tomography (PET) protocol, incorporating post-contrast T1-weighted/FLAIR acquisition for tumour delineation and diffusion tensor imaging. The PET radiotracer [11C]-(R)-PK11195 assessed translocator protein 18kDa (TSPO) distribution, whose upregulation is associated with inflammation/glioma progression. [11C]-(R)-PK11195 binding potential (BPND) maps were generated using the simplified reference tissue model, with the grey-matter cerebellar time-activity curve serving as the reference tissue input function. KMeans clustering of mean diffusivity (MD) intensity values defined spatially distinct “habitats” of high/low MD voxels within the glioma microenvironment. BPND values within high/low MD clustering habitats were evaluated, across glioma grades and isocitrate dehydrogenase (IDH) mutational status. Across all grade 2 and 3 gliomas (n= 6), mean TSPO BPND values in low MD habitats (0.0383 ±0.102) were significantly greater than high MD habitats (-0.045 ±0.142) (p= 0.003). In grade 4 gliomas (n= 5), no significant difference was observed in mean BPND values between low (0.514 ±0.176) and high (0.465 ±0.296) MD habitats (p= 0.543). IDH mutant gliomas (n= 7) exhibited significantly higher mean BPND in low MD habitats (0.116 ±0.225), relative to high habitats (0.052 ±0.287) (p= 0.021). IDH wildtype gliomas (n= 4) showed no significant differences between BPND values in low (0.498 ±0.199) and high MD habitats (0.424 ±0.325) (p= 0.467). Our novel findings demonstrate spatial heterogeneity in TSPO expression within 2/3/IDH mutant gliomas, a characteristic absent from grade 4/IDH wildtype varieties. Regions of restricted diffusion with high TSPO signal in grade 2/3/IDH mutant tumours indicate the heterogenous distribution of active TSPO-expressing immune/neoplastic cell populations, contrasting the homogenous distribution in grade 4/IDH wildtype gliomas, highlighting differences between their inflammatory profile and pathological features.