tbuckley/cabot-search huggingface dataset:
TMET-37. TARGETING LIPID MEDIATED NON-CANONICAL CELL DEATH IN MALIGNANT GLIOMA
Authors: Jennifer Salinas, Dimitri Cadet, Sarina Smolev, Dhruva Iyer, Caitlyn Loo, Weaverly Lee, Scott Dixon, David Nathanson
Journal: Neuro-Oncology (2024)

Abstract Resistance to canonical cell death mechanisms (e.g. apoptosis) is a hallmark of glioma and consequently driving the dismal outcomes of patients with glioma. Recent work has demonstrated gliomas are susceptible to non-apoptotic forms of cell death mediated by rewired lipid metabolism. Here we explored whether gliomas are vulnerable to other lipid-dependent forms of cell death. Our investigation revealed a large subset of patient-derived glioma cells that are exquisitely sensitive to a novel cell death pathway dependent on palmitate. Intriguingly, sensitivity to this type of cell death was linked to glioma tumor cells having a proneural identity and a specific enrichment in sphingolipid metabolic features. The catabolism of glioma sphingolipids established palmitate pools for protein S-palmitoylation, a necessary requirement to trigger palmitate mediated cell death in glioma, which was coupled to the exclusive expression of palmitoyl acyltransferases unique to proneural glioma tumors. Ongoing efforts aim to explore the mechanistic link between glioma identity, lipotype and susceptibility to palmitate dependent lethality. Taken together, these results identify a new approach to drive glioma cell death by targeting non-canonical cell death mediated by rewired glioma lipid metabolism.
QLTI-01. ASSESSING THE EFFECTIVENESS OF SUPPORT FROM ST. JUDE CHILDREN’S RESEARCH HOSPITAL TO VIETNAMESE TEAM IN TREATMENT FOR CHILDREN WITH BRAIN TUMORS
Authors: Hoa Thi Kim Nguyen, Lan Ngoc Bui, Duy Canh Phan, An Thi Thanh Dao, Anh Hoang Mai Nguyen, Thach Ngoc Hoang, Thanh Cam Do, Dinh Van Nguyen, Andini Handayani, Sally Blair, Catherine G Lam, Ibrahim Qaddoumi
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Treatment for children with brain tumors requires multidisciplinary team (MDT) which is lacking in Vietnam which negatively impacts outcome. This study aims to describe the implementation and promotion of MDT approach in Vietnam with the support of St. Jude Children’s Research Hospital. METHODS We conducted a prospective descriptive study of St. Jude Children’s Research Hospital’s activities with the Vietnamese team between August 2023 and March 2024 and its impact on education, patient care and disseminating of MDC approach in Vietnam. RESULTS Onsite and online training were provided for the Vietnamese team during this time. The onsite training included exchange visits for both teams and St. Jude support for Vietnamese colleagues to attend regional and international neuro-oncology conferences. Online case discussions have been held every month from January 2024 and there are 40-60 participants each meeting from 5 main oncology centers in Vietnam. There are 3- 4 complex case discussions each meeting. A zalo group (a social media platform) for Vietnamese doctors (92 doctors) with multidisciplinary team members was established. After discussion, references and summaries of each case were distributed to the zalo group. For emergency cases, email consults are requested directly for timely input. In addition, key educational textbooks covering different disciplines of neuro-oncology (pathology, radiology and medical) were provided to different Vietnamese teams. All participants (92 doctors) found the online discussion (100.0%) benefical to further their knowledge in different fields (chemotherapy, radiation, pathology and surgery) and the outcome of consultations which guided teams to manage difficult cases. For some cases, pathology samples with local reports are sent to St. Jude to review the diagnosis and classification. CONCLUSIONS Training plays an important role in bringing knowledge and building team-based experience for Vietnamese clinicians in the treatment for children with brain tumor.
EPID-36. CLINICAL FEATURES OF 614 PRIMARY INTRACRANIAL GERM CELL TUMORS: AN 15-YEAR EXPERIENCE OF A SINGLE CENTER IN CHINA
Authors: Jing-Jing Ge, Cheng Li, Feng-Jun Xue, Shao-Pei Qi, Chi Zhao, Chen-Chen Kong, Chuan Zhao, Jun-Ping Zhang
Journal: Neuro-Oncology (2024)

Abstract Incidence of primary intracranial germ cell tumors (ICGCT) in Asian countries is higher than Western countries. This study aims to describe the characteristics of ICGCT patients in China. Data on all patients with ICGCT who were seen at the Department of Neuro-oncology, Sanbo Brain Hospital, Capital Medical University from 2007 to 2022 were collected retrospectively. Patient demographics, disease characteristics and treatment outcomes were analyzed. A total of 614 patients were identified, with 309 germinomas and 305 non-germinomatous germ cell tumors (NGGCT). The median age at diagnosis was 12.8 years. The male-female ratio is 2.4 to 1. The primary disease sites were mainly pineal gland and suprasellar region. Adults (age≥23) were more likely to develop germinomas (65.3%). 78% patients received radiotherapy after initial diagnosis. In M0 patients, whole brain radiotherapy was the most common approach, while in M+ was craniospinal radiotherapy. Whole ventricle radiotherapy was uncommon (4%). The most common chemotherapy regimen for germinoma was a combination of bleomycin, cisplatin and etoposide/tenipside; while for the NGGCT was ifosfamide combined with carboplatin/cisplatin and etoposide. For germinoma, the median recurrence-free survival (RFS) and overall survival (OS) were 150.3 months and 222 months; the 10 year RFS and OS were 58.2% and 85.1%, respectively. For NGGCT, the median RFS and OS were 80.4 months and 166.7 months; the 10 year RFS and OS were 46.9% and 60.5%. At relapse, four (0.65%) developed secondary malignancies. Seven (1.14%) developed extracranial dissemination. Chemotherapy and radiotherapy could improve the RFS and OS. Higher radiation dose was associated with better prognosis. The prognosis of focal radiotherapy alone was poor. M0 germinoma treated with focal radiotherapy alone were more likely relapse. This study suggested that treatment outcomes of our ICGCT patients are comparable with those in Western centers. Adjuvant chemotherapy and whole brain/craniospinal radiotherapy are pivotal treatment.
SURG-15. THE INCONSISTENT TERMINOLOGY FOR EXTENT OF RESECTION IN GLIOBLASTOMA: A SYSTEMATIC REVIEW ON SIX DECADES OF NEURO-ONCOLOGICAL STUDIES
Authors: Nina C Teske, Leonard B Jung, Nico Teske, Niklas Thon, Jörg-Christian Tonn, Philipp Karschnia
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND More extensive resection leads to improved outcomes in patients with newly diagnosed glioblastoma. Insufficient recognition of extent of resection may introduce significant bias in clinical trials. This study aimed to systematically characterize the terminology used to describe resection in neuro-oncological studies. METHODS We conducted a comprehensive review of the PubMed database to identify neuro-oncological trials between January 1966 and January 2024. We selected studies providing information on extent of resection for newly diagnosed glioblastoma in adults. A standardized set of semantic and clinical variables was extracted for each study. RESULTS We screened a total of 1862 neuro-oncological studies, and 117 studies comprising 44 prospective interventional trials and 73 retrospective studies met our inclusion criteria. While a positive association between outcome and more extensive resection was almost universally reported, a broad range of 15 different semantic terms were used to describe extent of resection (e.g., “complete/incomplete”, “gross-total/subtotal”, or “total/partial” resection). Reflecting this inconsistent terminology, only 60 studies (60/117, 51%) provided explicit definitions for categorizing extent of resection. Of these 60 studies, 17 (17/60, 28%) used subjective measurements including intraoperative estimations for extent of resection, while 43 studies (43/60, 72%) relied on objective measurements of volumetrics on pre- and post-operative imaging. There was no difference in the number of objective definitions between prospective and retrospective studies. However, the number of studies with objective definitions was significantly higher in surgical studies compared to medical neuro-oncological studies and increased over recent years (before 2010: 21%; after 2010: 41%). CONCLUSION The terminology used to describe the extent of resection varies greatly across neuro-oncological studies. To minimize imbalances between study arms and enable comparisons across different institutions, adopting a standardized surgical nomenclature appears essential. The recent RANO resect classification for extent of resection might form the basis for such a standardized terminology.
ANGI-14. DRUGGABLE GENOME CRISPR SCREEN IN 3D HYDROGEL DEVICES REVEALS TARGETABLE KINASES AND PHOSPHATASES IMPLICATED IN CYTOSKELETAL REORGANIZATION IN INVADING GBM CELLS
Authors: Mufeng Hu, Anna Weldy, Erin Akins, Saket Jain, Alexander Chang, Sanjay Kumar, Manish Aghi
Journal: Neuro-Oncology (2024)

Abstract The invasive nature of glioblastoma cells into adjacent brain tissues is a key factor in its unfavorable prognosis. To decipher the mechanisms driving glioblastoma invasion, we developed microdissectable biomimetic 3D hydrogel invasion devices containing hyaluronic acid hydrogels decorated with integrin-binding peptides (RGD) and crosslinked with protease-cleavable crosslinkers. The ability to disassemble these devices and interrogate cells in the core vs. invasive fraction allows for high throughput screens. We thus performed a screen in GBM43 cells expressing CRISPR/Cas9 and a 13,250 gRNA library targeting the 2550 genes in the druggable human genome. Of seven initial hits from this screen, only two could be validated by single gene CRISPR and use of a drug to target the hit - ACP1 (also known as LMW-PTP) and Aurora Kinase B (AURKB). Integration of ChIP-seq and RNA-seq revealed no plausible transcriptional targets of ACP1 and AURKB that could drive invasion. Proximity labeling with the TurboID system identified CTTN (cortactin), an actin binding protein whose phosphorylation is integral to the formation of lamellipodia and invadopodia, as phosphorylated by AURKB and Ephrin A2 (EPHA2), whose dephosphorylation controls cell morphology, adhesion, migration and invasion by modifying the organization of the actin cytoskeleton and influencing the activities of integrins and intercellular adhesion molecules, as dephosphorylated by ACP1. These findings underscore the delicate balance between kinase and phosphatase activities in regulating the actin cytoskeleton broadly and at the cell’s front or “leading edge,” offering new therapeutic targets to disrupt the invasion that is a hallmark of glioblastoma.
RADT-21. EFFICACY AND SAFETY OF DONUT-SHAPED CIRCUMFERENTIAL SPINE CYBERKNIFE STEREOTACTIC BODY RADIOTHERAPY FOR METASTATIC SPINE DISEASE
Authors: David Park, Ahed Kattaa, Steven Chang
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Spinal metastases (SM) with epidural spinal cord compression (ESCC) are challenging to manage due to the risk of radiation-induced injury. Traditional approaches often avoid circumferential stereotactic body radiotherapy (SBRT) because of these risks. The efficacy and safety of donut-shaped circumferential SBRT, which envelops the spinal column while sparing the cord, remains underexplored. OBJECTIVE This study evaluates the safety and efficacy of donut-shaped circumferential spine CyberKnife SBRT in treating spinal metastases, focusing on preventing radiation-induced myelopathy and achieving local tumor control. METHOD We retrospectively analyzed patients treated with donut-shaped circumferential spine SBRT from 2014 to 2023. We evaluated demographics, grade of ESCC (Bilsky), prior treatments, symptoms, treatment parameters, and outcomes. Key measures included SBRT dosimetric data, radiation exposure to the spinal cord or cauda equina, adherence to dose-volume constraints, occurrence of post-SBRT myelopathy, other radiation-induced complications, and local tumor control. RESULTS Forty-eight lesions from 43 patients (median age: 65 years; range: 20-78) were analyzed. Only one patient underwent separation surgery for severe ESCC (Bilsky grade 3). The median clinical target volume (CTV) was 63.77 cc (range: 20.31-270.05), and the median margin dose was 24 Gy (range: 18-30). Over a median follow-up of 8 months (range: 1-91), local tumor control rates were 91.1% at 6 months, 87.1% at 1 year, 82.8% at 3 years, and 62.1% at 5 years. Median overall survival was 17 months. Of 20 lesions exceeding dose constraints, only one patient displayed clinical myelopathy symptoms, correlating with local tumor recurrence. There was no radiographic myelopathy or other radiation-induced complications during follow-up. CONCLUSION Donut-shaped circumferential spine CyberKnife SBRT provides effective and safe treatment for spinal metastases with or without epidural involvement. It achieves substantial local tumor control and has a minimal incidence of radiation-induced myelopathy, offering a viable non-surgical option for managing this complex condition.
EPID-26. STEREOTACTIC RADIOSURGERY FOR CRANIAL NERVE METASTASES: A SINGLE INSTITUTION EXPERIENCE
Authors: Amit Persad, Nastaran Shahsavari, Maleeha Ahmad, Tamra-Lee McCleary, David Park, Yusuke Hori, Sara Emrich, Louisa Ustrzynski, Armine Tayag, Xuejun Gu, Elham Rahimy, Erqi Pollom, Scott Solyts, Antonio Meola, Steven Chang
Journal: Neuro-Oncology (2024)

Abstract Cranial nerve metastases (CNM) can be primary via leptomeningeal metastasis or secondary by spread due to head and neck cancers or due to distant tumor metastasis to the skull base. In addition, they may cause cranial nerve-related symptoms that can impact patient quality of life. We performed a single-center retrospective cohort study of all patients with CNM treated with SRS at our institution between April 2003 and February 2021. Demographic and clinical information were retrieved from the electronic medical record. Median follow-up was 12.9 months. Our study cohort consisted of 9 patients with primary CNM and 8 with secondary CNM – for a total of 17 patients, with a total of 33 lesions (23 primary, 10 secondary). Eleven patients (64.7%) had symptoms caused by cranial nerve metastases. Symptoms were resolved in 5 of 11 patients (45.5%) after SRS. Patients with secondary CNM were more likely to have cranial nerve symptoms and more likely to have resolution of symptoms following SRS. The median time between SRS and symptom improvement was 3 months. Local tumor control was achieved in 30 of 33 lesions (90.9%). Local tumor control at 6 months and at 1 year were 100%. Our study suggests that SRS may be a safe and effective treatment for cranial nerve metastasis providing 90.9% local tumor control at final follow-up, and symptomatic stability or improvement in 90.9% of symptomatic cases. Patients with secondary CNM may stand to benefit more from a symptom management standpoint.
TMIC-01. TARGETABLE GENE EXPRESSION CHANGES MEDIATE EXTRAVASATION OF BREAST CANCER CELLS FROM THE CIRCULATION AND LOCAL PROLIFERATION IN THE BRAIN
Authors: Venina Kalistratova, Ramin Morshed, Eric Chalif, Sabraj Gill, Harmon Khela, Meeki Lad, Ankita Sati, Aakriti Mathur, Manish Aghi
Journal: Neuro-Oncology (2024)

Abstract As breast cancer migrates into the brain, it acquires distinct genomic, immunologic and phenotypic changes through interactions with the local microenvironment. We sought to determine how targetable gene expression changes mediate breast cancer extravasation into and proliferation within the brain. We created a brain metastatic cell line (“brain-seeking”) via serial intracardiac injection of mCherry+ 4T1 breast cancer cells in Balb/c mice and flow cytometry isolation of micrometastases. We conducted in vitro and in-vivo studies to uncover immunological and genetic differences between primary breast cancer and brain metastases. In culture, we observed significant upregulation in adhesion (p=0.01) and invasion (p=0.0004) along with upregulation of adhesion-promoting genes such as Sdc3, Serpine2 or ECM1 in brain-seeking cells. We observed significant differences in survival of Balb/c mice injected intracranially with brain-seeking cells vs. breast cancer cells (p=0.04). In the mammary fat pad (MFP), parental 4T1 cells caused increased mortality vs. brain-seeking cells (p=0.003). This rejection of brain-seeking 4T1 cells in the MFP could be due to prior adaptation to the brain microenvironment, while rejection of parental 4T1 cells in the brain could be due to lacking said adaptations. Consistent with this finding, of 20,382 analyzed genes in both cell lines, 108 related to immune regulation were significantly upregulated in brain-seeking cells including Cxcl1, Dusp1, C3. Flow cytometry showed increased cytotoxic and helper T cells in intracranially injected parental vs. brain-seeking cells (p &amp;lt;0.001). In the MFP, however, 4T1 parental cells displayed CD3+ T cell depletion and an increased number of neutrophils (p &amp;lt;0.05) while the “brain-seeking cells” showed increased numbers of CD3+ and CD4+ cells (p &amp;lt;0.01) and macrophages (p&amp;lt;0.05). This suggests that brain metastases evolve from their primary tumor through adhesive and invasive adaptations promoting extravasation, along with unique immunological adaptations that allow their proliferation free of immune surveillance in the brain microenvironment.
DDDR-13. OPTIMIZING BRAIN CANCER THERAPY: BALANCING TUMOR ERADICATION AND NORMAL TISSUE PRESERVATION WITH BPM31510
Authors: Abbas Khojasteh, Mustafa Tansel Kendirli, Niven Narain, Seema Nagpal, Maria-Dorothea Nastke, Stephane Gesta, Lawrence Recht
Journal: Neuro-Oncology (2024)

Abstract The challenges translating glioblastoma therapies lie in safeguarding normal neuronal and glial tissue. Considering that the central nervous system has the lowest regenerative capacity, the exclusive focus on tumor eradication while neglecting normal tissue response, impedes proper healing. This oversight leads to toxicities ultimately culminating in patient demise with marginal gain in survival. BPM31510 is a nanodispersion encapsulating highly hydrophobic oxidized Coenzyme Q10 (CoQ10), allowing for delivery of supraphysiological CoQ10 concentrations into cancer cells. Initial investigations demonstrated differential responsiveness between cancer and non-cancer cells in vitro, an effect associated with high superoxide levels exclusively in cancer cells. To evaluate this divergence between cancer and non-cancer cells, a competitive co-culture cell-based assay was developed with labeled pairs of glioblastoma and non-cancer cells incubated up to three weeks with various concentrations of BPM31510 to ascertain optimal concentration leading to preferential growth of non-cancer cells. Human astrocyte (HA), mouse fibroblast (NIH 3T3), and rat astrocyte (TNC1) cells were paired with U251 human glioma, mouse GL261 and rat C6 glioma, respectively. Cell growth and spatial extent of the plate containing non-cancer or tumor cells were monitored every other day. Using doxorubicin as control, no dosage was discerned in which non-cancer cells exhibited advantage over tumor cells (i.e., either cultures became all tumor cells or both cell lines were eradicated). Using various concentrations of BPM31510, we identified an optimal dose in which cancer cells diminished while non-cancer cells predominated, reflected by markedly elevated mitochondrial superoxide levels in cancer cells prior to cell death. A co-culture cell-based assay was developed to identify an optimal dose of BPM31510 with selective preservation of non-cancer cells alongside tumor cell death. This approach elucidates developing a “fine tuning” strategy, wherein BPM31510 is titrated over time, thereby promoting normal tissue and healing, and ultimately leading to superior and prolonged functional outcomes.
CNSC-32. CHARACTERISTIC ANALYSIS OF SPREAD AND METASTASIS OF HIGH-GRADE GLIOMA
Authors: Shaoqun Li, Mingya Lai, Lichao Wang, Yangqiong Zhang, Minting Ye, Juan Li, Ruyu Ai, Linbo Cai
Journal: Neuro-Oncology (2024)

Abstract OBJECT Exploring the clinical characteristics of spread and metastasis of high-grade glioma is helpful for clinicians to further understand high-grade glioma, optimize clinical decision-making, and make treatment plans. METHOD Clinical data of patients diagnosed with WHO Grade 4 glioma with spread and metastasis in the course of disease in Guangdong Sanjiu Brain Hospital from January 1, 2017 to December 31, 2020 were collected and analyzed. RESULTS 93 patients were included in the analysis, 59 males and 34 females, median age of 42 years (3-71 years). Tumors were located supratentorial in 78 patients (83.9%). Most patients (70, 75.3%) had tumors adjacent to the ventricular system. 28 patients (30.1%) had tumor spread at first diagnosis. All patients received surgical at first diagnosis, including total resection in 36 cases (38.7%), partial resection in 42 cases (45.2%), and biopsy in 15 cases (16.1%). In 48 patients (51.6%), ventricles were opened during operation. 69 cases (74.2%) were pathologically diagnosed with glioblastoma, 81 cases (92.0%) were IDH wild-type. MRI findings of dissemination were linear in 50.0% (46 cases), nodular type in 25.0% (23 cases), mixed type in 25.0% (23 cases), and the remaining 1 case was undetermined. Cerebrospinal fluid examination was performed in 37 cases, which 11 cases were cytological positive (29.7%). Median OS for patients with initial dissemination was 338 days. Of the 68 patients developed transmission after treatment, median OS fro initial diagnosis to transmission was 254 days, the overall median OS was 409 days. The overall median OS for all patients was 403 days. The median OS of newly diagnosed patients with tumor spread was lower than that of patients with tumor spread after treatment, but there was no statistical difference (p=0.05). CONCLUSION Most high-grade glioma patients develop tumor spread within 1 year, and these patients have unique clinical characteristics. The positive rate of cerebrospinal fluid tumor cells is low, MRI imaging is still the main diagnostic option.