tbuckley/cabot-search huggingface dataset:
TMIC-30. FOREBRAIN TO HINDBRAIN INVASION IN GLIOBLASTOMA IS DIRECTED BY ANATOMICALLY DISTINCT REACTIVE ASTROCYTES
Authors: Daniel Silver, Sabre Randall, Justin Lathia
Journal: Neuro-Oncology (2024)

Abstract Initial detection of glioblastoma (GBM) often reveals a large mass in the forebrain; however, the hazard for many patients lies in extensive invasion that can extend far from the primary tumor. New evidence suggests that end-stage GBM coincides with malignant infiltration of the pons and brainstem. Mechanisms that direct tumor cells from initial positions within the forebrain to terminal positions in the brainstem are largely unknown. Our analysis indicates that spatially defined, reactive astrocytes instruct GBM cells to either proliferate or invade. During development, astrocytes help establish directional gradients and boundaries that mediate proper routing of migrating neural cells and extending axons. We posit that onco-reactive astrocytes re-engage these guidance programs to direct tumor cells to the brainstem. To test this hypothesis, we exposed a series of human GBM models to media conditioned by cortical, midbrain, or brainstem reactive astrocytes. When treated with cortical conditioned media, tumor cells were driven into a state of hyper-proliferation, which mirrored early-stage forebrain tumor generation. In contrast, midbrain and brainstem conditioned medias suppressed proliferation and enhanced the rate of tumor cell migration. RNA sequencing corroborated these functional data, identifying cell division programs augmented in GBM cells exposed to cortical astrocyte conditioned media. This contrasted with axon development and guidance programs enriched in GBM cells exposed to midbrain and especially brainstem conditioned medias. Finally, mRNA and protein analysis identified region-specific engagement with the Eph-ephrin guidance system patterned along a forebrain to hindbrain trajectory. These data support a new hypothesis that GBM tumors recapitulate a form of neurodevelopment, invading specific anatomic regions based on cues generated by resident reactive astrocytes.
PATH-49. INTRA-OPERATIVE GENETIC ANALYSES FOR DECISION-MAKING DURING TUMOR REMOVAL OF ADULT-TYPE DIFFUSE GLIOMA USING RAPID QUANTITATIVE PCR DEVICE
Authors: Fumiharu Ohka, Sachi Maeda, Hiroki Shimizu, Kazuya Motomura, Kazuhito Takeuchi, Yuichi Nagata, Shoichi Deguchi, Yoshiki Shiba, Junya Yamaguchi, Yuhei Takido, Akihiro Nakamura, Shohei Ito, Ryuta Saito
Journal: Neuro-Oncology (2024)

Abstract 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-40. CLINICAL CHARACTERIZATION OF H3K27M-MUTANT GLIOMAS
Authors: Tatsuya Takezaki, Jun-ichiro Kuroda, Naoki Shinojima, Keitaro Kai, Takahiro Yamamoto, Kenji Fujimoto, Hirotaka Inoue, Hiroyuki Sueyoshi, Keisuke Matsuzaki, Yuki Takeshima, Jin Matsuura, Akitake Mukasa
Journal: Neuro-Oncology (2024)

Abstract Diffuse midline gliomas, H3K27M-altered(DMGs) are a recently defined entity of gliomas, occur in midline, infiltrate diffusely and have poor prognosis. We reviewed our cases of DMGs to describe clinical, pathological, molecular characteristics, retrospectively. We detected 39 H3K27M-mutant cases of our 959 consecutive gliomas(4.1%). All H3K27M mutations were identified genetically. 23 datasets of these H3K27-mutant gliomas are available to detect their clinical, pathological, molecular characteristics. 5 young(8 - 18 y.o.) and 18 adult (28-80 y.o.) were included. All except one H3K27M-altered were WHO Grade III or IV pathologically. Most common location was thalamus(10/23, 43.4%), pons(6/23, 26.1%), brainstem(3/23, 13.0%). 2 non-midline gliomas were included. In this cohort, Median overall survival were 494 days in young patients, 464 days in adult patients. Current adjuvant chemotherapy and radiation-therapy have not prolonged poor prognosis of DMG patients. It is necessary to explore novel therapeutic targets.
CTNI-32. A MULTICENTER PHASE 1 TRIAL OF TUCATINIB, TRASTUZUMAB, AND CAPECITABINE WITH STEREOTACTIC RADIOSURGERY IN PATIENTS WITH BRAIN METASTASES FROM HER2 POSITIVE BREAST CANCER (TUTOR)
Authors: Manmeet Ahluwalia, Ahmad Ozair, Mainak Bardhan, Shreyas Bellur, Amy Starosciak, Dilanis Perche, Atulya Khosla, Daniel Leon-Ariza, Muni Rubens, Yazmin Odia, Minesh Mehta, Rupesh Kotecha, Michael McDermott, Ana Sandoval-Leon, Reshma Mahtani, David Peereboom
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Nearly 20-40% of HER2+ breast cancer patients develop brain metastases (BMs), where stereotactic radiosurgery (SRS) is standard-for-care for local control. Tucatinib, an oral HER2-selective TKI, is safe and efficacious in HER2+ breast cancer in combination with capecitabine and trastuzumab. Synergism between these 3 drugs (TCT) and radiation may enhance DNA damage. This phase 1 trial aims to evaluate TCT plus SRS for HER2+ breast cancer BMs (BCBM). METHODS TUTOR is a pre-registered (NCT05553522), single-arm, multicenter, ongoing, phase 1 trial that aims to determine the safety and efficacy of TCT+SRS in HER2+ BCBM patients. Patients with age 18-80 years, ECOG score 0-2, normal organ function, and ≤10 newly-diagnosed BMs are being enrolled at six US centers. Any number of prior systemic therapies are allowed, except tucatinib and capecitabine. Key exclusion criteria include leptomeningeal metastases, intra-tumoral or peri-tumoral hemorrhage, and BMs ≤5 mm of optic chiasm/nerve. Primary endpoint is maximum tolerated dose (MTD) of tucatinib, in this 3 + 3 de-escalation study starting at dose level (DL) 300 mg BID. DL-1 is 250 mg BID, and DL-2 is 200 mg BID. Secondary endpoints include efficacy as determined by response rate, intracranial progression-free survival (PFS), extracranial PFS, and overall survival. Neurocognitive outcomes are assessed using Hopkins Verbal Learning, Controlled Oral Word Association, Trail Making, and Grooved Pegboard Tests. Toxicities are assessed using CTCAE v5.0. Quality of life is assessed using Functional Assessment of Cancer Therapy with Brain Tumor module. Patients are administered tucatinib with SRS as per treating radiation oncologist, followed by tucatinib for two weeks, i.e. dose-limiting toxicity (DLT) period, followed by TCT until progression or intolerable toxicity. DLTs are defined by Grade 3 or 4 thrombocytopenia, grade 4 anemia, grade 4 neutropenia lasting &amp;gt;7 days, febrile neutropenia, and any non-hematologic toxicity of grade ≥3 (excluding alopecia). Cohort expansion at MTD to 40 patients is planned. Patient enrollment started in February 2023 and remains ongoing.
CTNI-72. VAL-083 IN PATIENTS WITH RECURRENT GLIOBLASTOMA TREATED UNDER EXPANDED ACCESS PROGRAM
Authors: Carlos Kamiya-Matsuoka, Shaio-Pei Weathers, Rebecca Harrison, Nazanin Majd, Ashley Aaroe, Stephanie Knight, Teresa Hanna, Chirag Patel, john Langlands, Dennis Brown, Vinay Puduvalli
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Current standard-of-care for glioblastoma (GBM) includes surgery followed by chemoradiation with temozolomide (TMZ) followed by adjuvant TMZ. Almost all GBM patients experience disease progression despite upfront standard-of-care treatment, with a median overall survival of 3-9 months after first recurrence. There are limited treatment options at the time of disease progression, apart from participation in clinical trials. VAL-083 is a bi-functional DNA damaging agent that induces inter-strand DNA cross-links at N7-guanine in a manner independent of O6-methylguanine-DNA-methyltransferase (MGMT). METHODS Under an Expanded Access program (NCT03138629), we used VAL-083 to treat 30 patients with recurrent GBM who were not eligible to participate in clinical trials. Here we report safety and efficacy results. RESULTS Four patients (13.3%) with leptomeningeal disease were excluded from efficacy evaluation. All patients received chemoradiation with TMZ. Twelve (12/26; 46.2%) patients had ≥2 recurrences and 9/26 (34.6%) had prior lomustine. All tumors had ≥1 mutation, with 14/26 (53.8%) having ≥5 mutations; one patient had a hypermutator phenotype. The most common mutations were TERT (57.7%), PTEN (38.5%), TP53 (26.9%), and NF1 (26.9%). All patients started treatment with VAL-083 at 30 mg/m2/day administered on 3 consecutive days every 21 days. Eight (8/26; 30.8%) patients received bevacizumab concurrently with VAL-083. Eight (8/26; 30.8%) patients had a VAL-083 dose reduction. Patients received a median of 3.0 (5-95pth 1-10) VAL-083 treatment cycles. Median progression free survival (mPFS) and median overall survival (mOS) from last disease progression was 5.1 (95%CI: 2.7-7.2) and 9.8 (95%CI: 5.3-16.4) months, respectively. VAL-083 was well-tolerated and the most frequent adverse events were consistent with prior experience, i.e., thrombocytopenia and neutropenia. CONCLUSIONS Use of VAL-083 continues to show benefit in the treatment of GBM patients who have had multiple recurrences and have limited therapeutic options.
IMMU-30. IGV-001: A BIOLOGIC-DEVICE COMBINATION PRODUCT ELICITS POTENT ANTI-GBM RESPONSES AS A MONOTHERAPY AND IN COMBINATION WITH CHECK POINT INHIBITION
Authors: Jenny Zilberberg, Mark Exley
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Imvax is developing GoldspireTM, a personalized immunotherapy that combines whole tumor-derived cells with an antisense oligonucleotide against insulin-like growth factor 1 receptor (IGF-1R; IMV-001) in biodiffusion chambers (BDCs; 0.1 µm pore). BDCs are irradiated and implanted at abdominal sites for ~48h to deliver an antigenic payload and immunostimulatory factors that together train the immune system to attack tumor cells. The lead product, IGV-001, was evaluated in newly diagnosed glioblastoma (ndGBM) patients in a phase 1b study. Median overall survival (OS) of highest exposure IGV-001-treated Stupp-eligible patients (n=10) was 38.2 mos compared with 16.2 mos in standard-of-care-treated patients (p=0.044; ClinicalTrials.gov NCT02507583). A Phase 2b study in ndGBM is currently underway (ClinicalTrials.gov NCT04485949), where a primary endpoint of progression-free survival and key secondary endpoints of overall survival and safety will be evaluated. METHODS The orthotopically implanted GBM (luciferase-expressing GL261-luc2) model was utilized to evaluate the efficacy of mIGV-001 (the murine version of IGV-001) alone or in combination with anti-PD-1 immunotherapy. The following four groups were compared: mIGV-001 or BDC placebo + isotype or anti-PD-1 antibody (4 doses total every 3-4 days). GL261-luc2 cells were treated with IGF-1R antisense IMV-001. The treated cell suspension was loaded into clinical-grade BDCs (0.1-µm pore size, polyvinylidene difluoride membrane) at a density of 1 × 106 cells per BDC and then irradiated with 5–6 Gy. mIGV-001 or BDCs filled with saline were administered 28 days prior to tumor challenges and tumor progression and survival were monitored for an additional 100 days. RESULTS Preventative treatment with mIGV-001 limited tumor progression and extended OS in mice orthotopically (i.e., intracranially) challenged with GL261-luc2 cells. The therapeutic benefit of mIGV-001 was enhanced with anti-PD-1 treatment and the combination therapy was superior to either monotherapy.
NCMP-20. FACTORS RELATED TO PERMANENT AND TEMPORARY MOTOR DEFICITS IN PATIENTS UNDERGOING GLIOMA RESECTION: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Brian Conway, Stephanie Armstrong, Nada Botros, Sergey Tarima, Max Krucoff
Journal: Neuro-Oncology (2024)

Abstract Standard of care treatment for virtually all glioma subtypes starts with maximal safe resection. However, resections that result in motor deficits can negate any survival benefit from surgery and diminish quality of life. Because current evidence on functional outcomes following glioma resection often conflicts and is limited to a small number of case series, retrospective analyses, and reviews, here we performed the first PRISMA-compliant systematic review and meta-analysis of currently published data to identify factors related to permanent and temporary motor deficits after surgery. We searched Ovid Medline, Scopus, Web of Science, CINAHL/EBSCO, PsychInfo, Cochrane and Wiley for studies reporting motor outcomes following surgical resection of glioma. Outcomes were stratified by patient/tumor characteristics, pre-operative condition, and intra-operative factors for both permanent (≥3 months postop) and temporary (&amp;lt;3 months postop) motor deficits. Generalized estimating equations were used to generate odds ratios and 95% confidence intervals. A total of 1,162 titles and abstracts were reviewed for eligibility resulting in the evaluation of 211 full-text articles. Data were extracted from 55 studies including 1,801 patients with 223 (12%) permanent postoperative motor deficits, 428 (24%) temporary motor deficits, and the remaining 1,150 (64%) without motor deficit. Pre-operative deficit was the strongest predictor of permanent post-operative motor deficit (OR 10.56, CI 5.20-21.45, p=7.2E-11), while high pre-operative Karnofsky Performance Scale (KPS) (OR 0.98, CI 0.97-0.99, p=0.036) and subcortical tumor location (OR 0.15, CI 0.025-0.90, p=0.038) were associated with no permanent deficit. Supratotal resection was significantly associated with temporary motor deficits (OR 3.54E+12, CI 3.53+E13-3.56E+17, p&amp;lt;2E-16), and asleep craniotomies were associated with no deficit (OR 1.68E-01, CI 4.93E-02–5.71E-01, p=0.0043). Ultimately, this study represents the largest analysis of motor outcome data in glioma surgery to date.
EXTH-56. INVESTIGATING THE EFFECTS OF INDIRUBINS IN PEDIATRIC DIFFUSE HIGH GRADE GLIOMA MODELS
Authors: Jasmine Clark, Sean Lawler, Jorge Jimenez-Macias, Philippa Vaughn-Beaucaire, Shengliang Zhang, Wafik El-Deiry, Rishi Lulla
Journal: Neuro-Oncology (2024)

Abstract Diffuse midline glioma (DMG) is a highly invasive and fatal pediatric brain tumor that arises from glial cells within the pons of the brainstem. Despite focal radiation treatment, DMG continues to have a poor prognosis, with a median survival of less than 10 months. A significant challenge in treating DMG is the blood-brain barrier (BBB), which tightly restricts access to therapeutic agents, preventing drugs from reaching the brain at effective concentrations. Previous studies from the Lawler lab have shown that the indirubin derivative 6-bromoindirubin-3′-acetoxime (BIO-acetoxime/BIA) has anti-invasive properties and can enhance survival in glioblastoma xenograft models. We investigated the effects of BIA on pediatric glioma models using various assays. In an in vitro scratch migration assay, BIA significantly slowed cell migration at a concentration of 1µM in pediatric glioma cells over 72 hours. Additionally, BIA was shown to modulate tumor vasculature and improve drug delivery to tumors by targeting tight junctions in tumor-associated endothelium. BIA treatment increased dextran uptake into 3D BBB models and lowered endothelial cell permeability in vitro by reducing the expression of tight junction proteins, as shown by staining and a decrease in TEER values. Furthermore, BIA’s anti-angiogenic effects were demonstrated through staining, showing significant alterations in angiogenesis-related protein expression. To assess potential synergistic interactions, a drug screen was performed on a panel of pediatric glioma cell lines identifying several FDA-approved drugs that combine well with BIA. Drugs identified in the screen are currently under investigation. Our hypothesis is that BIA could be an effective therapeutic agent for DMG by targeting tumor invasion, angiogenesis, and improving drug potency and delivery through modulation of endothelial cell tight junctions. Future studies will focus on elucidating the underlying mechanisms and developing drug formulations for in vivo studies to assess the translational potential of this approach.
DISP-19. ETHNIC DISPARITIES IN METASTASIS PATTERNS AND TREATMENT UTILIZATION AMONG METASTATIC BREAST CANCER PATIENTS WITH BRAIN METASTASIS: A RETROSPECTIVE ANALYSIS OF US HEALTH SYSTEMS DATA (2019-2023)
Authors: Vivek Podder, Tulika Ranjan, Mainak Bardhan, Diya Jayram, Reshma Mahtani, Manmeet Singh Ahluwalia
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION The treatment landscape for metastatic breast cancer (MBC) with brain metastasis (BM) has evolved due to novel therapies. However, outcomes remain poor and vary among groups. This study investigated ethnic disparities in metastasis (mets) patterns and treatment use among MBCBM patients (pts). METHODS We analyzed deidentified data from seven US health systems in the Guardian Research Network from December 2019 to December 2023. Pts with MBC were categorized by IHC scores: hormone receptor+/HER2-, HER2-low (IHC 1+ or 2+ with negative FISH), HER2 positive, and Triple Negative (TNBC). We used descriptive and comparative statistical analysis. RESULTS Of 421 MBC pts, 200 (47.5%) had HER2+, 167 (39.7%) had HR+/HER2-, and 54 (12.8%) had TNBC. 159 (37.7%) were reclassified as HER2-low, primarily from HR+/HER2- (127; 76.0%) and TNBC (32; 59.3%). Bone mets developed in 29.6% of pts, more prevalent in HER2+ (39.5%), TNBC (25.9%), and HR+/HER2- (19.1%) groups. Non-Hispanics showed higher BM prevalence (74.4% vs. 25.6%). HR+/HER2- BM pts had higher bone mets (71.88%) than HER2+ BM (65.82%). TNBC BM pts had the highest rate of liver mets (57.1%). HER2-low BM pts showed mets across liver (40%), lung (34.29%), and bone (68.57%). In the HER2+ BM group, non-Hispanics had higher liver (40.13% vs. 32.35%) and bone mets (69.08% vs. 52.94%) than Hispanics. In TNBC BM group, Hispanics had higher liver mets (66.67% vs. 35%), while non-Hispanics had higher lung mets (32.5% vs. 11.11%). Both ethnic groups in HR+/HER2- category had high bone mets (78.95% vs. 73.33%). There were disparities in the use of CDK4/6 inhibitors, ICIs, and mTOR inhibitors, with Hispanics frequently using them. CONCLUSION HR+/HER2- BM pts were most affected by bone mets, followed by HER2+ BM. TNBC BM pts predominantly had liver mets. Non-Hispanics had higher BM prevalence. Hispanics frequently used ICIs, CDK4/6 and mTOR inhibitors, which were more frequently used by Hispanics. Further research should explore these disparities in mets patterns, treatment choices, and responses.
TMIC-14. RAPID EARLY PROGRESSION IN GLIOBLASTOMA: A COMPREHENSIVE REVIEW OF CLINICAL, IMAGING AND HISTOPATHOLOGICAL FEATURES
Authors: Mueez Waqar, Federico Roncaroli, Claire O’leary, Gabriella Forte, Jenny Wright, Shefali Parikh, Lindsay Sudell, David Coope, Ibrahim Djoukhadar, Gerben Borst
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND In glioblastoma patients, Rapid Early Progression (REP) refers to tumour growth between the time of surgery and postoperative chemoradiotherapy. Despite its high incidence relatively little is known about it. The aim of this study was to characterise REP using a combination of clinical, imaging and histopathology data. METHODS Ethical approval was obtained. Supratentorial IDH-wildtype glioblastomas undergoing gross-total resection (GTR) between 2015-2021 were included. REP was defined as a nodular increase in enhancement located within or around the surgical cavity, occurring within 6 weeks of surgery, that was not accounted for by initial areas of diffusion-restriction. REP cases were propensity-score matched to controls on baseline characteristics. Imaging was compared using mean apparent diffusion coefficient (ADC) and T1-postcontrast radiomics. Tissue analyses included DNA methylation subtyping and immunohistochemistry for markers of T-cells (CD3), microglia (P2RY12) and proliferation (PHH3). RESULTS REP occurred in 8/60 GTR cases (13%) and these patients were matched to 16 controls. REP cases had a worse preoperative performance status (median Eastern Cooperative Oncology Group [ECOG] 2 vs. 1), overall-survival (p=0.038) and progression-free survival (p = 0.029). REP was more common in patients over 65 years (27%) and significantly fewer REP patients received radical postoperative chemoradiotherapy (p=0.023). REP and control cases were well matched with respect to preoperative T1-postcontrast radiomics and mean ADC in enhancing (p=0.99) and non-enhancing regions (p=0.67). There was no relative excess of any one DNA methylation subtype in REP cases. The two groups had a similar proportion of T-cells (p=0.81), but REP cases had a trend towards a higher proportion of microglia (31% vs. 17%; p=0.22), and a lower proliferation rate (3% vs. 9%; p=0.19). CONCLUSION REP cases had a worse performance status from diagnosis and received less radical postoperative chemoradiotherapy protocols compared to controls, yielding a significantly shorter median OS/PFS. Differences in immune landscape and proliferation rate should be further investigated.