tbuckley/cabot-search huggingface dataset:
TMET-38. BIOCHEMICAL CHARACTERIZATION OF PSAMMOMATOUS MENINGIOMA USING MAGNETIC RESONANCE SPECTROSCOPY
Authors: Omkar B Ijare, Suzanne Z Powell, David S Baskin, Kumar Pichumani
Journal: Neuro-Oncology (2024)

Abstract Psammomatous meningioma is a histologic subtype of meningioma and is presented as a highly calcified intracranial or spinal lesion. Although computed tomography (CT) and short/zero echo-time MRI techniques can detect calcification in tumors, a complete biochemical profile of psammomatous meningiomas is not known. Here, we compare the metabolomic profiles of common meningiomas (WHO grade-I and grade-II) and a psammomatous meningioma using ex vivo proton magnetic resonance spectroscopy (1H MRS). The tumor specimens were collected from meningioma patients undergoing surgery for the resection of the tumor mass. Tumor samples were extracted in 5% perchloric acid, centrifuged, supernatants were vacuum dried and reconstituted in D2O containing 1.0 mM sodium 2,2-dimethyl- 2-silapentane-5-sulfonate-d₆ (DSS-d6, internal standard). Previously, we have identified the following metabolites in grade-I and grade-II meningioma tumors: leucine, isoleucine, valine, lactate, alanine, acetate, glutamate, succinate, glutamine, aspartate, creatine, phosphocreatine, phosphocholine, glycerophosphocholine, myo-inositol, scyllo-inositol, taurine, hypotaurine, glycine, phosphoethanolamine, and glucose. In the current study, psammomatous meningioma also showed the presence of all the above metabolites; however, the levels of these metabolites were lower concentrations compared to the grade-I and grade-II meningiomas, except for lactate. In addition to the above-mentioned metabolites, psammomatous meningioma showed the presence of citrate which was not detected in other meningioma subtypes. Citrate is a major component of bone and the presence of citrate (~614 µM/g, tissue) in psammomatous meningioma could be due to the calcification occurring in these tumors. Surgical pathology report of resected tissue specimen showed clusters and small whorls of meningothelial cells with scattered calcifications, consistent with psammomatous meningioma (WHO grade-I; Ki-67 = 3%). In conclusion, detection of citrate by 1H MRS in meningiomas can be helpful in the differential diagnosis of psammomatous meningiomas.
INNV-23. UNDERSTANDING THE BURDEN OF MIDH1/2 DIFFUSE GLIOMA AND THE COMPLEXITY OF NAVIGATING THE PATIENT PATHWAY: INSIGHTS FROM PATIENTS AND CAREGIVERS
Authors: Kathy Oliver, Mary Burton, Craig Cardinal, Shannon LaHay, Bernard Leon, Rebecca Mallett, Sarah Rogers, Chris Tse
Journal: Neuro-Oncology (2024)

Abstract 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.
TMIC-04. SPATIAL SEQUENCING OF MEDULLOBLASTOMA REVEALS BIOLOGICAL NICHES CORRELATED WITH HIGH-RISK FEATURES AND RELAPSE
Authors: Marina Michaud, Franklin Chien, Mojtaba Bakhtia, Matija Snuderl, Chanel Schroff, Matthew Schneiderjan, Tobey MacDonald, Manoj Bhasin
Journal: Neuro-Oncology (2024)

Abstract Medulloblastoma (MB) defines a heterogeneous set of neuroepithelial cancers of the posterior fossa. The MB tumor microenvironment (MB-TME) influences tumor progression and therapy response and has emerged as a growing target for novel therapeutic approaches. Prior single-cell analysis has characterized the MB-TME composition but does not reveal the spatial orientation of components. To address this gap, we performed 10X Visium spatial sequencing on sixteen pediatric MB samples obtained at surgical resection with samples representing the four molecular subtypes (WNT, N=1; SHH, N=6; Group 3, N=2; Group 4, N=5) and two matching samples at diagnosis and relapse. Spatial voxel clustering yielded clusters corresponding to malignant, immune, and stromal components of the TME, including tumor-associated astrocytes (TAAs), macrophages (TAMs), and vascular endothelium. Ten distinct clusters emerged representing malignant cell states, defined primarily by programs of cell cycle progression and neuronal differentiation. Notably, these MB cell clusters were differentially abundant between the MB subgroups, highlighting heterogeneity between disease subtypes. Moreover, examining the patterns of cellular spatial distribution in high-risk (HR) patients revealed dense regions of quiescent MB progenitors, while standard-risk patients showed greater heterogeneity within their TME. Proximity-dependent intercellular signaling further highlighted increased signaling by TAAs and vascular endothelium with decreased heat shock response signaling in HR patients. Comparing samples from relapse to diagnosis, TAMs, TAAs, and vascular endothelium were found to constitute a greater proportion of the TME. Subsequent niche-dependent gene expression and pathway analysis for TAAs localized near tumor vasculature in relapsed samples revealed increased expression of metastasis-associated pathways. Collectively, the results of our study enable new insight into the heterogeneity of the MB-TME, with close spatial association of quiescent MB progenitors correlating with high-risk clinical features. Quiescent MB progenitors have been documented to confer resistance through cellular dormancy, and identifying its molecular drivers may reveal potential targets for anticancer therapy.
TMET-27. MACHINE LEARNING-BASED IDENTIFICATION OF METABOLIC FLUXES IN PATIENT BRAIN TUMORS
Authors: Baharan Meghdadi, Anjali Mittal, Andrew Scott, Ningning Liang, Sravya Palavalasa, Abhinav Achreja, Alexandra O’Brien Ayesha Kothari, Weihua Zhou, Jie Xu, Angelica Lin, Kari Wilder-Romans, Donna Edwards, Zhe Wu, Jiane Feng, Anthony Andren, Li Zhang, Vijay Tarnal, Kimberly Redic, Nathan Qi, Theodore Lawrence, Costas Lyssiotis, Wajd Al-Holou, Daniel Wahl, Deepak Nagrath
Journal: Neuro-Oncology (2024)

Abstract Personalized oncology aims to match effective treatments for individual cancer patients based on the biology of an individual tumor. This approach is not possible for metabolic therapies due to our inability to quantify metabolic activity in patient tumors, even when patients are infused with 13C-glucose. We overcame this challenge by generating training data with a prior knowledge of 13C-glucose infused patient data and implementing a machine learning model to predict fluxes. We trained a convolutional neural network (CNN) to predict flux ratios. To validate our model, we compared predicted flux ratios to the experimental 13C-glucose-infused mouse models to predict treatment responses for: (1) pharmacologic inhibition of de novo GMP synthesis and (2) environmental serine restriction. Our GMP synthesis model predicted elevated GMP synthesis in GBM compared to cortex in a mouse model and discriminated between sources of GMP synthesis in patients. These findings allow prediction of potential responders to mycophenolate mofetil (MMF), which inhibits de novo but not salvage GMP synthesis. Furthermore, we previously showed that circulating serine uptake is higher in GBM than normal cortex, and a serine- and glycine-restricted diet slows tumor growth in mice. While de novo serine synthesis, circulating and microenvironmental-derived serine could account for serine sources in GBM, our model can distinguish between serine sources in patients, hence potentially predict response to dietary serine depletion. Thus, we have shown that our model may identify patients who will benefit from MMF treatment or a serine- and glycine-restricted diet, potentially enabling administration of highly effective personalized metabolic treatments for GBM patients.
QLTI-15. MEDICAL MALPRACTICE AND GLIOMA
Authors: Rose Fluss, Celina Crisman
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Medical malpractice affects the practice of medicine in every field and specialty. It is a particular concern in high risk specialties including neurological surgery, which has the greatest risk of malpractice litigation. Treatment of glioma patients is complex and requires diagnosis based on presentation and imaging, followed by the decision of resection versus biopsy to confirm diagnosis and potentially improve prognosis. The possibility of a complication accompanies every procedure and patients generally also go on to receive chemotherapy and radiation. Interdisciplinary care is a hallmark. We explored medical malpractice litigation pertaining to gliomas with a focus on outcomes and the role of the defendants as well as the liabilities prompting litigation. METHODS WestLaw Precision, an established legal database, was queried for all cases relevant to “glioma” occurring since 2000. Cases and settlements, in particular, were considered. Keywords included “glioma” and “medical malpractice” with the date range including all cases after January 1, 2000. Cases were identified and analyzed for variables of interest. RESULTS Fourteen relevant cases were identified and reviewed. There were three plaintiff verdicts, one settlement and ten defense verdicts in favor of the defense. Two cases involved minors, while all others concerned adults. Both cases pertaining to the care of minors with gliomas resulted in findings for the defense. The majority of cases centered on failure to diagnose occurring before surgery or treatment. Defendants included neurosurgeons, pathologists, radiologists, nurses and hospital systems. Although the number of cases considered here is small, jury verdicts in favor of plaintiffs resulted in far higher payouts compared with settlements. CONCLUSIONS Medical malpractice allegations relating to glioma treatment are shown to be rare and infrequent. The majority of cases alleged a failure to appropriately diagnose, before surgery or treatment took place. The great majority of cases reported within WestLaw Precision resulted in jury verdicts for the defense.
QLTI-21. STREAMLINING THE STUDY INTAKE PROCESS AT THE CANCER CLINICAL AND TRANSLATIONAL RESEARCH OFFICE (CCTRO)
Authors: Raid Faddah, Tobias Walbert, James Snyder, Shirish Gadgeel, Philip Philip, Lisa Lange
Journal: Neuro-Oncology (2024)

Abstract Challenges in the Protocol Intake/Activation process at the Henry Ford Cancer Center, particularly during the budget negotiation and coverage analysis (CA) phases, hamper operational efficiency and financial prospects. This study aimed to improve budget time and process efficiency. Process flow mapping, Value Stream Mapping (VSM), and cause-effect analysis using a fishbone diagram were used to identify and analyze key bottlenecks, focusing on the budget negotiation and CA phases. Budget negotiation took an average of 121.5 days in 2023 due to multiple procedures and a lack of standardized practices. Delays ranged from 127.75 days in August to a low of 69.84 days in November of 2023. The budget build process averaged 13.31 days, with an additional 7.57 days for approval, totaling 20.89 days. The CA phase had an average cycle time of 10.82 days (range 2-10 days). To improve approval times, it was recommended to implement an Electronic Document Management System to automate routing, signing, and tracking of budget and CA-related documents, standardized budget templates to streamline negotiations, a detailed electronic checklist to streamline task lists for document collection and budget negotiation, automated reminders for internal and external stakeholders to ensure timely submission of necessary documents, and timely submission policies enforced by a dedicated finance member on committees. Newly developed Key Performance Indicators (KPIs) such as ‘time to collect documents,’ ‘time between committees,’ and ‘time for budget negotiation process,’ along with a dual tracking system in Excel, were proposed to monitor and improve these metrics. The recommendations are expected to significantly enhance the efficiency of the Protocol Intake/Activation process. By reducing the budget negotiation phase to less than 60 days and optimizing the CA process, faster study initiation, better resource utilization, and improved responsiveness to research opportunities will be achieved. This study underscores the critical need to address operational challenges in clinical trial management to enhance CCTRO’s capability to conduct timely and effective research.
EPID-29. EPIDEMIOLOGICAL CHARACTERIZATION OF BRAIN METASTASES IN MELANOMA: A LARGE POPULATION BASED-STUDY FROM 2014-2024
Authors: Anita Kalluri, Patrick Kramer, Megan Parker, Kelly Jiang, Joshua Materi, Tej Azad, David Kamson, Kristin Redmond, Govind Warrier, Evan Lipson, Xiaobu Ye, Chetan Bettegowda, Jordina Rincon-Torroella
Journal: Neuro-Oncology (2024)

Abstract Brain metastases (BM) are the second most common cause of mortality in metastatic melanoma. Despite increased screening, mortality remains substantial. Additionally, population-based studies of melanoma BM capture only synchronous metastases, therefore up-to-date epidemiological and survival studies may better inform screening and management strategies. Thus, we retrospectively analyzed the TrinetX Oncology dataset to study the prevalence and survival patterns of patients with melanoma BM. Data from 13,505 patients with histologically-confirmed melanoma was extracted. Demographic and clinical parameters were compared between patients with and without BM via t-test and chi-squared analysis. Overall survival (OS) was evaluated using Kaplan-Meier and Cox regression analyses after cohorts were propensity-matched for age, sex, race, ethnicity, stage, extracranial metastases, excision of skin lesions, radiation, and antineoplastic utilization. In our study, the prevalence of BM was 7.3% (9.2% precocious, 22.5% synchronous, 68.3% metachronous). Compared to patients without BM, patients who developed BM were more often male (p&amp;lt;0.0001), non-Hispanic (p&amp;lt;0.0001), White (p&amp;lt;0.02), and presented with advanced-stage disease (p&amp;lt;0.0001). Patients with unspecified malignant melanoma (p&amp;lt;0.0001) and nodular melanoma (p&amp;lt;0.0001) were more likely to develop BM compared to those with other histological subtypes. Additionally, patients with BM were more likely to have ulceration (p&amp;lt;0.0001) and extracranial metastases (p&amp;lt;0.0001). Skin excision procedures were less common in patients with BM (p&amp;lt;0.0001), whereas radiotherapy and antineoplastics were more common. When assessed from melanoma diagnosis, patients who developed BM any time along their disease course had reduced OS (HR(95% CI): 2.265(1.934-2.653)). When assessed from metastatic onset, patients with BM had reduced OS compared to those with only extracranial metastases (HR (95% CI): 2.197(1.883-2.563)). Synchronous BM were associated with decreased OS compared to metachronous BM when assessed from melanoma onset (HR(95% CI): 0.6(0.442-0.815)), but there was no survival difference after BM development. In conclusion, BMs decrease OS in melanoma. Our findings may inform screening and management of patients at risk for melanoma BM.
CTNI-77. PHASE 1 DOSE FINDING STUDY EVALUATING THE SAFETY, TOLERABILITY, AND EFFICACY OF IOPOFOSINE I 131 IN CHILDREN, ADOLESCENTS, AND YOUNG ADULTS WITH INOPERABLE RELAPSED OR REFRACTORY HIGH-GRADE GLIOMAS: A TRIAL-IN-PROGRESS
Authors: Sameer Farouk Sait, Daniel A Morgenstern, Neeta Pandit-Taskar, Anirban Das, Miriam Pudel, Callie Fisher, Pat Zanzonico, Sofia Haque, Jarrod Longcor, Andrei Shustov, Julia Glade-Bender
Journal: Neuro-Oncology (2024)

Abstract Iopofosine I 131, a radioconjugate therapy targeting tumor lipid rafts, is being assessed in CLOVER-2 [NCT05610891]–an ongoing dose-finding study evaluating iopofosine in children, adolescents, and young adults with relapsed, refractory, recurrent high-grade gliomas (HGGs) and ependymoma. Major inclusion criteria include patients aged 10-25 years, previously confirmed HGGs or ependymoma, ≥1 measurable intracranial lesion (≥10 mm in longest diameter), and performance status ≥60. Patients are assigned 1:1 to 2 treatment arms which will be assessed in parallel. Arm 1 has 2 cycles, each composed of 2 doses of 20 mCi/m2 given 14 days apart (± 1 day). Cycle 2 is given 8 weeks (± 4 days) post-initial infusion. Arm 2 patients receive 3 cycles of 10 mCi/m2 per dose. Patients in either arm are eligible for 1 additional cycle at the physician’s discretion. If after the first 10 patients, Arm 1 is not tolerated, dosing is reduced to 15 mCi/m2 per infusion. If after the first 10 patients in Arm 2 are deemed to be ineffective and Arm 1 is deemed to be tolerated, dosing is increased to 15 mCi/m2 per infusion. Final visits occur 57 days following the last cycle initiation, with quarterly follow-ups in year 1 and annually in years 2 and 3. Primary endpoints include safety, tolerability, and progression-free survival (PFS). Secondary endpoints are dosimetry, recommended phase 2 dosing determination, overall survival, antitumor and therapeutic activity, and duration of response and clinical benefit. Safety analysis uses the Wilson score method and nonparametric Wilcoxon signed-rank test. Efficacy analyses use the Response Assessment in Pediatric Neuro-Oncology criteria and the Kaplan-Meier method to detect a median PFS of 5 months compared to a historical control of 2 months. For 90% power by a 1-sided, 1-sample log-rank test: ≥10 evaluable patients must be enrolled (≤90) across ≤15 sites.
EPCO-09. DICER1-MUTANT PRIMARY INTRACRANIAL SARCOMA: ASSESSING THE ONCOGENIC ROLE OF MIRNA DYSREGULATION
Authors: Pushan Dasgupta, Maria Gubbiotti, Gregory Buchold, Chetna Wathoo, Jeena Joseph, Zaid Soomro, Anza Zahid, Amol Ghia, Leomar Y Ballester, Kirk Hirata, Robert Macaulay, Xinhai Zhang, David Meredith, George Calin, Vinay K Puduvalli
Journal: Neuro-Oncology (2024)

Abstract Cross-cancer profiling has shown that mutations in human DICER1 are recurrent in diverse cancers including intracranial sarcoma. Due to the rarity of these tumors, treatment options for these patients remain poorly defined. DICER1 encodes an endoribonuclease that processes the hairpin precursor microRNAs (miRNAs) into functionally mature miRNAs. In particular, hotspot mutations in the RNase IIIb domain of DICER1 are predicted to confer an oncogenic role although the precise mechanism is unknown. In a case of a 28-year-old male who presented with multicentric right frontal dural and parenchymal enhancing masses and underwent partial resection, pathology showed a DICER1-mutant primary intracranial sarcoma with a hotspot E1813G mutation in the RNase IIIb domain. Additionally, due to a family history of an unknown fatal brain tumor in his mother, the patient had additional molecular testing which revealed a germline BRCA2 mutation. After surgery, the patient received intensity-modulated radiation therapy followed by 6 cycles of ICE (ifosfamide, carboplatin, etoposide) chemotherapy with significant radiographic response and clinical improvement. He remains progression-free on radiological surveillance for 13 months since diagnosis. The treatment was well tolerated with clinically manageable myelosuppression (including grade 3 thrombocytopenia). This is the first reported case of an adult DICER1-mutant primary intracranial sarcoma patient with a germline BRCA2 mutation although the interaction between these oncogenic mechanisms is unclear. Based on the role of DICER1 in miRNA processing and to test the hypothesize that DICER1 mutations drive primary intracranial sarcoma through dysregulation of miRNA function, we have established a multi-institutional collaboration that is collecting and profiling DICER 1 mutant primary intracranial sarcoma cases from across the United States preliminary results of which will be presented. Identification of a miRNA-driven oncogenic mechanism in these tumors may yield novel targeted approaches beyond intensive chemotherapy for these patients.
DISP-02. SOCIOECONOMIC FACTORS INFLUENCE OVERALL SURVIVAL IN CHEMORADIATION-TREATED NEWLY DIAGNOSED WHO GRADE 4 GLIOBLASTOMA
Authors: Abraham Dada, Mulki Mehari, Aymen Kabir, Alexander Aabedi, Cecilia Dalle Ore, Shawn Hervey-Jumper
Journal: Neuro-Oncology (2024)

Abstract Social determinants of health are known to influence health outcomes, yet the interactive effects of patient-specific socioeconomic variables on overall survival remain poorly characterized in patients with glioblastoma (GBM). We aimed to assess socioeconomic factors associated with overall survival in a clinically homogenous GBM population. Patients with newly diagnosed isocitrate dehydrogenase wild-type glioblastoma, who underwent maximal safe resection of contrast-enhanced (CE) and non-contrast enhanced tissue (NC) tissue with adjuvant chemoradiation from 1997-2017 were selected for inclusion. Socioeconomic factors were collected through retrospective chart review. Variables associated with overall survival on univariate cox proportional hazards models (p&amp;lt;0.05) were selected for multivariate analysis. 272 patients (42.6% female, 14.3% minority) were included. On univariate logistic regression, older age (HR: 1.23, p&amp;lt;0.001), greater residual CE tissue (HR: 3.95, p&amp;lt;0.001), were associated with reduced survival. Greater extent of resection NCE tissue (HR 0.94, p=0.028), higher postoperative KPS (HR 0.89, p=0.034), and unemployment (HR: 0.67, p=0.022), were associated with longer overall survival. On multivariate analysis, age was associated with reduced survival (HR: 1.31, p&amp;lt;0.001), while unemployment (HR:0.69, p=0.049) was associated with longer overall survival. Subgroup multivariate analyses was performed dividing patients into those &amp;lt;65 (n=185, 45% female, 11.9% minority, 48% employed) and those ≥65 (n=87, 37% female, 14% minority, 20% employed). In the &amp;lt;65 cohort, protective factors included retirement (HR: 0.49 p=0.004), and unemployment (HR:.57, p=0.006). Older age (HR: 1.03, p=0.004), and greater residual CE tissue (HR: 1.16, p=0.03) continued to be associated with poorer survival. No variables correlated with outcomes in the ≥65 cohort. Active employment was associated with reduced survival in GBM patients treated with standard care, potentially serving as a proxy for access to subsequent treatment.