tbuckley/cabot-search huggingface dataset:
NIMG-86. DISSEMINATED<i>CRYPTOCOCCUS NEOFORMANS</i> MIMICKING CENTRAL NERVOUS SYSTEM PROGRESSION OF DIFFUSE LARGE B-CELL LYMPHOMA
Authors: Adolfo Baez, Guy Handley, Sepideh Mokhtari, Shivan Shah, Vania Phuoc, John Greene
Journal: Neuro-Oncology (2024)

Abstract A 57-year-old male with stage IV diffuse large B-cell lymphoma (DLBCL), non-germinal center subtype, underwent 6 cycles of polatuzumab, rituximab, cyclophosphamide, doxorubicin, prednisone, and pegfilgrastim (Pola-R-CHP) then presented to the hospital with progressive confusion, double vision, hearing loss, and lower extremity weakness. MRI of the brain and spinal cord with and without IV contrast revealed extensive leptomeningeal enhancement along the brain, several cranial nerves, cervical and thoracic spinal cord with enhancement of the cauda equina. Cerebrospinal fluid (CSF) analysis studies revealed 41 nucleated cells/mm3, protein to 264 mg/dL, and an initial cryptococcal antigen titer of 1:1280; serial lumbar punctures peaked at an opening pressure of 39.5 cm H2O before improvement. Flow cytometry was negative on two CSF studies. Multiple cultures grew Cryptococcus neoformans before sterilization of CSF culture on day 13. He received induction therapy for 4 weeks with amphotericin B and flucytosine. Flucytosine treatment was limited due to cytopenias on day 9 and continued induction with amphotericin B and fluconazole. Fluconazole was switched for voriconazole based on minimal inhibitory concentrations by broth dilution, however, the drug was undetectable on therapeutic drug monitoring 2 weeks later and switched back to fluconazole. Subsequent positron emission tomography revealed ongoing hypermetabolic thoracic, mediastinal, and hilar lymph nodes compared to PET scans prior to chemotherapy for which he underwent transbronchial fine needle aspiration concerning for Cryptococcus involvement. He remained on fluconazole 800mg/day and MRI 11 months after the initial presentation demonstrated ongoing but slightly improved leptomeningeal enhancement. Due to persistent symptoms despite sterile CSF cultures, he underwent a three-day course of IV methylprednisolone 1000mg with some incomplete improvement in symptoms. The opening pressure normalized and the cryptococcal antigen titer decreased to 1:20 about 11 months after initial treatment. This case highlights the risk of opportunistic infections like cryptococcal meningitis in patients undergoing chemotherapy.
BIOM-65. ELEVATED MMP9 EXPRESSION IN ADHERENT AND LARGE VESTIBULAR SCHWANNOMAS: A PROMISING THERAPEUTIC TARGET
Authors: Han T N Nguyen, Bailey H Duhon, Hsuan-Chih Kuo, Melanie Fisher, Olivia M Brickey, Lisa Zhang, Jose J Otero, Daniel M Prevedello, Oliver F Adunka, Yin Ren
Journal: Neuro-Oncology (2024)

Abstract Vestibular schwannoma (VS) is the most common tumor of the cerebellopontine angle affecting up to 1 in 2000 adults and presents significant treatment challenges, especially when the tumor is adherent to the brainstem and cranial nerves. These tumors often require complex surgeries with high risks of complications such as hearing loss, facial paralysis, and incomplete tumor resection. Previous studies have linked immune cell infiltration and protease activation to aggressive VS. MMP9, a protease involved in extracellular matrix (ECM) remodeling, is associated with cancer invasion and progression, suggesting its potential as a biomarker and therapeutic target. This study explores whether MMP9 can classify VS and improve surgical outcomes. METHODS Fresh tumors were collected from patients undergoing surgery to establish primary VS cultures. Transcriptomic profiling was performed to examine expression of genes related to ECM remodeling, protease activation, and immune cell infiltration. MMP9 expression during schwannoma progression was validated using immunofluorescence staining and ELISA. Transwell invasion assays were performed to evaluate the role of MMP9 in schwannoma invasion. The efficacy of small molecule inhibitors against eIF4F (a transcription factor that binds to 5’ UTR of MMP9) and against MMP9 was tested in a mouse model of schwannoma. RESULTS MMP9 was the most abundantly expressed protease in VS. MMP9 expression increased with tumor size, and was higher in adherent than non-adherent VS (49.7 vs. 13.8 ng/mL, p=0.014). MMP9 expression was abundant in perivascular regions in adherent VS. Inhibition of eIF4F reduced schwannoma cell invasion mediated by MMP9.MMP9 inhibition in vivo- reduced tumor burden by 50% in mice. CONCLUSIONS MMP9 is a highly active protease in VS growth and adherent VS. Developing MMP9-targeted therapies could be a breakthrough in managing these challenging tumors.
NCOG-18. META-ANALYSIS OF DIRECT ENDOVASCULAR THROMBECTOMY VS BRIDGING THERAPY IN THE MANAGEMENT OF ACUTE ISCHEMIC STROKE WITH LARGE VESSEL OCCLUSION
Authors: Muhammad Ashir Shafique, Brandon Lucke-Wold, Muhammad Saqlain Mustafa, Syed Muhammad Sinaan Ali
Journal: Neuro-Oncology (2024)

Abstract Debates persist when using intravenous thrombolysis (IVT) before mechanical thrombectomy (MT) for acute ischemic stroke (AIS) due to large-vessel occlusion (LVO). This systematic review and meta-analysis synthesized evidence on outcomes in patients with acute ischemic stroke due to large vessel occlusion (AIS-LVO), comparing bridging therapy (BT) with MT alone. METHOD We conducted searches of PubMed, Scopus, Web of Science, and the Cochrane Central Register of Controlled Trials from inception to July 2023 to identify pertinent clinical trials and observational studies. RESULT 76 studies, involving 37,658 patients, revealed no significant difference in 90-day functional independence between DEVT and BT. However, a trend favoring BT for achieving functional independence with a modified Rankin Scale (mRS) of 0–1 was observed, having Odds ratio (OR) of 0.75 (95% CI 0.66–0.86; p &amp;lt; 0.001). DEVT was associated with higher postprocedural mortality (OR 1.44;95% CI 1.25–1.65; p &amp;lt; 0.001), but a lower risk of symptomatic intracranial hemorrhage compared to BT (OR 0.855; 95% CI 0.621–1.177; p = 0.327). Successful recanalization rates favored BT, emphasizing the importance of individualized treatment decisions (OR 0.759; 95% CI 0.594–0.969; p = 0.027). Sensitivity analyses were conducted to identify key contributors to heterogeneity. CONCLUSION Our meta-analysis underscores the intricate equilibrium between functional efficacy and safety in the evaluation of DEVT and BT for ACS-LVO. Fundamentally, while BT appears more efficacious, concerns about safety arise due to the superior safety profile demonstrated by DEVT. Individualized treatment decisions are imperative, and further trials are warranted to enhance precision in clinical guidance.
NCMP-07. ADVERSE NEUROLOGIC COMPLICATIONS FOLLOWING IMMUNE CHECKPOINT INHIBITORS FOR TREATMENT OF MELANOMA: COMPARATIVE ANALYSIS OF PD-1 INHIBITOR MONOTHERAPY TO COMBINATION THERAPY WITH CTLA-4 INHIBITORS
Authors: Nikita Das, Ravi Dhamija, David Kaelber, Michael Kelly, Peter Xie, Deven Reddy
Journal: Neuro-Oncology (2024)

Abstract In the past decade, FDA approval of several novel immune checkpoint inhibitors (ICI) has revolutionized treatment of advanced melanoma. However, severe immune-related adverse events (irAEs) from these medications have been reported. This study examines whether PD-1/CTLA-4 inhibitor combination immunotherapy confers increased incidence of neurologic irAEs in melanoma patients compared to PD-1 inhibitor monotherapy. A retrospective, multicenter cohort study performed using TriNetX research platform identified adult patients diagnosed with melanoma. Cohort 1 (n=9,105) included melanoma patients treated with PD-1 inhibitor monotherapy (pembrolizumab or nivolumab). Cohort 2 (n=4,727) included melanoma patients treated with PD-1/CTLA-4 inhibitor combination therapy (PD-1 inhibitor + ipilimumab). Propensity Score Matching generated final cohorts (n=4,667) using covariates: gender, race, age at diagnosis, and history of nervous system disorders. Odds ratios (OR) were determined for the occurrence of neurologic irAEs at 3 years and 5 years following therapy initiation. Kaplan Meier analysis estimated survival probabilities for each irAE subtype, as defined by the 2021 Neuro irAE Disease Definition Panel. At 3 years post-diagnosis, there was increased risk of meningitis [OR: 2.8, 95% CI: (1.8, 4.2)], encephalitis [OR: 3.1, 95% CI: (1.9, 5.1)], demyelinating syndromes [OR: 2.7, 95% CI: (1.4, 5.2)], vasculitis [OR: 1.2, 95% CI: (0.5, 2.8)], peripheral neuropathy [OR: 1.3, 95% CI (1.1, 1.5)], neuromuscular junction disorders [OR: 1.1, 95% CI: (0.7, 1.8)], and myopathy [OR: 1.4, 95% CI: (1.1, 1.9)] in melanoma patients receiving combination immunotherapy compared to those receiving anti-PD-1 monotherapy. Increased incidence of neurologic irAEs corresponded with marginally lower, yet statistically significant decreases in survival probability (p&amp;lt;0.01), except for vasculitis (p=0.2) and neuromuscular junction irAEs (p=0.3). At 5 years following therapy initiation, these trends persisted. Melanoma patients receiving anti-PD-1/CTLA-4 combination therapies are at greater risk of neurologic irAEs than patients on anti-PD-1 monotherapy. Incidence of neurologic irAEs may confer worsened survival prognosis for these patients.
CTNI-62. EVALUATION OF SAFER-SEQS CTDNA ASSAY OPTIMIZED FOR DETECTING LOW CTDNA COUNTS FROM CSF AND PLASMA: ASSESSING SENSITIVITY AND FEASIBILITY FOR CLINICAL IMPLEMENTATION
Authors: Grace Tobin, Chetan Bettegowda, Peng Huang, Michaella Iacoboni, Joy Fisher, Erin Dailey, Karisa Schreck
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Gliomas with BRAF alterations are often difficult to treat in the recurrent setting due to emergent resistance to FDA-approved targeted therapies. Additionally, it is difficult to assess response to therapy given the limitations of radiographic techniques and the infeasibility of serial tissue sampling. This protocol will serve as a prototype for determining the feasibility of using CSF and plasma circulating tumor DNA (ctDNA) as biomarkers for response to a novel-BRAF inhibitor, plixorafenib. Plixorafenib is a small-molecule selective inhibitor of Class 1 and 2 BRAF mutations that does not induce paradoxical reactivation of MAPK signaling. METHODS This clinical trial is designed as a single institution, signal-finding study to demonstrate the feasibility and sensitivity of detecting ctDNA at baseline and after one month of treatment with plixorafenib (primary endpoint). In addition, we will evaluate the correlation of ctDNA with disease status over time and response rate to plixorafenib. Patients aged 18 years or older with measurable recurrent BRAF-V600 mutant glioma (by RANO 2.0), who have received prior BRAF and/or MEK inhibitor therapy will be screened and consented for the study prior to surgery. Leptomeningeal disease allowed. A total of 12 evaluable patients will be enrolled. Patients will undergo clinically-indicated resection or biopsy for confirmation of disease progression and characterization of putative resistance alterations. All patients will have a ventricular reservoir placed at time of surgery with CSF and plasma sampling. Patients will initiate the study drug (oral plixorafenib 900mg daily with cobicistat 150mg daily) when clinically recovered from surgery. Patients will take the drug continuously for 28-day cycles. MRI, CSF, and plasma assessments will occur approximately every two months to evaluate disease status. Enrollment is planned to begin November, 2024.
TMIC-44. ANDROGEN LOSS WEAKENS ANTI-TUMOR IMMUNITY AND ACCELERATES BRAIN TUMOR GROWTH
Authors: Juyeun Lee, Justin Lathia, Yoon-Mi Chung, Nima Sharifi, Lee Curtin, Kristin Swanson
Journal: Neuro-Oncology (2024)

Abstract Many cancers, including glioblastoma (GBM), exhibit a male-biased incidence and outcome disparity. The underlying reasons for this sex bias are unclear but likely involve differences in tumor cell state and immune response. This effect is further influenced by sex hormones, including androgens, which have been shown to inhibit anti-tumor T cell immunity in other solid tumors. Using a series of pre-clinical models, we observed that androgens drive anti-tumor immunity in brain tumors, contrasting with their effect in other tumor types. Upon castration, tumor growth was accelerated in GBM and brain tumor models, while the opposite effect was observed when tumors were located outside the brain. This castration effect could be reversed by testosterone administration. Flow cytometry revealed decreased T cell function, indicated by reduced anti-tumor cytokines (IFNγ and TNFα), and increased T cell exhaustion in both tumors and peripheral tissues in castrated mice, suggesting systemic immunosuppression. Indeed, the survival difference was completely abrogated in T cell deficient mice (RAG1 knockout). Mechanistically, increased hypothalamus-pituitary-adrenal (HPA) axis activity in castrated mice was responsible for the observed systemic immunosuppression, particularly in those with brain tumors. Blocking glucocorticoid receptors reversed the accelerated tumor growth in castrated mice, indicating that elevated glucocorticoid signaling mediated the castration effect. This mechanism was brain-specific rather than GBM-specific, as hyperactivation of the HPA axis was also observed with intracranial implantation of non-GBM tumors. Neuroinflammation caused by brain tumors was stronger in castrated mice, and proinflammatory cytokines like IL-1 and TNF induced HPA axis hyperactivation. Together, these findings highlight that brain tumors drive distinct endocrine-mediated mechanisms in the androgen-deprived setting and highlight the importance of organ-specific effects on anti-tumor immunity.
DDDR-44. REPURPOSING SSRI/SNRI TARGETING NEUROTRANSMITTER SIGNALING TO OVERCOME RESISTANCE TO CDK9 INHIBITORS IN DIFFUSE MIDLINE GLIOMA
Authors: Rebecca L Murdaugh, Brittany R Eberl, Rosemary U Richard, Jack Tremblay, Alfred Dei-Ampeh, Jamie N Anastas
Journal: Neuro-Oncology (2024)

Abstract Diffuse midline glioma (DMG) is a subset of aggressive brain tumors with few effective therapies. Cyclin-dependent kinase 9 (CDK9i) inhibitors such as zotiraciclib (ZTR) are in clinical trials for glioma, but CDK9i treatment alone may be ineffective due to the development of resistance. To identify CDK9i resistance mechanisms, we analyzed the transcriptomes of DMG xenograft tumors after three weeks of treatment with ZTR, which revealed that transcripts encoding synaptic signaling regulators such as glutamate receptors were overexpressed in surviving cells, suggesting that altered regulation of synaptic signaling may mediate CDK9i resistance. We also performed drug synergy screens using a library of FDA-approved and bioactive compounds and found that drugs that modulate neurotransmitter signaling, such as SSRIs and SNRIs (selective serotonin and serotonin/norepinephrine reuptake inhibitors), increased DMG sensitivity to an IC25 dose of ZTR. Follow-up studies confirm that combinations of structurally distinct CDK9i (ZTR, AZD4573) and SSRI/SNRI (sertraline, duloxetine) synergistically reduce DMG growth in neurospheres by BLISS analysis and show that co-treatment with CDK9i and SSRI/SNRI strongly induces the apoptotic marker cleaved caspase 3 and reduces the CDK9 target phos-Pol2Ser2. Additional phospho-proteomic analyses identified differentially phosphorylated proteins following CDK9i+SSRI treatment, including chromatin regulators, Pol2 elongation factors, and splicing regulators. Further RNAseq studies reveal that CDK9i+SSRI treatment resulted in more robust transcriptional changes than either drug alone, including the downregulation of transcripts associated with ZTR resistance such as GRIA3/4, and SYT12. These observations suggest that CDK9i +SSRI/SNRI drug combinations may overcome some of the transcriptional changes underlying CDK9i resistance. Finally, preclinical studies show that co-treatment with low doses of AZD4573 and sertraline reduces the growth of orthotopic DMG xenografts and prolongs overall survival. Taken together, these data suggest that SSRI/SNRI and CDK9i might be used in combination to synergistically reduce DMG growth and overcome CDK9i resistance.
DISP-09. IMPROVING ADHERENCE TO CANCER CARE IN UNDERSERVED PATIENTS WITH CENTRAL NERVOUS SYSTEM TUMORS
Authors: Cleopatra Elshiekh, Ashley Phillips, Ashley Rodriguez, Bharat Narang, Francesca Gany, Joshua Budhu
Journal: Neuro-Oncology (2024)

Abstract Patients with central nervous system tumors have disease-specific symptoms such as aphasias, motor symptoms, neuropsychiatric symptoms, or seizures that make treatment adherence difficult. This is further exacerbated by the social determinants of health – patients from historically marginalized groups or those with lower socioeconomic status have additional barriers to treatment. The Integrated Cancer Care Access Network (ICCAN) is a multi-institutional patient navigation program assisting patients who express socioeconomic needs during cancer treatment. In this pilot program, we assessed the impact of ICCAN on treatment adherence and quality of life of CNS cancer patients from marginalized backgrounds. 42 participants with primary brain tumors or brain metastases were recruited from inpatient and outpatient services at Memorial Sloan Kettering Cancer Center to enroll in ICCAN-CNS. Patients were eligible if they were 18 years or older, receiving active treatment or under active surveillance, and screened positive for an essential need. Through standardized patient interviews and questionnaires, we evaluated their needs such as food access, housing, and financial needs. The clinical research coordinator interviewed the patients via phone, taking approximately 60 minutes. The interviews comprised an Essential Needs Assessment, Health Related Social Needs Assessment, NCCN Distress Thermometer, and an ICCAN-CNS questionnaire focused on neurology-specific symptoms. Caregivers helped complete the questions for patients with cognitive impairments. Patients were then matched with resources based on their initial needs assessment. The interviewer conducted 2, 4, and 6-month follow-ups to see if new needs emerged for which resources were provided. Response to the program was overwhelmingly positive with many patients expressing gratitude for the resources provided to them. This pilot demonstrates the feasibility of CNS tumor patients participating in the ICCAN intervention and the need for additional patient navigation programs and interventions that focus on the social determinants of health.
SURG-36. ACCURACY OF THE ROSA ONE BRAIN ROBOTIC PLATFORM FOR THE PLACEMENT OF NEUROBLATE AND VISUALASE LASER INTERSTITIAL THERMAL THERAPY PROBES
Authors: Anneliese Rademacher, Zunaira Imran, Hassan Fadel, Jacob Pawloski, Anthony Anzalone, Katie Latack, Ian Lee
Journal: Neuro-Oncology (2024)

Abstract Laser interstitial thermal therapy (LITT) is a minimally invasive treatment option for patients with intracranial lesions. The success of LITT is dependent on accurate placement of the laser probe in target tissue. Placement can be facilitated by various stereotactic methods, including the Robotic Surgical Assistant (ROSA) ONE Brain robotic platform. The aim of this study is to examine the accuracy of stereotactic probe placement utilizing the ROSA robot. Primary outcomes were entry distance, target distance, and entry angle error. Accuracy differences between two major LITT platforms, the Neuroblate (Monteris Medical) and Visualase Systems, were compared. A prospective institutional database was used to identify all patients who underwent LITT for intracranial tumors utilizing the ROSA robot between 2013-2023. The sign test was used to compare error values to test their difference from a null value of 0. Spearman correlation was used to assess the relationship between angle of error and trajectory length. Kuskal-Wallis test was used to compare errors and trajectory length between the two companies. Of the 105 patients who underwent LITT during the study period, 337 probes were placed. For Visualase probes, median entry distance (1.1mm, IQR=0.4-2.0), target distance (1.6mm, IQR =0.9-2.4), and entry angle error (1.5°, IQR=0.9-2.5), were significantly different than zero (p=&amp;lt;.0001). For Neuroblate probes, median entry distance (1.5mm, IQR=1.0-2.1), target distance (1.8mm, IQR=1.1-2.4), and entry angle error (1.8°, IQR=1.1-2.5) were significantly different than zero (p=&amp;lt;.0001). When comparing laser systems, there was a significant difference in median entry distance error with Neuroblate having a higher error (1.5mm, IQR=1.0-2.1) than Visualase (1.1mm IQR=0.4-2.0, p=0.0041). Stereotactic placement of LITT probes utilizing the ROSA robotic system was not able to achieve perfect alignment with the planned trajectory. When comparing the systems, Visualase probes were placed more accurately at the entry point than Neuroblate probes.
BIOM-52. THE DYNAMIC GLIOMA CSF PROTEOME: IMPACT OF LOCATION AND RESECTION FOR DISEASE MONITORING
Authors: Cecile Riviere-Cazaux, Christopher Graser, Arthur Warrington, Matthew Hoplin, Katherine Andersen, Noor Malik, Lucas Carlstrom, Keyvan Ghadimi, Benjamin Himes, Ignacio Jusue-Torres, Jann Sarkaria, Fredric Meyer, Jamie Van Gompel, Sani Kizilbash, Ugur Sener, Franziska Michor, Jian Campian, Ian Parney, Terry Burns
Journal: Neuro-Oncology (2024)

Abstract While serial sampling of glioma tissue is rarely performed before recurrence, cerebrospinal fluid (CSF) can be acquired serially to evaluate candidate monitoring and pharmacodynamic biomarkers in patients with gliomas. However, the impact of key variables to consider in longitudinal CSF, including anatomical location and post-surgical changes, remains unknown. To that end, pre- versus post-resection intracranial CSF samples from patients with gliomas were obtained at early (1-16 days; n=20) or delayed (86-153 days; n=11) timepoints, as well as lumbar-versus-intracranial glioma CSF samples (n=14). Using aptamer-based proteomics, we identified significant differences in the glioma CSF proteome between lumbar, subarachnoid, and ventricular CSF. Indeed, intracranial CSF in paired lumbar/intracranial samples had nearly 1600 unique aptamers, regardless of which intracranial location was compared to the paired lumbar CSF, including in enrichment style analyses that evaluated the overlap between protein states. Importantly, resection had a significant, evolving longitudinal impact on the CSF proteome, with subsets of proteins associated with early versus delayed post-resection changes, many of which were enriched for inflammatory-related pathways. Interestingly, despite increased contamination from surgical debris, enrichment for plasma-associated proteins decreased with resection (FDR: 0.000), suggesting that a portion of the baseline glioma panel could be derived from plasma-originating analytes due to blood-brain barrier disruption. Despite these challenges, our data still revealed preliminary candidate monitoring biomarkers, such as brevican, that increased with progression (example patient: fold-change of 3.58x and 2.08x through lomustine and bevacizumab, respectively), but not pseudoprogression (Fold change less than 1.5). Serial intracranial CSF samples suggested the early potential for disease monitoring and evaluation of pharmacodynamic impact of targeted therapies, including bevacizumab and pembrolizumab. In conclusion, our available data to date suggest that the intracranial glioma CSF proteome provides an abundant and evolving source of candidate biomarkers to longitudinally discern the impact of resection and systemic treatments.