bluuebunny/crossref_metadata_2025 huggingface dataset:
BIOS-03. CLINICAL PRESENTATION, MANAGEMENT, AND OUTCOME IN NEUROLYMPHOMATOSIS: A SYSTEMATIC REVIEW AND ANALYSIS OF INDIVIDUAL PATIENT DATA FROM 459 CASES
Authors: Kaulen Leon D , Hielscher Thomas , Doubrovinskaia Sofia , Hoffmann Dirk C , Kessler Tobias , Traub Benjamin-Leon , Baehring Joachim , Wick Wolfgang
Published: November 2024

BACKGROUND

Neurolymphomatosis (NL) refers to lymphomatous infiltration of the peripheral nervous system (PNS). NL diagnosis and treatment are challenging given the broad differential diagnosis of peripheral neuropathy, the lack of larger cohorts and the subsequent unavailability of prognostic factors or consensus therapy. This study aimed to define characteristics and prognostic factors of NL.

METHODS

A systematic review of the literature (2004-2023) was performed using PubMed and Scopus databases and reported following PRISMA guidelines. Clinical, radiological, pathological and outcome information were extracted. Multivariable survival analyses were performed using Cox proportional hazard models.

RESULTS

A total of 459 NL cases from 264 studies were accumulated. NL was the first manifestation of malignancy (primary NL) in 197 patients. PNS relapse of known non-Hodgkin lymphoma (secondary NL) occurred in 262 cases after a median 12 months. NL predominantly presented with rapidly deteriorating, asymmetric painful polyneuropathy. Infiltrated structures included peripheral nerves (56%), nerve roots (52%), plexus (33%) and cranial nerves (32%). Diagnosis was established at a median of 3 months after symptom onset with substantial delays in primary NL. It mainly relied on PNS biopsy or FDG-PET, which carried high diagnostic yields (> 90%). Post mortem diagnoses were rare (3%). Most cases were classified as B-cell (90%) lymphomas. Tumor-directed therapy was administered in 96% of patients and typically consisted of methotrexate or rituximab-based polychemotherapy. Median overall survival was 18 months. Primary NL without concurrent systemic disease outside the nervous system (hazard ratio [HR]: 0.44; 95% confidence interval (CI): 0.25-0.78; p = 0.005), performance status (ECOG < 2, HR: 0.30; 95% CI: 0.18-0.52; p < 0.0001), and rituximab-based treatment (HR: 0.46; 95% CI: 0.28-0.73; p = 0.001) were identified as favorable prognostic markers on multivariable analysis when adjusting for clinical and sociodemographic parameters.

CONCLUSIONS

Advances in neuroimaging modalities, particularly FDG-PET, facilitate NL diagnosis and offer a high diagnostic yield. Rituximab-based therapy improves NL outcome. Findings may assist clinicians in early recognition, prognostic stratification, and treatment of NL.
CNSC-40. GTP SIGNALING PATHWAY PROMOTES NHEJ REPAIR BY INDUCING NUCLEAR ACTIN POLYMERIZATION IN GLIOBLASTOMA
Authors: Zhou Weihua
Published: November 2024

OBJECTIVES

We recently identified that GTP promotes non-homologous end joining (NHEJ) by triggering a GTP-Rac1-PP5-Abi-1/S323 cascade and we sought to define the molecular mechanisms.

METHODS

Crispr/Cas9, CDNA overexpression and immunoblot were used to modulate and confirm protein levels. Cellular fractionation and immunofluorescence (IF) were used to determine the localization of proteins. Laser micro-irradiation was used to induce DNA damage and monitor the recruitment of DNA repair proteins.

RESULTS

We found that GTP-activated protein Rac1 and Abi-1, the two key components of the newly identified pathway, shuttled into the nucleus post-RT in glioblastoma (GBM) cells. These effects were further enhanced by the GTP precursor guanosine but blocked by GTP depletion. Furthermore, Abi-1 and Rac1 accumulated in the nucleus of the cells expressing constitutively active Rac1 but not dominant negative Rac1 after RT, which suggests that Rac1/Abi-1 nuclear translocation is Rac1 activity dependent. We previously discovered that GTP-Rac1 promotes DNA repair by facilitating the dephosphorylation of Abi-1 (S323). Here, we discovered that dephosphomimetic Abi-1 (S323A) but not phosphomimetic Abi-1 (S323D) shuttled into nucleus after RT. Because Rac1 canonically binds to Abi-1 and promotes actin polymerization in the cytosol, we next wanted to determine if RT-induced nuclear Rac1/Abi-1/S323A could enhance nuclear actin polymerization, which could enhance NHEJ repair. We found that Abi-1/S323A but not Abi-1/S323D increases nuclear filament actin formation post-RT and activating the GTP-Rac1-Abi-1/S323A axis (through guanosine supplementation, expression of constitutively active Rac1 or expression of dephosphomimetic Abi-1/S323A) enhanced the recruitment and stability of KU80 at sites of DNA damage, which could be blocked by actin polymerization inhibitor cytochalasin D. Furthermore, inhibiting actin polymerization overcame radiation resistance in GBM cells with an active GTP-Rac1-Abi-1/S323A axis.

CONCLUSIONS

GTP-Rac1-PP5-Abi-1/S323 cascade promotes NHEJ repair by inducing the nuclear assembly of filament actin and disrupting this regulation could improve treatment responses in GBMs.
CNSC-64. BEYOND THE LOCAL TUMOR MICROENVIRONMENT: CHARACTERIZING CHANGES TO NEURONAL ACTIVITY INDUCED BY PEDIATRIC HIGH-GRADE GLIOMA
Authors: Farnsworth Hannah , Pinter Meghan , Carleton Elana , Franklin Alexis , Gentry Kaylee , Davis Rachel , Hoffman Hannah , Venkatesh Humsa
Published: November 2024

Bidirectional electrochemical signaling between neurons and tumor cells is emerging as a critical regulator of pediatric high-grade glioma (HGG) pathology. Neuron-tumor interactions are known to induce local neuronal hyperactivity. However, recent work tracing the projections of these neuron-tumor networks revealed that HGG neuronal recruitment extends beyond the local tumor microenvironment (TME). These findings suggest that tumor-induced hyperexcitability may spread beyond the local TME and drive brain-wide circuit-level changes. To elucidate how non-tumor innervated brain regions are affected by TME hyperactivity we first characterized neuronal hyperactivity induced by a cortical patient-derived pediatric high-grade cell line in vitro on human iPSC-derived neurons. In vitro calcium imaging experiments demonstrated an increase in the number of calcium fluctuations in glioma co-cultured neurons. In parallel, multi-electrode recordings revealed increased population spiking activity and amplitude in neurons co-cultured with glioma cells. We then xenografted these HGG cells into the prefrontal cortex of mice and performed whole brain-clearing and cFos staining on tumor-bearing vs saline-injected control samples. As cFos is an immediate early gene activated by neuronal activity, we utilized the density of cFos expression as a readout-out of neuronal activation in our atlas-aligned segmented brain section analyses. We expectedly observed increased cFos expression within the ipsilateral primary and secondary motor region, which collectively comprise the local TME. Interestingly, we additionally observed elevated cFos in non-tumor bearing brain regions on both the ipsilateral and contralateral hemispheres, largely in layer 2/3 cortical neurons. These neurons form extensive cortico-cortical projections, and we coincidingly observed increased cFos expression in known cortical projection targets of the prefrontal xenograft location, such as somatosensory, visual, and retrosplenial cortices. Our findings suggest that tumor-induced neuronal hyperactivity extends beyond the local TME in a brain-wide manner and potentially follows established neuronal circuits, rendering these connected regions vulnerable to alterations in neuronal activity.
STEM-12. A NEURONAL STEM-LIKE PHENOTYPE IN GRADE 4 IDH-MUTANT ASTROCYTOMA WITH CDKN2A/B LOSS IS ASSOCIATED WITH CUX2 DEFICIENCY
Authors: Grief Dustin , D’Angelo Fulvio , Caruso Francesca , Flick Matthew , Sereduk Christopher , Ceccarelli Michele , Hu Leland , Loftus Joseph , Tran Nhan , Ensign Shannon Fortin
Published: November 2024

Diffuse gliomas represent the most common type of primary adult malignant brain tumor historically diagnosed and graded from histologic criteria alone. Gliomas harboring isocitrate dehydrogenase (IDH) 1 or 2 mutations are associated with lower grade tumors and portend a favorable prognosis relative to IDH-wildtype glioma. However, the loss of CDKN2A/B in IDH-mutant astrocytoma confers an aggressive high grade phenotype and is the strongest implicated molecular alteration associated poor clinical survival, thus is now sufficient to define a grade 4 tumor regardless of histologic grade. However, there remains no effective therapies targeted at molecular subgroups in aggressive gliomas to date. Here, we sought to elucidate the biologic pathways and functional outcomes associated with the acquisition of high-grade behavior under loss of CDKN2A/B in IDH-mutant astrocytoma to inform future therapeutic strategies. We analyzed a cohort of patient IDH-mutant astrocytomas with RNA sequencing data and found the increased expression of regulators of embryonic nervous system development and signaling concurrent with CDKN2A/B loss. Using grade 4 IDH-mutant astrocytoma patient-derived (PDX) and cell-lines harboring CDKN2A/B homozygous deletion, we stably re-expressed p14ARF, p15INK4B, and p16INK4A using a Tet-inducible system. IDH-mutant cell lines with re-expression of p14, p15, or p16 displayed differential transcription factor activation, impaired neurosphere capability, decreased colony formation, and lower neurosphere proliferation. Intriguingly, RNA-seq data revealed CUX2, a transcription factor known to control neuronal precursor behavior, as the likely candidate regulating the differential expression profile across CDKN2A/B status. We observed increased CUX2 expression in cell lines stably re-expressing p14, p15, and p16. We validated the CUX2 signature across publicly available datasets of IDH-mutant astrocytoma where CUX2 expression negatively correlated with loss of CDKN2A/B in patient tumors. Together our work suggests CUX2 deficiency in IDH-mutant astrocytoma with CDKN2A/B deletion enables an increased neuronal stem-like phenotype in these grade 4 tumors.
STEM-16. EXPLORING THE ROLE OF HYPOXIA AND MACROPHAGES ON GLIOBLASTOMA QUIESCENCE AND STEMNESS AS MEDIATORS OF RADIORESISTANCE
Authors: Pradhan Puja , Agudelo Luis , Karwacinski Victor , Constante Nicole , Olson Cheryl , Li Jiabo , Shih Ling-kai , Carneiro-Lobo Tatiana , Brat Daniel
Published: November 2024

Our ultimate goal is to identify, characterize and therapeutically target the glioma cell population that is responsible for treatment resistance and recurrence following chemoradiation. Two cell types that may have overlapping phenotypes and are known to influence radioresistance are 1) quiescent cells and 2) glioblastoma (GBM) stem cells (GSCs). The extent of overlap between these populations is unknown as are the influence of hypoxia and immune cells on their radioresistant properties. We have shown that hypoxia and co-culturing with THP-1 macrophages dramatically increases the percentage of GSCs. Using the Fluorescent Ubiquitination-based Cell Cycle Indicator (FUCCI) system expressed in patient-derived gliomas, we used flow cytometry to distinguish cells based on their cell cycle status (G1/G0 and G2/M) and classified them as quiescent (high p27, low Ki67) or GSC (high CD133/CD44 co-expression). We found that the fraction of cells in G0 expressed high p27 and low Ki67, indicating cell cycle suppression and low proliferation, respectively. G0 glioma cells also contained a high percentage of GSCs, but GSCs were also distributed in G1 and G2/M. Following exposure to hypoxia, flow cytometry of FUCCI GBM cells showed an increase of cells in G0. After 3 Gy radiation under normoxic conditions, GBM cells demonstrated a shift to increased levels of G2/M cells compared to non-irradiated cells. In hypoxia, however, GBM cells sustained their population of cells in G0 and did not exhibit such cell cycle shifts. Our results indicate that both hypoxia and macrophages cause GSC enrichment and that hypoxia increases the proportion of quiescent cells in G0. Additional study is necessary to determine the extent of overlap between the GSCs and quiescent cells and to identify the intrinsic cell properties that drive tumor recurrence.
STEM-20. MULTI-OMICS OF HUMAN MEDULLOBLASTOMAS AND GENETIC LINEAGE TRACING IN VIVO INDICATE CELLULAR PLASTICITY
Authors: Yu Bohyeon , Jung Jangham , Diaz Aaron
Published: November 2024

Recent single-cell studies implicate the glutamatergic lineage of the rhombic lip (RL) as the origin of group (G) 3/4 medulloblastomas (MBs) and a stalled differentiation program as underlying malignant transformation. While the cellular compositions of G3/G4 MBs are consistent with a truncated neurodevelopmental hierarchy, it is unknown whether G3/G4 MBs exhibit cellular plasticity. We profiled tumors from 38 patients who underwent surgery for MB at UCSF via single-nucleus RNA sequencing (snRNA-seq). We developed in vivo genetic lineage-tracing systems with a single-cell readout and applied them to patient-derived G3 MB xenografts. High-complexity lentiviral barcode libraries were transduced into D283 and D425 patient-derived cell lines. Barcoded cells were injected into the brains of immunocompromised mice. Both preimplantation barcoded cultures and mature tumors were profiled by single-cell RNA-sequencing (scRNA-seq). This captured both endogenous RNA and barcode transcripts. RL neuro-developmental cell-type labels were transferred from public single-cell data from fetal cerebellum to single-cell data from our patient samples and xenograft models. Remarkably, xenografts produced similar cell types, in similar proportions to those found in human MBs. Moreover, the distribution of cell types found in the xenografts was conserved at the level of individual clones, indicating cell-intrinsic regulation of tumor composition. We developed approaches to use barcode and expressed point-mutation data to reconstruct intra-clone genetic phylogenies. We then used the transcriptional phenotypes of the observed cells to infer ancestral phenotypes for each clone’s phylogeny. We compared clade to sub-clade differences in cell type against the neural-developmental hierarchy found in the fetal RL. We observed significant rates of dedifferentiation events from unipolar brush-like cells to RL-progenitor phenotypes. These studies indicate that G3 MB cellular composition is homeostatic and conserved at the level of individual clones. Yet, these tumors exhibit plasticity, as has been observed in other brain cancers such as glioblastoma.
RADT-01. PRE-OPERATIVE SINGLE FRACTION VERSUS FRACTIONATED STEREOTACTIC RADIOTHERAPY: A SINGLE-INSTITUTION ANALYSIS OF 299 RESECTED METASTASES
Authors: Perlow Haley , Luu Sydney , Reddy Sohil , Bradshaw Jared , Hennings Sarah , Matsui Jennifer , Klamer Brett , Upadhyay Rituraj , Oliver Alexandria , McGregor John , Lonser Russell , Prevedello Daniel , Elder James , Wu Kyle , Prabhu Roshan , Zhu Simeng , Singh Raj , Beyer Sasha , Grecula John , Blakaj Dukagjin , Thomas Evan , Raval Raju , Palmer Joshua
Published: November 2024

The treatment standard for patients with large or symptomatic brain metastases and limited intracranial disease is surgical resection followed by post-operative (post-op) stereotactic radiosurgery (SRS). The multicenter PROPS-BM cohort showed how pre-operative (pre-op) SRS may lead to a reduced incidence of radiation necrosis (RN), local failure (LF), and meningeal disease (MD) compared to historical controls. Fractionated treatments can deliver a higher biological effective dose and may reduce the incidence of LF and MD. We hypothesize that pre-op fractionated stereotactic radiation therapy (FSRT) will reduce the incidence rate of RN, MD, and LF when compared to patients who receive pre-op SRS. Patients who had surgical resection and pre-operative radiation to at least one brain metastasis at a single institution were retrospectively analyzed. Outcomes were evaluated on a per-lesion basis. The primary outcome was a composite endpoint defined by 1) LF, 2) MD, and/or 3) Grade 2 or higher (symptomatic) RN. 260 patients with 299 resected brain metastases were eligible for analysis. 64 metastases received SRS and 235 metastases received FSRT. 38 patients had multiple metastases resected pre-operatively. The median gross tumor volume was 4 ccs for SRS and 10 ccs for FSRT (p<0.001). Overall, 4 (6.3%) SRS and 6 (2.6%) FSRT patients experienced LF. 4 (6%) SRS and 21 (8.9%) FSRT patients experienced Grade 2 or higher RN. 3 (4.7%) SRS and 11 (4.7%) FSRT patients were diagnosed with MD. 14% of both SRS and FSRT patients experienced the composite endpoint. There were no statistically significant differences in outcome between these two treatment groups. In our study, pre-op SRS and FSRT both appear to be safe and effective options to treat resectable brain metastases. It is important to prospectively compare pre-op SRS and FSRT in matched cohorts to assess any differences in treatment efficacy and toxicity.
RADT-15. THE ROLE OF STEREOTACTIC RADIOSURGERY IN WHO GRADE II MENINGIOMAS: RESULTS FROM A LARGE EUROPEAN MULTICENTER STUDY
Authors: Santacroce A , Tuleasca C , Liščák R , Kollova A , Motti E , Lindquist C , Radatz M , Frischer J , Lippitz B , Álvarez R Martínez , Skeie B Sandvei , Nicolato A , Longhi M , Unger F , Sabin I , Mindermann T , Bundschuh O , Horstmann G A , van Eck A T C , Nakamura M , Steiger H -J , Ewelt C , Alsofy S Zafy , Lewitz M , Régis J , Muacevic A , Hofmann T , Ehret F , Picozzi P , Faedo S , Franzini A , Masaranov S , Greve Tobias
Published: November 2024

BACKGROUND

This study evaluates the outcomes of WHO grade II meningiomas treated with stereotactic radiosurgery (SRS) using a large, multi-institutional European database. We aim to investigate the long-term tumor control rate and morbidity associated with SRS.

METHODS

Data from 355 consecutive patients treated between 1992 and 2022 at 16 European radiosurgery centers were retrospectively analyzed. After excluding 40 patients due to loss to follow-up, results from 315 patients were included. Clinical and imaging data were independently collected by each center and uniformly entered into a multicenter database.

RESULTS

The median age of patients was 56 years, with 54% being female. The median follow-up duration was 46.3 ± 36.9 months. Tumors had prior surgical treatment and biopsy in 99% and 1% of cases, respectively. Tumors received previous radiotherapy or SRS in 27.4% of cases. SRS was performed due to local progression in 89.6% of cases, residual tumor in 6.4%, and distant progression in 4.0%. SRS characteristics included a median target volume of 5.1 cm³ and a median margin dose of 16 Gy (53.5% isodose). The 3-year local control rate was 72.0%, with a progression-free survival rate of 66.6% and an overall survival rate of 89.7%. Transient and permanent morbidity rates were 6.4% and 3.5%, respectively. Multivariate analysis identified previous radiotherapy and age as significant factors influencing these outcomes.

CONCLUSIONS

This study is the largest to date on SRS in WHO grade II meningiomas. Our data shows that SRS is a viable and safe treatment option for residual and recurrent WHO grade II meningiomas
RADT-33. GAMMA KNIFE RADIOSURGERY FOR ORBITAL CAVERNOUS HEMANGIOMA: A SYSTEMATIC REVIEW AND SINGLE-ARM META-ANALYSIS
Authors: Chen Hsien-Chung , Franklin Brodus , Punukollu Anurraag , Pineda Felipe , Palavani Lucca
Published: November 2024

Gamma knife radiosurgery (GKRS) for orbital cavernous hemangioma (OCH) has emerged as a promising method due to its significant clinical improvement and low incidence of complications. This study aimed to evaluate the safety and efficacy of GKRS for the treatment of OCH. Following the PRISMA framework, we searched PubMed, Cochrane Central, and Embase for studies reporting outcomes of GKRS for OCH, including complications, visual improvement, proptosis, tumor reduction rate, and tumor progression rate. From 1856 search results, six studies with 100 patients were included. Only five minor complications related to GKRS were reported, including three with orbital pain and two with periorbital chemosis, resulting in a complication rate of 13% (95% CI: 7% - 25%). Visual acuity and visual field improvement rates after GKRS were 80% (95% CI: 63% - 96%) and 71% (95% CI: 47% - 95%), respectively. Proptosis improved in 94% of cases (95% CI: 83% - 100%). The tumor reduction rate was 77% after GKRS (95% CI: 69% - 85%). In conclusion, GKRS for OCH appears to be a safe technique, as evidenced by the rate of clinical improvement and radiological improvement. However, studies are limited by the absence of a control group, and additional studies are needed to evaluate the relative efficacy of GKRS compared with alternative surgical modalities for OCH.
CTIM-03. IMMUNE CHECKPOINT INHIBITOR NIVOLUMAB IN PEOPLE WITH RECURRENT SELECT RARE CNS CANCERS: RESULTS OF INTERIM ANALYSIS IN A NON-HEAVILY PRETREATED COHORT
Authors: Argao Lorenzo , Yuan Ying , Wall Kathleen , Kunst Tricia , Chambers Claudia , Vera Elizabeth , Huguely Caitlin , Watanabe Masashi , Grajkowska Ewa , Abdullaev Zied , Acquaye-Mallory Alvina , Aldape Kenneth , Anderson Brita , Boris Lisa , Bota Daniela A , Briceno Nicole , Burton Eric , Choi Anna , Cimino P J , Giglio Pierre , Kamiya-Matsuoka Carlos , Kumthekar Priya U , Levine Jason , Lindhorst Scott M , Ozer Byram , Panzer Marissa , Pillai Tina , Polskin Lily , Pratt Drew , Quezado Martha , Tweneboah-Koduah Renee , Wu Jing , Armstrong Terri S , Gilbert Mark R , Penas-Prado Marta
Published: November 2024

BACKGROUND

There is a paucity of salvage therapies for patients with rare CNS tumors. Nivolumab (PD-1 inhibitor) is approved for a variety of systemic cancers. We developed a multisite basket Phase II trial to evaluate Nivolumab for patients with recurrence of one of 12 selected rare CNS cancers. Efficacy is measured by Disease Control Rate (DCR; confirmed CR/PR or durable SD for ≥ 6 months) in 2 cohorts: heavily and non-heavily pretreated (≥ 3 prior therapies, vs. ≤ 2; including radiation and/or standard or experimental drugs). Cohort 1 has been completed. We report efficacy results and safety data of a preplanned interim analysis in Cohort 2 (non-heavily pretreated).

METHODS

In addition to progressive disease, eligibility includes available tumor tissue; age ≥ 18; KPS ≥ 70; no steroids at trial entry. Planned accrual: 75 in each cohort. Nivolumab dose: 240 mg IV every 2 weeks (4 doses), followed by 480 mg every 4 weeks (14 additional doses). Interim analysis was planned when the sample size reached 32 in each cohort.

RESULTS

As of December 1, 2023, among 27 evaluable patients treated in the non-heavily pretreated cohort, 10 achieved SD ≥ 6 months (DCR 37%; 95% CI 19.4%,57.6%) – 6 high-grade meningiomas; 1 each: myxopapillary ependymoma with lung metastases; solitary fibrous tumor, gliomatosis (astrocytoma IDH mutant WHO grade 2), chordoma. A total of 56 Grade 3-5 AEs occurred; 13 (Grade 3-4) related to nivolumab, including Grade 3 gait disturbance (3); cerebral edema, cognitive disturbance, colitis, headache, hypotension, hypoxia, lymphopenia, pain, and pruritus (1 each), and one Grade 4 cerebral edema. The three Grade 5 AEs were disease-related.

CONCLUSION

Preliminary efficacy analysis exceeded the “go” boundary (i.e., > 5 responders) in the non-heavily pretreated cohort. Nivolumab showed an acceptable safety profile. Cohort 2 will continue to complete a planned accrual of 75 patients.
CTIM-19. A PHASE 1, SAFETY LEAD-IN AND RANDOMIZED, OPEN-LABEL, PERIOPERATIVE STUDY OF VORASIDENIB COMBINED WITH PEMBROLIZUMAB IN RECURRENT OR PROGRESSIVE ENHANCING IDH-1 MUTANT GLIOMA: TRIAL IN PROGRESS
Authors: Wen Patrick , de la Fuente Macarena , Kumthekar Priya , Peters Katherine , Clarke Jennifer , de Groot John , Arrillaga-Romany Isabel , Puduvalli Vinay , Mellinghoff Ingo , Chong Robert , Jain Payal , Barboux Valentine , Chisamore Michael , Abshire Michelle , Mahboub-Johnson Paria , Hassan Islam , Knipstein Jeffrey , Cloughesy Timothy
Published: November 2024

BACKGROUND

Vorasidenib (VOR) is an oral, brain-penetrant dual inhibitor of isocitrate dehydrogenase 1/2 mutant (mIDH1/2) enzymes. VOR is being investigated in a phase 3 study in residual or recurrent grade 2 non-enhancing gliomas, in which interim analysis showed VOR significantly improved progression-free survival and delayed time to next intervention. A prior neoadjuvant perioperative study in recurrent, non-enhancing grade 2/3 gliomas showed that VOR treatment was associated with interferon signal activation and increased T-cell infiltration, suggesting 2-hydroxyglutarate suppression may prime the tumor immune microenvironment for immune checkpoint blockade. This study (NCT05484622) evaluates the safety and tolerability of VOR+pembrolizumab to determine the recommended combination dose (RCD) of VOR (safety lead-in phase) and evaluates CD3+ T-cell infiltration in tumors following a 28-day preoperative period.

METHODS

Enrollment: US patients with recurrent or progressive grade 2/3 mIDH1 R132H glioma. Key eligibility: measurable enhancing disease, Karnofsky Performance Status ≥70, resectable (perioperative phase only). Following a March 2024 protocol amendment, inclusion criteria were expanded to include patients with oligodendroglioma in addition to patients with astrocytoma. Safety lead-in dosing: Cohort 1, VOR 40mg QD+pembrolizumab 200mg Q3W in 21-day cycles. The perioperative phase is randomized 1:1:1 to preoperative combination, VOR 40mg QD, or untreated for 28 (+7) days; all patients could opt to receive the VOR RCD in combination with pembrolizumab 200mg Q3W postoperatively. Primary objectives: safety and tolerability of VOR RCD administered with pembrolizumab; CD3+ T-cell infiltration in resected tumors following presurgical treatment with combination compared to untreated tumors.

RESULTS

Seven patients with recurrent or progressive enhancing grade 2/3 astrocytoma with an mIDH1 R132H were dosed in the safety lead-in phase. No dose-limiting toxicities were detected during this phase.

CONCLUSION

VOR 40mg QD+pembrolizumab 200mg Q3W was confirmed as the RCD for the perioperative phase. This phase was opened to enrollment in May 2023, and recruitment is ongoing.
CTIM-34. EFFECTS OF NEOADJUVANT IMMUNE CHECKPOINT INHIBITION ON PEDIATRIC AND ADULT HIGH-GRADE GLIOMAS
Authors: Keren-Gill Hadar , Herrera Gilbert , Baisiwala Shivani , Markus Lauren , Sun Lu , Everson Richard , Oren Michal Yalan , Govender Dinisha , Margol Ashley , Chi Susan , Prados Michael , Kline Cassie , Mueller Sabine , Davidson Tom Belle , Prins Robert
Published: November 2024

High-grade gliomas (HGG) are lethal tumors with few long-term survivors affecting adult and pediatric patients. Studies investigating immune checkpoint inhibition (ICI) suggest administration of neoadjuvant anti-PD1 blockade (neo-aPD1) enhances local and systemic anti-tumor responses. This data is supported by increased T cell density in the tumor and proportion of cytotoxic T cells in peripheral blood. In a previous randomized clinical trial, neo-aPD1 improved survival in adult with recurrent glioblastoma. In this study, we utilized multiplex immunofluorescence (mIF), and single-cell RNA sequencing (scRNA-seq) to investigate the effects of neoadjuvant ICI on the TME and compare between pediatric and adult populations. Tissue samples from adult patients with recurrent GBM treated with neo-aPD1 (n=22) or adjuvant only therapy (n=5) were obtained from our UCLA off-label neo-PD1 study. Tissue samples were also obtained from pediatric patients with recurrent/progressive HGG treated with neoadjuvant ICI from the ongoing Pediatric Neuro-Oncology Consortium study PNOC19. Samples included diagnostic tissue from two patients and on study surgery tissue from four patients. All tissue samples were subjected to mIF and underwent imaging analysis to assess immune cell infiltration by quantifying lymphoid and myeloid cell densities across the two treatment groups. Our preliminary findings elucidated a trend of higher T cell infiltration in adult neoadjuvant compared to adjuvant-only treated patients (median density 58.11 vs 15.15 T-cells/mm2). Compared to their adult counterparts, neoadjuvant ICI treated pediatric patients had even more robust total T cell infiltration (median density 268.10 vs 58.11 T-cell/mm2, pediatric vs adult respectively). scRNA-seq analysis revealed a greater enrichment of monocytic macrophages in the pediatric population compared to tissue resident microglia in the adults. This early data requires analysis of additional samples to better understand differences in the anti-tumor immune response between adult and pediatric recurrent/progressive HGG patients.
CTNI-34. A RANDOMIZED PROSPECTIVE TRIAL OF POST-OPERATIVE FLUID RESTRICTION TO DECREASE THE INCIDENCE OF DELAYED HYPONATREMIA AND READMISSION AFTER TRANSSPHENOIDAL SURGERY
Authors: Silverstein Julie , Mok Shinghei , Klaassen Doriann , Hwang Jenie , Blount Sydney , Williams Kelley , Fong Brendan , Luo Chongliang , Kim Albert
Published: November 2024

BACKGROUND

Delayed hyponatremia (hypoNa) is the leading cause of readmission following transsphenoidal surgery (TSS). Some institutions have adopted post-operative fluid restriction (FR) protocols based on retrospective studies. We present results of a prospective randomized controlled trial evaluating post-TSS FR.

METHODS

300 participants scheduled for TSS (2016-2023) at a single institution were included. Patients with CKD, CHF, AVP deficiency on postoperative day (POD) 3, chronic hypoNa, untreated adrenal insufficiency/hypothyroidism, and those for whom FR was felt unsafe were excluded. Patients were randomly assigned to control (CON, n=94) or moderate FR (FR1, n=39). Participants in CON group were instructed to drink ad lib. Participants in FR1 were FR to 1.8 liters/day (2 liters/day if > 100 kg) from POD3-14. Based on interim analysis suggesting a trend toward reduced hypoNA, FR was changed to strict FR (FR2, n=62) of 1 liter/day (1.2 liters/day if > 100 kg). Serum sodium (Na) was monitored inpatient and on POD 3, 7, 10, and 14, and readmissions evaluated. Fluid intake and thirst were assessed.

RESULTS

In the intention-to-treat analysis, incidence of hypoNa (Na < 135 mEq/L) was 31.9% CON, 28.2% FR1, and 21% FR2, and severe hypoNa (Na < 125 mEq/L) 7.4% CON, 5.1% n FR1 and 0% FR2. Readmission for hypoNa occurred in 6.4% (n=6) CON, 7.7% (n=3) FR1 and 1.6% (n=1) FR2. Severe hypoNa occurred more frequently in CON vs. FR2 (P=0.04), and nadir Na was higher in FR2 vs. CON (P=0.02). Although thirst scores were similar among groups, an individual’s thirst score correlated with compliance

CONCLUSION

Results of this randomized study show a reduction in severe hypoNa and readmission for hypoNa in patients on FR from POD3-14 after TSS vs. patients instructed to drink ad lib. This provides strong evidence that post-TSS FR decreases rate of delayed hypoNa and related readmission.
CTNI-48. A PHASE 1 STUDY OF ERAS-801, A POTENT, SELECTIVE, AND CENTRAL NERVOUS SYSTEM (CNS)-PENETRANT EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) INHIBITOR, FOR PATIENTS WITH RECURRENT GLIOBLASTOMA MULTIFORME (GBM)
Authors: Wen Patrick , Ahluwalia Manmeet , Odia Yazmin , McKean Meredith , Snyder James , Colman Howard , Lobbous Mina , Nghiemphu Leia , Chong Robert , Yang Jennifer , Patel Hina , Vecchio Daniela , Lokku Armend , Brail Les , Mellinghoff Ingo
Published: November 2024

EGFR is among the most common targets for genetic alterations in GBM. Changes in EGFR gene amplification and the extracellular domain result in receptor overexpression or constitutive activation, and enhanced oncogenic signaling. ERAS-801 is a potent, selective, and highly CNS-penetrant EGFR inhibitor being developed for the treatment of GBM, with a focus on tumors harboring EGFR genetic alterations. THUNDERBBOLT-1 is the first-in-human phase 1 dose escalation and expansion trial evaluating ERAS-801 monotherapy for patients with recurrent GBM. ERAS-801 is administered orally once daily for continuous 28-day cycles. As of April 10, 2024, a total of 52 patients were treated across 7 dose cohorts: 20 mg (n=3), 40 mg (n=5), 80 mg (n=3), 160 mg (n=6), 240 mg (n=25), 280 mg (n=4), or 320 mg (n=6). Key patient characteristics were median age of 60 years, 67% male, mostly one prior therapy, and 81% tumors with alterations. The MTD was 240 mg. Dose-limiting toxicities were observed at 320 mg (n=2, Grade 2 QT prolongation, Grade 3 rash and Grade 3 dermatitis acneiform), 280 mg (n=3, Grade 3 QT prolongation), and 240 mg (n=1, Grade 3 QT prolongation) doses. The most common treatment related adverse events (TRAEs), in >10% of patients, were dermatitis acneiform, diarrhea, and nausea. Electrocardiogram QT prolongation occurred in 11.5% of patients and was not associated with clinical findings. ERAS-801 showed rapid absorption; peak plasma concentration was generally achieved within 6 hours post dose. PK exposure increased in a dose-dependent manner over the doses evaluated. Across all doses there was a confirmed partial response (using mRANO) in 1 patient and 6 patients achieved a PFS of 6 months. ERAS-801 shows well behaved PK with substantial CNS penetration, preliminary safety, and tolerability in patients with recurrent GBM. The TRAEs were reversible, manageable, and consistent with known toxicities of EGFR inhibitors.
CTNI-63. RHENIUM (186RE) OBISBEMEDA (RHENIUM NANOLIPOSOME,186RNL) FOR THE TREATMENT OF LEPTOMENINGEAL METASTASES (LM): SUMMARY OF THE PHASE 1 DOSE ESCALATION STUDY AND PHASE 2 ADMINISTERED DOSE SELECTION
Authors: Brenner Andrew , Youssef Michael , Kumthekar Priya , Bao Ande , Michalek Joel , Phillips William , Patel Toral , Floyd John , Hedrick Marc , Juverdianu Leonardo , Blouw Barbara , LaFrance Norman , Moore Melissa
Published: November 2024

BACKGROUND

Leptomeningeal metastases (LM) is a devastating systemic cancer complication most often seen with breast, lung, and melanoma, with limited treatment options and poor survival. Rhenium (186Re) Obisbemeda (186RNL) provides the combination of effective therapeutic beta radiation, simultaneous gamma-decay for imaging, and ~90-hour physical half-life for optimal radiation delivery. A summary of the Phase 1 dose escalation study, expected to be completed, will be presented.

METHODS

ReSPECT-LM is a Phase 1 dose escalation study for patients with LM from any primary cancer. Adult patients are given a single dose of 186RNL via intraventricular catheter (Ommaya reservoir) in an outpatient setting to determine the maximum tolerated/feasible dose (MTD/MFD), safety, and tolerability. Seven administered dose cohorts in a 3 + 3 design, from 6.6 mCi to 109.96 mCi, were anticipated.

RESULTS

For the first 5 cohorts, doses were well-tolerated; most AEs were Grade 1 and 2 with 1 DLT (Cohort 5) at time of abstract submission. CSF tumor cell enumeration assays were performed with a maximum reduction over baseline seen at Day 28. Radiation absorbed doses were calculated for the ventricles, cranial subarachnoid space, and spinal fluid and showed a linear increase with administered dose, with liver and spleen remaining low. Neurological symptoms were reported to improve. We expect the Phase 1 conclusion and the RP2D to be determined for conference reporting; additionally, based on duration of benefit seen during the Phase 1, a multidose paradigm will be initiated to extend benefit.

CONCLUSION

A single dose of 186RNL for patients with LM has been well-tolerated, with high absorbed doses to the treatment area, acceptable organ doses, and promising clinical improvement and reductions in tumor cell count. Phase 2 is expected to begin enrollment by Q4 2024. Additionally, based on these data, a Phase 1 multidose study is planned to be initiated this year.
CTNI-66. IDH-MUTANT GLIOMA PATIENTS TREATED WITH VORASIDENIB: ONGOING DATA FROM THE VORASIDENIB EXPANDED ACCESS PROGRAM
Authors: Cloughesy Timothy , Peters Katherine , Colman Howard , Taylor Jennie , Mellinghoff Ingo , Shih Helen , Chacar Christelle , Dewey Jonathan , Wen Patrick
Published: November 2024

BACKGROUND

Vorasidenib (VOR) is an oral, brain-penetrant dual inhibitor of mutant isocitrate dehydrogenase 1/2 (mIDH1/2) demonstrating clinical efficacy and safety in patients with mIDH1/2 glioma in the phase 3 INDIGO study (NCT04164901). Servier launched an expanded access program (EAP, NCT05592743) in November 2022 designed to provide access to VOR for patients with mIDH1/2 glioma. Early clinical outcomes of patients treated in this EAP are presented.

METHODS

Eligible participants were aged ≥12 years with mIDH1/2 glioma and, in the opinion of the treating oncologist, would potentially benefit from treatment with VOR. Safety assessments occur every two weeks for the first two 28-day cycles, then monthly for the duration of treatment.

RESULTS

As of the March 31, 2024 data cutoff, 71 participants have initiated treatment with VOR. Mean (SD) age was 42.7 (14.8) years; 39 (55%) were male; and 34 (48%) with astrocytoma. mIDH mutation status was 46 (65%) mIDH1. One participant had separate tumors with either mIDH1 or mIDH2 identified. The majority of participants had grade 2 gliomas (n=51 [72%]) and non-contrast–enhancing disease (n=49 [69%]). As of the data cutoff, 62 (87%) participants remain on treatment, with the majority initiating treatment within the past 6 months (n=49 [69%]). Nine (13%) participants have discontinued treatment due to: radiographic progressive disease (n=3); clinical progressive disease (n=4); adverse event (AE) unrelated to treatment (n=1); or other reason (n=1). Three participants have died (disease progression [n=2], unrelated infection [n=1]). At least one AE of any grade was seen in 35 (49%) participants, with 4 (6%) experiencing unrelated serious AEs. Eight (11%) patients had AEs of special interest (defined as grade 2 or higher ALT/AST elevations). Ten (14%) patients had AEs that led to dose interruption and one (1%) patient had dose reduction. Additional treatment duration and various subgroup analyses will be presented.
DNAR-16. TARGETING APOBEC CYTIDINE DEAMINASES TO ENHANCE RADIOSENSITIVITY IN GLIOMA
Authors: Marin Bianca M , Gujar Amit , Kocakavuk Emre , Johnson Kevin C , Amin Samirkumar B , Verhaak Roel G W
Published: November 2024

Glioma is the most common and aggressive primary adult brain tumor. Radiation therapy (RT) is a critical part of glioma treatment, but radioresistance severely limits its therapeutic efficacy. To better understand how radioresistance develops, we analyzed 212 paired primary and recurrent gliomas from the Glioma Longitudinal Analysis Consortium. We found a significant increase in mutational signatures associated with the activity of the Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) family of cytidine deaminases in RT-treated recurrent gliomas (p<0.001, paired Wilcoxon signed-rank test). Further analysis of post-treatment mutations showed that RT increased APOBEC mutational signatures independent of other factors (p<0.001, multivariable log-linear regression), suggesting that APOBEC proteins become activated by radiation. However, their role in promoting tumor evolution and treatment resistance is currently unknown. Further analyses of extended signature contexts and expression data nominated APOBEC3B (A3B) and APOBEC3G (A3G) as candidates for creating these mutational signatures. To investigate their roles in RT response, we knocked out (KO) A3B and A3G individually in patient-derived glioma cell lines before RT. Compared to Control cells, irradiated A3B-KO and A3G-KO cells acquired significantly fewer APOBEC mutational signatures by whole genome sequencing (p<0.05, Kruskal–Wallis test) and exhibited enhanced radiosensitivity in vitro. Interestingly, the KO cells displayed a significant decrease in mutational signatures associated with Non-Homologous End-Joining (NHEJ), one of the main pathways for repairing the RT-induced DNA damage (p<0.05, Kruskal–Wallis test), suggesting that APOBEC deletion impaired DNA repair. This was further supported by persistent gH2AX DNA damage foci 48h post-RT and reduced autophosphorylation of DNA-dependent protein kinase (DNA-PK), a vital component of the NHEJ pathway, particularly in A3G KO cells. Overall, our results identify APOBEC proteins as potential targets for radiosensitizing gliomas and highlight the clinical utility of using mutational signatures to predict and monitor response to treatment.
DDEL-13. ENHANCING THE EFFICACY OF THE BBB-PENETRANT PEPTIDE-DRUG CONJUGATE PT(IV)-M13 WITH THE KINASE INHIBITOR BIA TO IMPROVE INTRA-TUMORAL DELIVERY AND INHIBIT DNA REPAIR
Authors: Vaughn-Beaucaire Philippa , Macias Jorge Luis Jimenez , Miller Edward , Pentelute Bradley , Lawler Sean
Published: November 2024

The blood-brain and blood-tumor barriers (BBB and BTB) constitute major obstacles to effective GBM therapy. These barriers impede the penetration of the great majority of pharmacological agents into brain tumors. This study introduces a dual-modality approach aimed at enhancing drug delivery to GBM through manipulating BTB permeability and facilitating targeted drug delivery through a novel BBB penetrant drug conjugate. First, we investigated the effects of the broad specificity kinase inhibitor 6-bromo-indirubin-3’-acetoxime (BIA), a derivative of the natural medicinal indirubin, on BTB integrity. These studies revealed that BIA diminishes trans-endothelial electrical resistance and reduces the expression of VE-cadherin in human cerebral microvascular endothelial cells (hCMEC/D3), indicating a loosening of tight junctions. This effect was also observed in mouse GBM models, suggesting a BIA-induced increase in BTB permeability, enhancing the intra-tumoral accumulation and efficacy of non-brain-penetrant therapeutic agents in murine GBM models. Secondly, we have developed Pt(IV)-M13, a perfluoroaryl stapled variant of the cell-penetrating peptide TP10 conjugated to Pt(IV), a prodrug form of cisplatin. This conjugate demonstrates an ability to penetrate the BBB, enhancing drug delivery while limiting exposure to healthy brain tissue, Pt(IV)-M13 exhibits a promising cytotoxic effect on GBM cells, sparing non-tumorous cells, and increases the survival of GBM tumor-bearing mice significantly compared to controls. Our data includes quantitative analysis of platinum accumulation in tumor tissues versus non-targeted regions, highlighting the specificity and potential of this approach. Furthermore, we have found that BIA synergizes with Pt(IV)-M13 in vitro, via inhibition of DNA repair, and are currently investigating the safety and efficacy of administering BIA in conjunction with Pt(IV)-M13 in vivo. This novel strategy holds potential to significantly impact the clinical management of GBM, emphasizing the importance of targeting the BTB in future therapeutic strategies.
DDEL-17. INTRA-TUMORAL CONVECTION ENHANCED DELIVERY OF DEXAMETHASONE REDUCES INFLAMMATORY SIGNATURES AND EXTENDS SURVIVAL IN GBM MODEL
Authors: Dadario Nicholas , Teasley Damian , Lei Liang , Rolfe Nathaniel , Winans Nathan , Kotidis Corina , Khoury Nadine , Yoh Nina , Furnari Julia , Sperring Colin , Upadhyayula Pavan , Ifediora Nkechime , Humala Nelson , Mahajan Aayushi , Zhao Wenting , Gill Brian , Sims Peter , Canoll Peter , Bruce Jeffrey
Published: November 2024

Dexamethasone is the most widely utilized drug for glioblastoma (GBM). However, systemic delivery of dexamethasone in GBM patients is associated with significant side effects and increasing doses with worse survival. Convection-enhanced delivery (CED) can deliver high doses of immunotherapy directly into the tumor microenvironment (TME) while avoiding systemic toxicity. Here, we report that high doses of dexamethasone can be delivered locally by CED without side effects and increase survival in a GBM model along with reduced inflammatory myeloid signatures. We investigated CED of dexamethasone treatment on survival(n=40), adverse side effects, and the immunological TME through peripheral analyses, liquid chromatography–mass spectrometry, and histology in a preclinical syngeneic mouse model. Additionally, we assessed the transcriptional responses of human GBM slices and stem-cell-derived human microglia after steroid treatment through bulk and single-cell RNA sequencing. We found that 7-day treatment with CED of dexamethasone produced a significant survival advantage in glioma-bearing mice compared to non-treated control(p=0.03). Systemic dexamethasone achieved low levels of drug in the TME and caused dysregulated blood glucose, blood counts, and peripheral organ weights, while high CED doses avoided these side effects(p< 0.05 each). Steroid treatment of acute GBM slices and lipopolysaccharide-activated microglia in-vitro both reversed inflammatory myeloid signatures associated with poor survival and recurrence on RNA sequencing analyses. We demonstrate the preclinical efficacy of delivering high local doses of dexamethasone in a GBM model through CED and observed prolonged survival along with reduced adverse inflammatory myeloid signatures. No side effects were demonstrated after chronic CED treatment of dexamethasone while systemic delivery achieved poor tumor penetration and caused known hematologic and metabolic side effects supporting the potential to optimize the clinical use of this therapy. CED of dexamethasone provides us a new treatment paradigm to locally control inflammatory signatures in the glioma TME in a controlled fashion.
DDDR-20. CLINICAL EFFICACY OF PYROTINIB COMBINING WITH STEREOTACTIC RADIOSURGERY IN HER2-POSITIVE BREAST CANCER BRAIN METASTASES
Authors: Zhen Juanjie , Bashir Shoaib , Yang Yanying , Wang Hui , Lai Mingyao , Cai Linbo
Published: November 2024

BACKGROUND

Up to 50% of patients with breast cancer (BC) and human epidermal growth factor receptor 2 (HER2) positive present with disease progression in brain metastases (BM). Pyrotinib, an oral irreversible pan-HER receptor tyrosine kinase inhibitor, has shown efficacy in active central nervous system (CNS) metastases. However, clinical efficacy of pyrotinib combining with stereotactic radiosurgery (SRS) in BCBM is unclear.

METHODS

This retrospective, observational study collected data from 52 HER2+ BC patients with brain metastasis who received pyrotinib-based therapy in Guang dong Sanjiu brain hospital from 2019 to 2023. Among these patients, 36 received pyrotinib-based therapy combining with SRS concurrently, or within 1 months. Age, stage at diagnosis, dates of BM, primary tumor subtypes, prior systemic therapy, CNS-directed local therapy, the objective response and survival status were collected. The assessment of adverse effects was based on CTCAE 4.0.

RESULTS

34 patients were evaluable for efficacy (median age: 51.5). With a median follow-up duration of 19.6 months, 1 patient (0.3%) achieved CR, while 27 patients (79.4%) had PR, resulting in an ORR of 82.3%. The median CNS PFS was 13.2 months (95% CI, 4.9-21.7). Median overall survival (OS) was 22.6 months (95% CI, 17.5-27.6). The most common grade 3 or worse treatment-emergent adverse event was diarrhea (6 [17.6%]).

CONCLUSIONS

Our results suggest that pyrotinib combining with SRS is associated with promising efficacy and a satisfactory safety profile for Her2+ breast cancer brain metastases.