bluuebunny/crossref_metadata_2025 huggingface dataset:
CSIG-13. TARGETING GENETIC DEPENDENCIES EXPOSES DIFFUSE MIDLINE GLIOMA CELL OF ORIGIN VULNERABILITIES
Authors: Dun Matthew D , Jackson Evangeline , Vo Tuan , Savary Clara , Riley Madisen , Douglas Alicia , Findlay Izac , Germon Zacary , Mannan Abdul , Thomas Bryce , Duchatel Ryan , Jayaraman Ranjith
Published: November 2024

Diffuse midline glioma (DMG), including diffuse intrinsic pontine glioma (DIPG), are uniformly fatal brain cancers affecting children, adolescents, and young adults. These tumors are characterized by ‘oncohistone’ mutations in histone H3 genes (H3F3A, HIST1H3B, HIST1H3C), resulting in the substitution of lysine 27 to methionine (H3K27M), resulting in dominant negative hypomethylation at lysine 27 (H3K27) and a global loss of gene silencing. CRISPR-Cas9 loss-of-function gene deletion screens identified mutation-independent dependencies on PIK3CA and MTOR genes for tumor growth and proliferation, highlighting a targetable molecular dependency across DMG patient-derived models (n=38). However, systemic PI3K/mTOR inhibition increased blood glucose and insulin levels, promoting hyperinsulinemia/hyperglycemia and reduced efficacy in vivo. To exploit genetic dependencies while maintaining compliance and therapeutic benefit, we optimized combinations of clinically relevant PI3K inhibitors (paxalisib, GCT007, everolimus) with the antiglycemic drug metformin to restore glucose homeostasis and decrease DMG insulin receptor activity in vivo, extending the survival of DIPG xenograft models. Phosphoproteomic profiling of DIPG models treated with PI3K/mTOR inhibitors promoted calcium-activated PKC signaling. The brain-penetrant PKC inhibitor enzastaurin in combination with paxalisib, synergistically extended the survival of DIPG xenograft models, including those mimicking disease progression, with further benefits potentiated using metformin in a multimodality approach. Combined PI3K-PKC inhibition in vivo promoted differentiation of OPC-like DMG to more OC-like cells, enhancing PDGFRA-JAK/STAT proinflammatory signaling, showing features of demyelination and MHC-II+ antigen expression, including PD1/PDL1. In parallel, combined PI3K/mTOR and PDGFRA inhibition using paxalisib and avapritinib synergistically extended the survival of patient-derived xenograft models, showing the preclinical relevance of simultaneously targeting these vulnerabilities. Together, we reveal that therapeutic inhibition of PI3K/mTOR and compensatory PKC signaling, while mitigating side effects with metformin, altered the chromatin architecture, leading to cellular differentiation and opening the door for clinically relevant checkpoint inhibitors. This combination strategy addresses DMG genetic dependencies, cellular and systemic responses to precision therapies, while harnessing the immune system for potential clinical translation.
CSIG-14. ACROLEIN INDUCES THE MIR-30A-5P/NCAM AXIS THROUGH THE AKT/GSK3Β/Β-CATENIN PATHWAY, PROMOTING GLIOMA PROGRESSION
Authors: Chen Pin-Yuan , Liu Pei-Yu , Huang Chy-In , Wang Hsiang-Tsui
Published: November 2024

Glioblastoma (GBM), the most aggressive brain tumor, exhibits resistance to treatment and thrives in low-oxygen (hypoxic) environments, leading to the accumulation of reactive oxygen species (ROS). Hypoxia activates the hypoxia-inducible factor (HIF)-1α pathway, enhancing tumor malignancy. Acrolein, a reactive aldehyde produced during lipid peroxidation in hypoxia, induces toxicity through DNA damage, inflammation, mitochondrial dysfunction, and oxidative stress. Our previous study found elevated acrolein levels in hypoxic glioma cells and linked acrolein-induced DNA damage (Acr-dG) with poor GBM prognosis. However, the role of acrolein in GBM progression remains unclear. This study aims to elucidate the impact of acrolein on GBM. In vitro experiments demonstrated acrolein production under hypoxia, which increased glioma cell migration and spheroid formation. RNA sequencing identified five affected pathways: cell adhesion molecules, PI3K-AKT signaling, ECM-receptor interaction, MAPK signaling, and neuroactive ligand-receptor interaction. Acrolein downregulated NCAM (neural cell adhesion molecule) via the miR-30a-5p-AKT-GSK3β/β-catenin axis in GBM cell lines and patient-derived cells. Overexpressing NCAM reduced cell migration and spheroid formation. Lower NCAM levels in GBM tissues correlated with poor patient survival. This study suggests the potential of NCAM as a therapeutic target for GBM and provides insights into early detection and treatment strategies for this malignancy.
CSIG-19. IDENTIFICATION AND TARGETING OF TUMOR DRIVER SCHWANN(NF2LOSS) CELLS IN SPORADIC AND NF2-RELATED VESTIBULAR SCHWANNOMAS
Authors: Laws Maxwell , Asuzu David , Rampalli Ihika , Mullaney Dustin , Laraba Liyam , Mandel Debjani , Zhang Xiyuan , Elkahloun Abdel , Sisay Bayu , Maric Dragan , Johnson Kory , Abdullaev Zied , Aldape Kenneth , Shern John , Parkinson David , Chittiboina Prashant
Published: November 2024

Vestibular schwannomas (VS) arise from myelinating Schwann cells of CN VIII and are associated with severe morbidity due to local tumor growth. Sporadic and neurofibromatosis type 2 (NF2) associated VS are both characterized by NF2 (merlin) loss but the mechanisms remain unexplored. Using a multiomic approach, we dissected the role of NF2 loss in VS tumor formation and proliferation. We obtained surgical samples from 15 patients undergoing surgery for VS (sporadic, n=4; NF2, n=9), and performed single-cell or single-nucleus RNA sequencing (scRNAseq, n=4; snRNAseq, n=15), transposase-accessible chromatin (snATAC-seq, n=9), whole exome (n=12), and bulk DNA methylation assays (n=15). Transcription factor binding was assayed with ChIPseq. We validated our key findings with immunoblot, ELISA, RNAscope (n=8), and multiplex immunocytochemistry (mIHC; n=8). NF2fl/fl;Periostin-Cre+mice versus their Cre- control littermates treated with novel inhibitors of TEAD auto-palmitoylation (VTs). We mapped the VS transciptome and identified canonical Schwann cells, macrophages, T-cells and endothelial cells. Using the cells that had Chr22 loss (second hit deletions at the NF2 locus), we generated a NF2loss gene signature. We then identified Schwann(NF2loss) cells in all tumors, and found these enriched for YAP1/TAZ-TEAD, NRG1, and HIF-1α signaling pathways. Schwann(NF2loss) cells showed increased TEAD1 expression and chromatin accessibility for TEAD family transcription factor motifs. TEAD1 binding was observed at promoters of genes including VEGFA, EGFR, with strong enrichment for mitogenic pathways. We also found that VEFGA expression was restricted to Schwann(NF2loss) cells, and confirmed this with RNAscope and mIHC. Schwann(NF2loss) cells were key regulators of macrophages (M2-subtype, tissue resident) through M-CSF/IL-34 signaling. NF2fl/fl;Periostin-Cre+ mice showed increased VEGFA expression, and that was reversible by TEAD inhibition in-vivo with VTs. We report that Schwann(NF2loss) cells are key tumor drivers in VS. These cells are highly proliferative (YAP/TAZ-TEAD axis), drive angiogenesis (VEGFA expression), and promote tumor mass accretion (macrophage influx via M-CSF/IL-34 pathway) that can all be targeted via TEAD inhibition.
CSIG-21. THE ROLE OF GUT MICROBIOTA IN GLIOBLASTOMA: INSIGHTS FROM MICROBIOME-GENE EXPRESSION INTERACTIONS
Authors: Bekal Mahesh , Wang Isabel , Wang Daniel , Dono Antonio , Arjuna Srividya , Ballester Leomar , Esquenazi Yoshua
Published: November 2024

Glioblastoma, the most aggressive form of primary brain tumor, remains a formidable clinical challenge due to its invasiveness and resistance to therapy. Emerging evidence suggests that the gut microbiome plays a crucial role in modulating cancer progression through complex interactions with host physiology. In this study, we investigated the influence of gut microbiota and tumor gene expression by analyzing stool and tissue samples from glioblastoma patients. Utilizing 16S rRNA sequencing of stool samples and NanoString gene expression analysis of tumor tissue samples, we explored the relationship between gut microbiome taxa and gene expression levels in tissue. Pathway analysis using KEGG and Gene Ontology databases was employed to elucidate the functional implications of these interactions. Our findings reveal contrasting effects of specific gut microbiota taxa and gene expression, with Fusobacterium demonstrating a potential oncogenic role, while Bifidobacteriaceae and Akkermansiaceae display potential tumor-suppressive effects. Fusobacterium is associated with the upregulation of key oncogenes and pathways promoting cancer cell survival, growth, and metabolism, whereas Bifidobacteriaceae and Akkermansiaceae are linked to the downregulation of genes involved in pathways promoting cancer cell survival and proliferation, such as MAPK signaling and stress response pathways, potentially inhibiting cancer cell growth. These results highlight the intricate interplay between gut microbiota composition and cancer biology and underscore the potential of gut microbiota modulation as a therapeutic strategy in glioblastoma management.
CSIG-22. PHARMACOLOGIC INHIBITION AND KNOCKDOWN OF CAMK2 IMPAIR GROWTH OF PATIENT-DERIVED GLIOBLASTOMA CULTURES
Authors: Ronnen Rebecca , Wang Shuai , Haddock Sara , Ravn-Boess Niklas , Golub Danielle , Stephan Gabriele , Sabio Jonathan , Donaldson Hayley , Bonanni Luke , Zuniga Adler Guerrero , Karnavas Theodoros , Placantonakis Dimitris
Published: November 2024

INTRODUCTION

Glioblastoma (GBM), a primary brain malignancy with a median survival of 15-18 months, presents a pressing challenge in neuro-oncology. Patient-derived GBM cultures (PDGCs) exhibit spontaneous calcium (Ca2+) waves, which are thought to drive tumor growth and represent a therapeutic target. The mechanisms underlying the generation and the effectors of these Ca2+ waves remain elusive. We hypothesize CAMK2, a Ca2+/calmodulin-dependent protein kinase expressed as four distinct isoforms, is a key effector of such Ca2+ waves by phosphorylating substrates that promote tumor growth.

METHODS

Using multiple PDGCs, CAMK2 isoform-specific mRNA levels were assessed via qRT-PCR both at baseline and after shRNA-mediated knockdown (KD). Tumorsphere formation and WST-8 assays were performed to assess PDGC clonogenic potential after either KD or pharmacologic inhibition with the cell-permeable CAMK2 inhibitor KN93.

RESULTS

The relative mRNA levels of CAMK2 isoforms across three PDGC lines were, in decreasing order: CAMK2D, CAMK2G, CAMK2B, and CAMK2A. Expression of CAMK2D- and CAMK2B-specific shRNAs significantly reduced tumorsphere growth compared to control shRNA. CAMK2D KD reduced sphere formation by 55.13 ± 3.54% (p=0.0001) and 47.72 ± 9.55% (p=0.008) in separate PDGC lines, while CAMK2B KD reduced sphere formation by 41.15 ± 11.51% (p=0.021) and sphere size by 41.78% ± 10.50% (p=0.049) (n=3/experiment). KN93 treatment reduced tumorsphere formation by 59.23 ± 1.40% (p=0.0006) and 42.94 ± 13.0% (p=0.032) in two PDGC lines (n=3) and PDGC viability, while CAMK2-inactive analogue KN92 and DMSO minimally impacted viability (p<0.0001, two-way ANOVA).

CONCLUSION

CAMK2D and CAMK2B KD, as well as KN93 treatment, reduce tumorsphere formation, suggesting CAMK2 has a tumorigenic role in GBM. Further investigation of CAMK2 isoforms and in vivo validation are underway. Future aims include directly testing the link between spontaneous Ca2+ waves and CAMK2 activation and identifying CAMK2 phosphorylation targets that mediate tumor growth.
CSIG-29. BRAF INHIBITOR THERAPY IN BRAF-MUTATED PRIMARY BRAIN TUMORS: A SINGLE-CENTER EXPERIENCE
Authors: Baykal Duru , Ser Hazal , White Jessica , Neth Bryan , Uhm Joon , Ruff Michael , Sarkaria Jann , Wilson Jessica , Yan Elizabeth , Meyer Fredric , Celda Maria Peris , Sener Ugur
Published: November 2024

BACKGROUND

BRAF pathway alterations are frequent in glial/neuroepithelial tumors. BRAF-targeted therapy with BRAF inhibitors (BRAFi) and/or MEK inhibitors (MEKi) has proven efficacy in clinical trials, though mainly enrolling pediatric patients. We sought to investigate real-world data for adult patients with BRAF-pathway mutant glial/neuroepithelial neoplasms treated with BRAFi/MEKi.

METHODS

Adults with BRAF-pathway mutated glial/neuroepithelial neoplasms treated with BRAFi/MEKi were retrospectively reviewed.

RESULTS

Five patients (n=4 female, median age at diagnosis 36) were identified (tumor types: glioblastoma n=1, high-grade astrocytoma with epithelioid features n=1, low-grade neuroepithelial tumor n=1, pilocytic astrocytoma n=1, pleomorphic xanthoastrocytoma n=1). Four had BRAF V600E and one had NF1 p.S2687Cfs*5 mutant tumors. Prior to targeted therapy initiation, patients underwent a median 2.4 treatments including surgery (n=4), radiation therapy (n=4), chemotherapy (temozolomide n=4; carboplatin/vincristine n=1). BRAF-targeted therapies included dabrafenib/trametinib (n=4), binimetinib/encorafenib (n=2), binimetinib (n=2). One NF1-mutant glioblastoma received binimetinib followed by binimetinib/bevacizumab. Median BRAFi/MEKi treatment was 15.2 months (range: 6-36 months). Toxicities included leukopenia (n=3), peripheral edema (n=1), reduced ejection fraction (n=1), skin rash (n=5), transaminitis (n=1) with all patients requiring dose reductions and 3 cases requiring discontinuation. Among patients where BRAFi/MEKi was discontinued due to toxicity, 2 received other treatments at progression, then switched to a different BRAFi/MEKi combination, which they tolerated (duration 6-10months). Best radiographic response was partial response, noted in 3 patients treated with dabrafenib/trametinib. Four patients remain alive and continue BRAFi/MEKi.

CONCLUSIONS

In this cohort of heavily-pretreated patients with glial/neuroepithelial neoplasms, BRAF-targeted therapy was associated with durable responses. Interestingly, two patients who were unable to tolerate one combination of BRAFi/MEKi were able to tolerate a different combination with sustained response. Our findings support ongoing use of BRAF targeted therapy for CNS tumors. Optimal timing and duration of treatment requires further prospective evaluation in adult patients.
CSIG-30. EXPLORING THE ROLE OF CAPICUA (CIC) IN RESISTANCE MECHANISMS OF MEK INHIBITORS IN GLIOBLASTOMA
Authors: Persaud Phooja
Published: November 2024

Glioblastoma multiforme (GBM) is the most common and fatal primary brain tumor, resistant to conventional therapy. Despite its heterogeneous nature, a key feature of GBM is aberrant kinase signaling. Specifically, hyperactivation of receptor tyrosine kinases (RTK) and their downstream tumorigenic effectors Ras/MEK/Extracellular Signal Regulated Kinase (ERK) pathway are attributed to the aggressive nature of GBM. Capicua (CIC) is a High Mobility Group (HMG) box transcriptional repressor that directly binds to DNA and counteracts the transcription of genes typically expressed only in response to RTK activation such as oncogenic transcription factors ETV1/4/5. Hyperactive MEK/ERK signaling in GBM causes CIC degradation. The mechanism of CIC’s repressor function is not well understood, however, transcriptional repressors (like CIC) typically form co-repressor complexes to repress target genes. We discovered a novel interaction between CIC and the transcriptional regulator yin yang 1 (YY1), a context-dependent transcription factor that can repress or activate gene expression. We uncovered that 90-kDa ribosome S6 protein kinase (p90RSK), a downstream effector of ERK and a known CIC regulator, mediates the CIC/YY1 interaction. Interestingly, we found re-activation of p90RSK following MEK/ERK inhibition implicating p90RSK in the resistance mechanism of RTK/MEK/ERK inhibition in GBM. We hypothesize that p90RSK inhibition will stabilize the CIC/YY1 co-repressor complex and re-sensitize towards MEK/ERK inhibition. Patient-derived glioma stem-like cells (GSCs) were treated with increasing doses of BI-D1870 or LJI308 (p90RSK inhibitors) with and without selumetinib (MEK inhibitor) and various functional assays were performed to examine the effect of p90RSK inhibition on the CIC/YY1 complex and sensitization to MEK/ERK inhibition. Treatment with BI-D1870 and LJI308 markedly reduced viability and mRNA expression of ETV1/4/5 indicating that p90RSK inhibition may mediate CIC /YY1 DNA binding ability. Importantly, inhibiting p90RSK sensitized GSCs to MEK/ERK inhibition. These results highlight the importance of downstream p90RSK inhibition in stabilizing CIC/YY1 repressor complex function and sensitizing cells to RTK/MEK/ERK inhibition.
CSIG-33. CERAMIDE-1-PHOSPHATE/CERK ARE REGULATORS OF ETMR GROWTH AND POTENTIAL THERAPEUTIC TARGETS
Authors: Maas Allison , Liapis Evangelos , O’Neill Kelly , Hanson Derek , Carter Claire
Published: November 2024

Embryonal tumor with multilayered rosettes (ETMR) is a highly aggressive CNS neoplasm which occurs almost exclusively in infants and is associated with an extremely poor prognosis. To identify functional signaling lipids that contribute to the aggressive nature of ETMR and that can be targeted therapeutically, we carried out mass spectrometry imaging on human ETMR patient samples, the patient-derived cell line BT183, and normal neural stem cells. We identified an accumulation of ceramide-1-photphate (C1P) within the rapidly proliferating embryonal tumor cells in patient samples and the cell model. We also detected high accumulation of C1P within the aberrant vascular proliferations in patient samples. Ceramide-1-phosphate is a pleiotropic bioactive signaling lipid that controls cell fate. C1P and its synthesizing enzyme, ceramide kinase (CERK), are known mitogens that have been shown to regulate cell proliferation in several non-CNS cancers. C1P is known to mediate the upregulation of PI3K/Akt/mTOR, MAPK/MEK/ERK1/2, Rho kinase, JNK, to promote cell survival and migration. After spatially mapping C1P accumulation in patient samples and our in vitro 3D models, we next carried out IHC to correlate lipid accumulation with its synthesizing enzyme, CERK. CERK was found to be abundantly accumulated in both endothelial and tumor cells within the tumor microenvironment of patient samples. Western blot analysis of CERK demonstrated a significant increase in the ETMR 3D tumorspheres compared to the NSC neurospheres. Treatment of the ETMR 3D tumorspheres with the CERK inhibitor, NVP-231, potently reduced cell growth and viability. Western blot analysis of ETMR tumorspheres at 8 and 24 hours post-treatment demonstrated a time-dependent decrease in N-MYC and a subsequent increase in p53. Studies are ongoing to validate these findings in vivo and to elucidate the signaling pathways that C1P/CERK regulate in both the vascular and tumor cells in ETMR.
RADT-02. PRE-OPERATIVE VERSUS POST-OPERATIVE FRACTIONATED STEREOTACTIC RADIOTHERAPY: A SINGLE-INSTITUTION ANALYSIS OF 534 RESECTED METASTASES
Authors: Perlow Haley , Hennings Sarah , Bradshaw Jared , Reddy Sohil , Luu Sydney , Matsui Jennifer , Klamer Brett , Dibs Khaled , Harrell Marshall , 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

Patients with large or symptomatic brain metastases and limited intracranial disease typically have surgery followed by post-operative (post-op) stereotactic radiosurgery (SRS). However, SRS can lead to elevated rates of radiation necrosis (RN), meningeal disease (MD), and local failure (LF). Fractionated treatments can deliver a higher biological effective dose and may reduce the risk of LF, and pre-operative (pre-op) treatments may reduce the risk of RN and MD through treating smaller volumes and tumor sterilization. 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 post-op FSRT. A retrospective analysis was performed at a single institution and included patients who had surgical resection and radiation to at least one brain metastasis. Patients with multiple metastases resected, either during the same surgery or at different times in the disease course, were eligible for inclusion. 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. 458 patients with 534 resected brain metastases were eligible for analysis. 235 metastases received pre-op FSRT, and 299 metastases received post-op FSRT. Overall, 15% of patients had multiple brain metastases resected. Overall, 6 (2.6%) pre-op and 13 (4.3%) post-op patients experienced LF. 21 (8.9%) pre-op and 38 (12.7%) post-op patients experienced symptomatic RN. 11 (4.7%) pre-op and 29 (9.7%) post-op patients were diagnosed with MD (p=0.031). 14% and 24% of metastases that received pre-op and post-op FSRT, respectively, experienced the composite endpoint (p=0.005). In our study, pre-op FSRT compares favorably to post-op FSRT primarily due to a 50% reduction in the incidence of MD. Differences in symptomatic RN or LF were small on adjusted analyses. Prospective validation of pre-op FSRT is needed.
RADT-03. CONTRAST-ENHANCING LESIONS INDUCED BY CNS-DIRECTED INTENSITY MODULATED PROTON THERAPY: DEMOGRAPHIC AND CARDIOVASCULAR RISK FACTORS ANALYSIS
Authors: Gal Omer , Yu Jen , Mehta Minesh P , Hall Matthew D , Press Robert H , Odia Yazmin , McDermott Michael W , Fellows Zachary , Wroe Andrew , Gutierrez Alonso N , Kotecha Rupesh
Published: November 2024

INTRODUCTION

Lesions exhibiting radiation-induced contrast enhancement (RICE) may develop following cranial intensity modulated proton therapy (IMPT). The mechanisms underlying their development may be shared or amplified by existing patient comorbidities. The objective of this study was to assess a potential relationship between individual or composite cardiovascular risk criteria and RICE development, independent of dosimetric considerations.

METHODS

Data were reviewed for patients treated at a single tertiary care institution between 2017-2023. Time to RICE development was assessed using Kaplan-Meier. Cox regression analysis was used to determine hazard ratios (HRs) with 95% confidence intervals (CIs). Host-related risk factors for RICE development were assessed in a univariable analysis (UVA). A binary logistic regression model was built to ascertain the effects of age and cardiovascular risk factors on the likelihood of developing RICE (expressed as QRISK3 relative risk).

RESULTS

The study cohort included 137 patients; the median age was 40 years (range: 1-85), 51% female, and 53% Hispanic. Cardiovascular risk factors included smoking (18% past, 6% current), diabetes (7%), hypertension (22%), dyslipidemia (15%) and high body mass index (BMI, 50% were obese with BMI>25). At a median follow-up of 3 years, RICE developed in 36 (26%) patients. On UVA, RICE development was only associated with age ≥18 compared to <18 (HR 3.3, 95% CI: 1.2-9.4, p=0.024). None of the other evaluated risk factors were significantly associated with RICE (p>0.05). Additionally, logistic regression analysis showed increasing age was associated with likelihood of developing RICE (χ2=6.95, p=0.031), while QRISK3 score was not.

CONCLUSIONS

In this contemporary series of patients treated with IMPT, age was the only host factor associated with RICE, while other cardiovascular risk factors, evaluated individually or using established composite risk scores (QRISK3) were not associated with RICE. Additional research is needed to identify potential patient characteristics associated with RICE.
RADT-08. THIRD RECURRENT WHO 1 SPINAL MENINGIOMAS. CASE SERIES AND CLINICAL OUTCOMES FOLLOWING SURGERY OR DEFINITIVE RADIOTHERAPY
Authors: Haisraely Ory
Published: November 2024

INTRODUCTION

Spinal meningiomas (SM) account for approximately 1.2–12.7% of all meningiomas and 25% of spinal cord tumors. Most are benign (WHO grade 1), but a small percentage are atypical (WHO grade 2) or anaplastic (WHO grade 3). These tumors are typically solitary and non-invasive with low recurrence rates post-surgery. This study aims to compare the efficacy of definitive radiotherapy (RT) versus third surgery for recurrent SM WHO grade 1, focusing on local control, progression-free survival (PFS), and toxicity.

METHODS

A retrospective review approved by the Institutional Review Board included patients diagnosed with recurrent SM WHO grade 1 who underwent second surgery between 2008-2020. Patients who received radiation after the first surgery or upgraded to WHO grade 2 or 3 were excluded. Data on demographics, tumor characteristics, surgical techniques, and radiation therapy details were analyzed using descriptive and inferential statistics.

RESULTS

The study included 48 cases of third progression SM WHO grade 1. The median age was 53 years, and 70.8% were female. Tumor locations were primarily thoracic (75%). There was no significant difference in PFS between the third surgery and RT groups, with 36-month PFS rates of 77.4% and 76.4%, respectively. RT-related toxicities were manageable, and neurological improvements were noted in both groups, with more pronounced improvements in the surgical group. RT showed better pain control outcomes.

CONCLUSION

Both definitive RT and third surgery are effective for managing recurrent SM WHO grade 1, with comparable PFS. RT is a viable alternative, especially for high-risk surgical patients, providing effective pain control and manageable toxicities. Further studies with larger cohorts and longer follow-ups are recommended to validate these findings and refine treatment protocols for recurrent SM, ultimately improving patient outcomes and quality of life.
RADT-11. FACTORS ASSOCIATED WITH LOCAL FAILURE AFTER STEREOTACTIC RADIATION TO THE SURGICAL BED OF BREAST CANCER PATIENTS WITH A SINGLE BRAIN METASTASIS
Authors: Haisraely Ory , Taliansky Alicia , Kaidar Orit Person
Published: November 2024

BACKGROUND

Metastatic breast cancer is the second most common cancer associated with brain metastases (BCBM). In our study we evaluated variables that influence local control in this breast cancer patients with a single BCBM who underwent surgical resection and stereotactic radiation to resection cavity.

METHODS

After ethics approval, we conducted a retrospective review of the medical records of BCBM patients treated with stereotactic radiation for BCBM between 2011 to 2022. Only breast cancer patients with a single BCBM who underwent surgical resection and stereotactic radiation to the surgical cavity were included. Clinical and dosimetric variables were analyzed to evaluate their impact on local control. Statistical analysis included descriptive analyses. X2 test was used for categorical variables. Total dose, dose per fraction, biologically effective dose (BED), and planning target volumes were analyzed as both continuous and categorical variables at different thresholds. A binary regression model was applied to study variables shown to impact local control.

RESULTS

A total of 62 patients included local control was 70.9% at 12 months. HER-2 disease, luminal-B, size of BCBM, time from craniotomy, total dose, inclusion of corridor, and non-cystic lesion were significant for local control.

CONCLUSION

Our data supports previous publications about the importance of tumor bed delineation, dose and fractionation, and time from craniotomy as factors associated with better local control. Our study shows that the role of BCBM subtype and new systemic therapies in contributing to local and intracranial control should be further explored.
RADT-22. EFFICACY AND SAFETY OF CYBERKNIFE STEREOTACTIC RADIOSURGERY FOR OCCIPITAL CONDYLE METASTASIS
Authors: Park David , Kattaa Ahed , Chang Steven
Published: November 2024

BACKGROUND

Occipital condyle metastasis (OCM) is a rare condition characterized by severe occipital pain and neurological symptoms due to lower cranial nerve deficits, stemming from its anatomical location. Despite the widespread use of stereotactic radiosurgery (SRS) for cranial metastases, its specific impact on OCM remains underexplored.

OBJECTIVE

This study evaluates the efficacy and safety of CyberKnife SRS in treating OCM, focusing on symptom control and local tumor control.

METHOD

We retrospectively analyzed cases of OCM treated with SRS at our institute from 2012 to 2023, evaluating patient demographics, presenting symptoms, treatment parameters, and outcomes. Key measures included occipital pain, dysfunctions of cranial nerves IX, X, and XII, and local tumor control.

RESULTS

Eighteen patients (10 females) with a median age of 64 years (range: 40-79) were treated. Common presentations included occipital pain (44%) and lower cranial nerve deficits (28%). The median target volume was 6.95 cc (range: 0.95-72.7), and the median margin dose was 20 Gy (range: 16-40). The median follow-up period was 7 months (range: 1-44). Notably, only one patient experienced tumor recurrence and subsequently died from primary cancer progression five months after treatment. SRS achieved a 93.8% local tumor control rate over three years, with a median overall survival of 13 months. Among those presenting with symptoms, 87.5% reported pain relief, and 80% observed improvements in cranial nerve function. The only patient without clinical symptom improvement also had tumor recurrence.

CONCLUSION

CyberKnife SRS is a promising treatment for OCM, offering significant pain relief and improvement in neurological symptoms with excellent local control rates. This non-invasive therapy provides a valuable alternative to surgery, potentially enhancing the quality of life for patients with limited treatment options due to this challenging condition.
RADT-23. MOLECULAR PROFILING OF GLIOMAS: INSIGHTS INTO RADIONECROSIS AND PSEUDOPROGRESSION THROUGH NEXT-GENERATION SEQUENCING
Authors: Santos Monica , Restini Felipe , Fagundes Sayonara , Moraes Fábio , Marta Gustavo , Hanna Samir , Maldaun Marcos
Published: November 2024

BACKGROUND

Gliomas, the most common primary tumors of the CNS, presenting diagnostic and therapeutic challenges due to their heterogeneity. Next-generation sequencing (NGS) enhances diagnostic precision by identifying genetic alterations, guiding accurate diagnosis and personalized treatment strategies. Post-treatment complications such as radionecrosis and pseudoprogression present additional diagnostic difficulties, often mimicking tumor recurrence. This study aimed to evaluate the association between genetic alterations detected by NGS and treatment-related complications.

METHODS

This retrospective study analyzed data from electronic medical records at a Brazilian Radiation Therapy Department (2018-2023). The study included patients with gliomas who underwent surgical resection followed by adjuvant radiochemotherapy and subsequently developed complications such as radionecrosis and pseudoprogression. Genetic alterations detected by the HSL 500 (NGS) test were evaluated for their association with these complications using Fisher’s Exact Test.

RESULTS

Out of 192 patients treated for glioma, 46 (23.96%) experienced treatment-related complications, with 20 patients having available NGS test results. Among these, eight cases were identified as pseudoprogression, fifteen as radionecrosis, with three patients presenting both conditions. All 20 patients with NGS results were diagnosed with high-grade gliomas, eight of whom underwent reirradiation, resulting in two cases of radionecrosis post-reirradiation. Although no statistically significant association was found between genetic alterations and radionecrosis or pseudoprogression, specific mutations were prevalent in each group. In radionecrosis cases, the most common mutations were TERT promoter (c.1-124C>T) (n=9, p=0.613) and EGFR amplification (n=8, p=1.0). In pseudoprogression, frequent mutations included TERT promoter (c.1-124C>T) (n=6, p=0.642), EGFR (n=5, p=0.67), PTEN (n=4, p=1.0), NF1 (n=2, p=0.537), and P53 (n=2, p=0.197).

CONCLUSION

Molecular testing for glioma characterization is crucial for diagnosis and prognosis, aiding in understanding treatment-related complications. Strategies to avoid radionecrosis and pseudoprogression are vital to improve patient quality of life, especially in high-grade gliomas. Further studies are needed to confirm these trends and explore clinical relevance of mutations.
RADT-24. WALLERIAN DEGENERATION OF THE CORTICOSPINAL TRACT IN GLIOMAS: A RETROSPECTIVE ANALYSIS AND A SYSTEMATIC REVIEW OF MOTOR FUNCTION IN ELOQUENT AREAS POST-RADIATION THERAPY. HOW IMPORTANT IS MOTOR FUNCTION FOR PATIENTS WITH GLIOMAS IN RADIATION THERAPY?
Authors: Santos Monica , Rodrigues Natasha , Gibram Franceliny , Brunelli Julia , Mancini Anselmo , Moraes Fábio , Marta Gustavo , Hanna Samir , Maldaun Marcos
Published: November 2024

BACKGROUND

The quality of life for patients with gliomas is significantly impacted by tumor characteristics, treatment modalities, and radiation dosages. Variability in radiotherapy protocols and differences in tissue tolerance necessitate a detailed risk-benefit assessment, especially in eloquent brain areas responsible for motor functions.

METHODS

A retrospective analysis of electronic medical records from a Brazilian Radiation Therapy Department (2018-2023) was conducted. Patients with gliomas who underwent surgical resection and adjuvant radiochemotherapy, subsequently developing Wallerian Degeneration of the Corticospinal Tract (WDCT), were included. Additionally, a systematic search was performed in PubMed, Embase, and Cochrane databases, focusing on radiotherapy in eloquent areas and evaluating motor function. Of the 1,064 studies identified, 11 underwent full-text review by two independent examiners.

RESULTS

Among 192 glioma patients, 13 (6.77%) developed WDCT, all with high-grade gliomas, including 3 post-reirradiation cases. Retrospective dosimetric analysis of the corticospinal tract was performed for two patients who had tractography. Patient 1, with right frontoparietal tumor, had an ipsilateral corticospinal tract volume of 10.6 cm³, a max dose of 62.81 Gy, and 0.5 cc receiving 62.2 Gy; the contralateral tract volume was 18.5 cm³, with 0.5 cc receiving 51 Gy. Patient 2, with right frontal tumor, had an ipsilateral corticospinal tract volume of 31.1 cm³, a max dose of 42.76 Gy, and 0.5 cc receiving 42.37 Gy; the contralateral tract volume was 30.3 cm³, with 0.5 cc receiving 24.19 Gy. The systematic review identified 5 studies reporting pre- and post-radiotherapy motor outcomes in eloquent areas, with 4 focusing exclusively on gliomas. However, heterogeneity in radiotherapy techniques and outcome assessments precluded a meta-analysis.

CONCLUSION

Motor function in glioma patients undergoing radiation therapy remains an underexplored area. Future studies should focus on standardized assessments of functional outcomes to establish dose constraints and optimize treatment protocols, thus improving the quality of life for glioma patients.
RADT-29. ASSOCIATION OF ANATOMIC PROXIMITY OF BRAIN PARENCHYMAL METASTASIS TO THE CSF SPACE AND UPFRONT STEREOTACTIC RADIOSURGERY TO SUBSEQUENT LEPTOMENINGEAL METASTASIS DEVELOPMENT IN BRAIN METASTATIC NSCLC
Authors: Bashir Shoaib , Hong Weiping , Lai Mingyao , Cai Linbo
Published: November 2024

OBJECTIVE

The most common solid systemic malignancies that metastasize to the leptomeninges are lung cancer, especially non-small cell lung cancer (NSCLC). Generally, patients develop leptomeningeal metastasis (LM) subsequent to brain parenchymal metastases (BM). However, its predictors remain unknown. Hence, the present study was carried out to explore the predictors of LM in brain metastatic NSCLC patients.

METHODS

The final analysis included 112 pathologically definite NSCLC patients with BMs treated in our center between July 1, 2014, and December 30, 2020. Of 112, one-half had LM. Three radiologists analyzed radiologic images independently. Anatomic proximity of BMs to the CSF space (dural-based metastases, periventricular or major CSF cisterns such as basal cisterns and cisterna magna) was measured and stratified into CSF space invading/bordering and detached lesions. The endpoint was the occurrence of LM or death, whichever occurred first. Univariable and multivariable logistic regressions were performed to identify potential predictors for LM.

RESULTS

Of 112, 48 (42.8%) were males, and 64 (57.2%) were females. Most patients (90.2%) had adenocarcinoma histology. The median follow-up time was 10.1 months (IQR, 4.2-18.4 months) following BM diagnosis. Univariate logistic regression analysis demonstrated that histology (OR 0.084, 95%CI 0.004-0.461, P=0.020), EGFR/ALK/ROS1 mutation (OR 3.868, 95%CI 1.583-10.079, P=0.003), CSF space invading/bordering lesion (OR 10.278, 95%CI 4.203-27.375, P=0.000), extracranial metastasis control (OR 2.7, 95%CI 1.191-6.309, P=0.019), upfront stereotactic radiosurgery (SRS) (OR 0.024, 95%CI 0.001-0.12, P=0.000), and target therapy (OR 4.476, 95%CI 1.877-11.464, P=0.001) were the potential predictor. CSF space invading/bordering lesion (OR 7.443, 95%CI 2.099-32.853, P=0.003) and upfront SRS (OR 0.035, 95%CI 0.002-0.212, P=0.003) remained statistically significant in the multivariate logistic regression analysis.

CONCLUSION

CSF space invading/bordering BMs may increase the risk of LM development in brain metastatic NSCLC patients, while upfront SRS targeting BM potentially decreases the risk. A prospective study is warranted to affirm.
RADT-30. MANAGEMENT OF PRESUMED PSEUDOPROGRESSION WITH EARLY BEVACIZUMAB IN THE THREE MONTHS AFTER HIGH DOSE RADIATION THERAPY FOR GLIOBLASTOMA
Authors: Back Michael , Challis Benjamin , Horsley Patrick , Kastelan Marina , Cove Nicola , Jackie Yim , Drummond James , Wong Matthew , Lee Adrian , Wheeler Helen
Published: November 2024

BACKGROUND

Optimal management for symptomatic steroid-refractory pseudoprogression (rPsP) following IMRT for Glioblastoma remains poorly defined. This study examined radiological volumetric response and clinical outcomes following use of early Bevacizumab (earlyBEV), defined as commencing during or within 3 months of IMRT.

METHODS

Consecutive patients managed with Stupp60Gy IMRT between 2016-2023 for Glioblastoma were analysed for those patients receiving earlyBEV for rPsP. Volumetric analysis was performed with sequential MRI T1gd/T2 sequences using preBEV and postBEV scans. Primary endpoint was volumetric reduction of T1gd/T2 volumes at month+2/3 postBEV. Clinical response, overall survival and pattern of relapse, specifically distant failure was assessed.

RESULTS

Forty-one (14%) of 289 patients received earlyBEV for rPsP, with median follow-up of 9.9months (q1-3:8-25) for survivors. Compared to remaining 248 patient cohort, earlyBEV had worse initial ECOG0,1 (50%vs76%); less near-total resection (5%vs42%); and less MGMT methylation (35%vs46%). Additionally at diagnosis the initial tumours had larger T1gd and T2 volumes. Median time to commencement of earlyBEV was 1.4months postIMRT; including seven patients during IMRT. All patients responded to BEV, with reduction in symptoms, steroid use and radiological volume, though one died pre-assessment. Median T1gd and T2 volumes before earlyBEV were 37cm3 (q1-3:23-63cm3) and 116cm3 (q1-3:90-148cm3) respectively, which were 95% and 78% larger than at diagnosis. Median survival postBEV was 8.1months (95%CI:7.5-8.6). Median volumes postBEV reduced to 16cm3 (q1-3:8-23cm3) and 41cm3 (29-55cm3); which was a percentage reduction for T1gd and T2 of 57% and 65%. Midline shift reduced from 5mm(q1-3:3-8mm) to zero in two-thirds of patients. Patients requiring earlyBEV had worse survival compared to remaining cohort (p<0.001); with median OS 11.9months (95%CI:10.4-13.5) vs 19.9months (95%CI:18.4-21.5). A component of distant relapse was evident in 48% of earlyBEV vs 34% in remaining cohort. One serious adverse event occurred with fatal intracranial haemorrhage day10 after initial BEV dose.

CONCLUSION

This study data confirms efficacy of earlyBEV for managing steroid-refractory pseudoprogression, but also the worse prognosis of this high-risk cohort.
RADT-35. PATTERNS OF INTRACRANIAL RESPONSE AND RELAPSE AFTER CNS-DIRECTED RADIOTHERAPY (CNS-RT) FOR PATIENTS WITH CHEMOREFRACTORY OR PROGRESSIVE SECONDARY CNS LYMPHOMA (SCNSL)
Authors: Cederquist Gustav , Tringale Kathryn , Hajj Carla , Moore Zachary , Hubbeling Harper , Dreyfuss Alexandra , Fregonese Beatrice , Falchi Lorenzo , Scordo Michael , Grommes Christian , Yahalom Joachim , Imber Brandon
Published: November 2024

PURPOSE/OBJECTIVE

Progressive SCNSL after failure of CNS-directed systemic therapy is a challenging clinical scenario. CNS-RT can effectively salvage, but its optimal role is poorly defined.

METHODS

We analyzed diffuse large B-cell patients who received brain RT for progressive SCNSL following 1+ line of therapy for active SCNSL (not prophylaxis). Overall survival (OS) was calculated by Kaplan-Meier and RT response was evaluated using IPCG or RANO criteria for parenchymal or leptomeningeal disease, respectively. Risk of intracranial failure assumed death as a competing risk. Pre-RT SCNSL patterns were classified as parenchymal-only versus diffuse (periventricular or leptomeningeal). Local failure was progression only of pre-RT lesion(s).

RESULTS

We identified 55 patients with median follow up of 3.5m. 85% had neurologic symptoms, 45% had extracranial disease. Patients received a median of 2 prior SCNSL-directed therapies (IQR 1-3); 91% received methotrexate-based regimens with median 21d between last methotrexate and RT. Median CNS-RT dose was 30 Gy in 10 fractions delivered to whole brain (n=44, 80%), partial brain (n=9, 16%), or craniospinal axis (n=2, 4%). Median OS was 3.5m. Overall response for 38 evaluable was 79% (24% complete), with median of 60d to best response. 58% were successfully bridged with CNS-RT to subsequent therapies and 12m intracranial failure risk was 37% for those bridged, and 64% for those not bridged (p=0.05). 19 had parenchymal-only disease (10 unifocal, 9 multifocal) with median largest lesion diameter 4.1cm (range 1.7–7.4). 19 had diffuse pattern (12 periventricular, 7 leptomeningeal). 7 with parenchymal-only disease failed intracranially, 5 of which were local. 8 with diffuse disease failed intracranially, only 1 of which was local (p = 0.035).

CONCLUSION

SCNSL patients referred for RT had symptomatic, treatment-refractory disease. While CNS-RT response rates were high, duration was often limited, suggesting RT is best used for bridging/palliation. Patients with parenchymal-only disease were enriched for local failure, suggesting potential suitability of involved site CNS-RT, though further validation is needed.
RADT-39. CENTRAL NERVOUS SYSTEM BRIDGING RADIOTHERAPY (CNS-BRT) ACHIEVES RAPID CYTOREDUCTION PRIOR TO CAR T-CELL THERAPY FOR AGGRESSIVE B-CELL LYMPHOMAS
Authors: Cederquist Gustav , Schefflein Javin , Devlin Sean , Shah Gunjan , Shouval Roni , Hubbeling Harper , Tringale Kathryn , Fregonese Beatrice , Hajj Carla , Boardman Alexander , Dahi Parastoo , Lin Richard , Ghione Paola , Salles Gilles , Perales Miguel-Angel , Palomba M Lia , Falchi Lorenzo , Scordo Michael , Grommes Christian , Yahalom Joachim , Imber Brandon
Published: November 2024

BACKGROUND

CAR T-cell therapy (CART) for central nervous system lymphoma (CNSL) is a promising strategy, yet responses are frequently not durable. Bridging radiotherapy (BRT) is used for extra-cranial lymphoma to improve CART outcomes through cytoreduction of high-risk lesions. We hypothesized that CNS-BRT would achieve similar, significant cytoreduction prior to CART for CNSL.

METHODS

We analyzed CNSL patients with non-Hodgkin B-cell lymphomas who received CNS-BRT prior to commercial CART. Best CNS response post-CART was evaluated using the International Primary CNS Lymphoma Collaborative Group (IPCG) or RANO for parenchymal or leptomeningeal lesions, respectively. Cytoreduction from CNS-BRT was calculated as change in lesion size prior to CART.

RESULTS

Twelve patients received CNS-BRT, with median follow up of 11.8m (IQR: 8.5–21.9). Ten had CNSL (9 secondary, 1 primary) and 2 patients had epidural disease (evaluable for toxicity). All ten CNSL patients had progressive disease at the time of CNS-BRT. RT targets included whole brain (n=3), involved site (partial) brain (n=4), involved site spine (n=4), and orbits (n=1) with median dose 24Gy (range: 15-33). 1/12 patients experienced grade ≥3 cytokine release syndrome (CRS), and 3/12 patients experienced grade ≥3 immune effector cell-associated neurotoxicity syndrome (ICANS). CNS-BRT achieved a 74.0% (95%CI: 62.0–86.0) mean reduction in lesion size from baseline (p=0.014) at a median of only 12d from BRT completion and pre-CART infusion. Best CNS response included 8 complete responses (CR), 1 partial response (PR), and 1 progressive disease (PD). Three patients experienced CNS relapse outside the BRT field for a 12-month estimated risk of CNS progression post-CART of 20.0% (95%CI: 3–49).

CONCLUSIONS

Early data suggest CNS-BRT achieves rapid cytoreduction and favorable CNS response. The rates of severe CRS/ICANS were similar to comparison series of CNSL patients treated with CART without BRT suggesting an acceptable safety profile. Our data support further study of BRT as a bridging strategy for CNSL-directed CART.
RADT-40. EVALUATION OF SMALLER CLINICAL TARGET VOLUMES AND PATTERNS OF PROGRESSION IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA TO INFORM FUTURE DIRECTIONS IN RADIATION TREATMENT PLANNING
Authors: Hill Jordan , Tan Yujue , Tjong Michael , Youssef Gilbert , Aizer Ayal , Tanguturi Shyam , Shi Diana , Haas-Kogan Daphne , Huang Raymond , Wen Patrick , Rahman Rifaquat
Published: November 2024

BACKGROUND

NRG Oncology Group guidelines recommend a clinical target volume (CTV) including generous expansions and incorporation of T2/FLAIR to account for potential tumor infiltration for glioblastoma patients, though smaller CTV expansions may be feasible. We retrospectively reviewed a large cohort of GBM patients to characterize patterns of recurrence and to assess the potential for smaller CTV margins.

METHODS

312 consecutive adult patients with histologically confirmed diagnosis of glioblastoma treated with radiation therapy and temozolomide at a single institution were included in this study. All relevant clinical and pathological data was retrieved from local electronic medical records. MRIs from four timepoints 1) Pre-operative, 2) post-operative, 3) post-radiation and 4) time of progression were reviewed and fused with each other with rigid registration. We created a gross tumor volume including the resection cavity and residual enhancing tumor (GTV-GAD) and a GTV which included the GAD-GTV and pre-radiation T2/FLAIR signal (GTV-FLAIR). Multiple CTV expansions were applied to the GAD-GTV and FLAIR-GTV to evaluate coverage of subsequent progressive disease.

RESULTS

We evaluated 312 patients with a median age of 59.8 (range 20-93), 59% male, 61% KPS ≥ 90, 49% underwent gross total resection (51% subtotal resection/biopsy), 43% methylated and 57% unmethylated. CTV expansions of 2 cm, 1.5 cm, 1 cm, 0.5 cm, and 0 cm from GTV-GAD would have covered the epicenter of recurrent tumor in 90.7%, 88.1%, 84.6%, 77.5%, and 53.5% of cases respectively. CTV expansions from GTV-FLAIR of 2 cm, 1.5 cm, 1 cm, 0.5 cm, and 0 cm would have covered the epicenter of recurrent tumor in 93.5%, 92.6%, 91.3%, 88.1%, and 78.8% of cases respectively. On multivariable analysis, GAD-GTV and FLAIR-GTV volume were not associated with progression-free or overall survival(P>0.05).

CONCLUSION

Based upon our analysis, smaller treatment volumes could represent an opportunity to reduce treatment-related morbidity without compromising clinical outcomes.