bluuebunny/crossref_metadata_2025 huggingface dataset:
CSIG-14. THE PDGFRA-REGULATING LNCRNA LINC02283 IS AMPLIFIED IN HIGH-GRADE GLIOMA AND FACILITATES GLIOMAGENESIS
Authors: Goenka Anshika , Song Xiao , Tiek Deanna , Hu Bo , Cheng Shi-Yuan
Published: November 2022

Long non-coding RNAs (lncRNAs) regulate numerous physiological processes and the etiology of diseases including cancers. However, lncRNA-based therapies are limited because the mechanism of action of many lncRNAs and their interaction with binding partners is not completely understood. We have identified LINC02283, a novel oncogenic lncRNA, highly expressed in the PDGF Receptor A (PDGFRA)-mutation driven cohort of high-grade glioma (HGG) patients which accounts for ~8% of glioma cases. LINC02283 gene co-amplifies with the PDGFRA locus and is upregulated in HGG. LINC02283 expression and copy number variation were highly correlated to that of PDGFRA expression and amplification respectively, and high LINC02283 levels leads to worse survival in HGG patients. We found that LINC02283 transcription is essential for the survival of Glioma Stem cells (GSCs) with PDGFRA amplification mutation, and its inhibition significantly improves survival in orthotopic HGG xenograft models. Interestingly, overexpression of LINC02283 in GSCs with wild type (wt) - PDGFRA, enhance PDGFRA signaling, increases cell proliferation and worsens survival in orthotopic HGG xenograft models. Inhibition of PDGFRA signaling using AG1296, represses the high endogenous LINC02283 levels in PDGFRA-mutant GSCs, reduces LINC02283 induced signaling in PDGFRA-wt GSCs, and suppresses cell proliferation in both the cellular models of HGG. Moreover, LINC02283 co-localizes and interacts with the wild-type and mutant PDGFRA to enhance its signaling and that of its downstream targets Akt and Erk. In a feedback regulation, dysregulated PDGFRA signaling induces LINC02283 levels to enhance cell proliferation in GSC and GBM cellular models through activating its downstream, Akt and Erk signaling pathways, as their inhibition reduces the lncRNA induction and function. Thus, blocking the LINC02283-PDGFRA interaction could be a plausible therapeutic strategy in HGG. Altogether, our results provide strong evidence of lncRNAs as drivers of PDGF Receptor A activity and HGG progression and support the potential of lncRNAs as possible therapeutic targets.
CSIG-17. SCD5 PROTECTS GLIOBLASTOMA STEM CELLS FROM DEATH AND DIFFERENTIATION BY MODULATING INTRACELLULAR LIPID COMPOSITION
Authors: Mnatsakanyan Hayk , Pechdimaljian Caline , Jha Roshani , Sammarco Alessandro , Su Baolong , Williams Kevin J , Bensinger Steven J , Badr Christian E
Published: November 2022

Glioblastoma (GBM) is the most common malignant brain cancer in adults, enriched in a small subpopulation of glioma stem cells (GSC), which can drive tumor recurrence and therapeutic resistance. Considerable evidence suggests that the endogenous levels of unsaturated fatty acids (FA) are crucial regulators of GSCs survival and self-renewal. Stearoyl-CoA desaturase-1 (SCD-1) is the most abundant desaturase in humans. We have previously shown that SCD1 activity is required for GSCs self-renewal and brain tumor initiation. However, SCD1 orthologous isoform, SCD5, has been poorly characterized and its potential role in GBM has not been previously reported. We have observed that SCD5 is highly enriched in GSC both at the mRNA and protein levels. Genetic downregulation of SCD5 in GSCs led to a remarkable decrease in stem cell markers, impaired cell viability and the ability to form neurospheres. Further, the downregulation of SCD5 in GSCs orthotopically implanted in mice resulted in delayed tumor growth and extended overall survival. Shotgun lipidomics in GSCs after either SCD1 or SCD5 knock-down revealed a largely distinctive lipidome profile, highlighting the divergent role of these two isoforms in GBM lipid metabolism. Surprisingly, lipidomics analysis showed that both SCD1 and SCD5 are required to synthesize a variety of lipid species involved in receptor tyrosine kinase (RTKs) and GPCRs signal transduction, directly linking FA synthesis with the oncogenic signaling. We confirmed these results by immunoblot analysis. Using specific tagging and immunofluorescence analysis, we observed that, despite a spatial overlap in SCD1 and SCD5 expression, SCD5 is uniquely present in some subcellular locations. This suggests that different functions of these isoforms could be related to different subcellular localization. Altogether, our results underscore a novel function of SCD isoforms in GSCs metabolism and highlight SCD5 as a potential therapeutic target for GBM.
CSIG-18. ANTI-TUMOR EFFECTS OF VERTEPORFIN AND PHOTODYNAMIC THERAPY IN COMBINATION WITH STANDARD OF CARE ON PATIENT-DERIVED GBM CELL LINES
Authors: Sudhir Sweta , Anastasiadou Maria , Price Gabrielle , Hadjipanayis Constantinos
Published: November 2022

Glioblastoma (GBM) is the most common and aggressive primary brain tumor with a median survival of approximately 15 months. GBM tumorigenicity frequently arises from aberrant signaling transduction pathways involving receptor tyrosine kinases (RTKs), such as EGFR and PI3K. Amplification of the Epidermal Growth Factor Receptor (EGFR) gene upregulates Hippo pathway transcription factors YAP1 and TAZ, leading to tumor cell proliferation, radiation resistance, and poor survival. Verteporfin (VP), also known as Visudyne, is an FDA-approved macular degeneration photosensitizer that has photodynamic effects when combined with 489 nm of light. Additionally, VP is a small-molecule inhibitor of the YAP/TAZ/TEAD complex that has been shown to reduce tumor migration and is in phase I clinical trial as a chemotherapeutic for patients with recurrent GBM. We now investigate if VP is an effective photosensitizer for PDT in GBM and if it enhances the effects of TMZ and RT. Compared to VP alone, VP+PDT reduced the IC50 of VP treatment in GBM cells +/- EGFR amplification. Light activation of VP has a significant antitumor effect as observed with cytotoxicity in comparison to vehicle and VP treated cells (p< 0.01). Compared to control, VP, VP+PDT+TMZ, and CRT show significantly less intravasation (p< 0.01). Furthermore, Western blot analysis shows differential expression of YAP, TAZ and TEAD compared to Control and VP after treatment with VP+PDT. Differential YAP signaling is observed via IF staining in EGFR+ GBM cells treat with VP+PDT. Our research supports the use of VP as a photosensitizer in GBM cells. We found downregulation of the hippo pathway and decrease tumorigenicity of GBM cells. Application of VP-PDT treatment in combination with standard of care may be proven beneficial in GBM patients. We plan to further explore these in vitro findings in mice models and investigate other pathways including immune response with NanoString analysis.
CSIG-22. THE MOLECULAR NETWORK OF CAMTA-1 IN GLIOMA CELLS
Authors: Haeusser Lara , Kuhlburger Laurence , Czemmel Stefan , Govindarajan Parameswari , Merk Daniel , Nahnsen Sven , Tabatabai Ghazaleh
Published: November 2022

Calmodulin-binding transcription activator 1 (CAMTA1) is a transcription factor located on chromosome 1p, and we have recently reported that CAMTA1 expression reduced neurosphere formation and tumor growth in nude mice, suggesting that CAMTA1 can function as tumor suppressor in experimental glioma. In the present study, we investigated the molecular network of CAMTA-1 in glioma cells. We established glioma cell lines with a doxycycline-inducible overexpression of CAMTA1. We performed a cap analysis of gene expression (CAGE) on these overexpressing cell lines to identify differentially regulated transcriptional start sites. We particularly focused on regulated target genes encoded on chromosome 19q. We identified an interaction of CAMTA1 overexpression with changes in the differential expression of Zink finger (ZNF) genes located on 19q. We will present novel data on a potential molecular interaction between chromosomes 1p and 19q.
CSIG-23. ALTERATIONS IN THE TRANSSULFURATION PATHWAY DRIVE GLIOBLASTOMA INVASION IN THE PERITUMORAL WHITE MATTER
Authors: Garcia Joseph , Jain Saket , Akins Erin , Carrete Luis , Zheng Allison , Gill Sabraj , Kumar Sanjay , Aghi Manish
Published: November 2022

Glioblastoma is the most common and lethal adult brain tumor with a median survival under two years. The poor prognosis glioblastoma carries is largely due to cellular invasion, which enables escape from resection and drives inevitable recurrence. Although numerous molecular factors have been proposed as driving glioblastoma invasion, the search for targetable pathways to mediate glioblastoma invasion has been largely unfruitful. Despite a well-established relationship between metabolic reprogramming and cancer cell survival, little attention has been paid to the metabolic alterations needed for invading tumor cells to thrive in peritumoral white matter. To address this knowledge gap, we defined the links between tumor metabolism and invasion using metabolomics, transcriptomics, and CRISPR screens in biomimetic 3D hydrogels and regional biopsies of patient glioblastomas. Metabolomic and lipidomic screening of 315 metabolites and 691 lipids revealed cystathionine, a cysteine precursor in glutathione synthesis in the transsulfuration pathway, as well as hexosylceramides and glucosyl-ceramides, which counteract oxidative stress, to be enriched in invasive tumor cells in hydrogels and patient samples. Immunostaining confirmed elevated secondary ROS markers in invasive GBM cells in hydrogels and patient specimens. While adding ROS promoted GBM invasion in hydrogels, ROS sequestration had no effect. A CRISPR screen of 3000 metabolic genes revealed cystathionine gamma lyase (CTH), which catalyzes the last step in the transsulfuration pathway, to be essential for glioblastoma invasion. Genetic and pharmacologic CTH inhibition suppressed glioblastoma invasion in hydrogels in a manner rescued by exogenous cysteine. Thus, invasive glioblastoma cells exhibit high ROS levels, metabolic adaptations to ROS, and increased invasion in response to ROS. While targeting ROS directly did not slow invasion, targeting metabolic adaptations to ROS in the transsulfuraton pathway suppressed invasion. Our work defines the first link between metabolic adaptations and glioblastoma invasion, intriguing findings warranting future exploration.
CSIG-24. EPIGENETIC SUPPRESSION ALLOWS GBM TO MAINTAIN P53 WILD-TYPE STATUS
Authors: Park Jung , Schulder Michael , Boockvar John
Published: November 2022

Introduction

Glioblastoma (GBM) is the most common primary brain malignancy in adults. The vast majority of GBM cases maintain wild-type status of p53, the protein considered to be the most critical tumor suppressor. How GBM displays such a malignant phenotype despite retaining normal p53 protein is unknown. We also aim to translate these molecular findings into therapeutics via a randomized clinical trial.

METHODS

A variety of molecular biological techniques were employed. These include CRISPR-CAS, next generation sequencing, stereotactic mouse brain injections, and histological analyses of human GBM tumors. Approval for a small, single site, blinded, randomized clinical trial for newly diagnosed GBM is underway. Overall survival, recurrence-free survival, immunohistochemical analyses will be assessed.

RESULTS

Human p53 wild-type GBM cell lines express Brd at higher levels compared to p53 mutant cell (~10 fold, p < 0.05). Cell viability assays show that deletion of Brd leads to a ~50% decrease (p < 0.05) in cell survival. Critically, this effect is abrogated upon deletion of p53 itself, showing that Brd functions through the inhibition of p53’s tumor suppressive effects. Furthermore, immunoprecipitation of Brd shows that it is a member of a complex of proteins that bind to p53 target genes. The importance of these findings are corroborated in vivo, as mice stereotactically injected with human GBM cells that lack Brd survive ~2-fold longer (p < 0.05) than mice that retain Brd. We have begun the process to start clinical trials with an already FDA-approved drug (currently used for the treatment of lymphoma and sarcoma) that blocks the Brd pathway.

CONCLUSION

Brd is the key suppressor of p53 target genes in GBM. Brd binds to a multimeric protein complex, which inhibits p53 target genes. Thus, the tumor suppressive effects of p53 are prevented in GBM. Inhibition of this pathway in GBM patients is underway.
CSIG-34. LIN28B-LET-7-PBK PATHWAY IS AN IMPORTANT REGULATOR OF GROUP 3 MEDULLOBLASTOMA PROLIFERATION
Authors: Shahab Shubin , Sun Jessica , Kunhiraman Haritha , Schneiderjan Matthew , Juraschka Kyle , Kumar Sachin , Taylor Michael , MacDonald Tobey , Kenney Anna
Published: November 2022

Children with Group 3 medulloblastoma (MB) have a very poor long-term outcome and many do not survive beyond 5 years. Several drivers for Group 3 MB have been identified but none have resulted in targeted therapy to date. LIN28B is a stem cell factor upregulated in Group 3 MB and is associated with worse survival. Here we investigate the role of the LIN28B pathway in Group 3 MB development. Pharmacologic inhibition of the LIN28B pathway is feasible and may provide a unique opportunity to target this tumor. Using LIN28B knockdown and overexpression in Group 3 MB cells we test LIN28B’s effect on proliferation, self-renewal and metastasis. We investigate the effect of LIN28B knockdown on survival as well as proliferation and apoptosis markers using orthotopic xenografts in vivo. We also investigate the role of let-7 and its downstream target PBK on Group 3 MB proliferation. Finally, we use a LIN28 inhibitor 1632 and a PBK inhibitor HITOPK032 to treat Group 3 MB cell lines and then assess their impact on proliferation and apoptosis. We find that down-regulation of LIN28B or PBK using shRNA results in significant reduction in cell proliferation. In contrast overexpression of LIN28B increases Group 3 cell proliferation and tumor sphere formation. LIN28B knockdown also significantly (p< 0.01) increases survival in mice with orthotopic Group 3 tumors. The LIN28 inhibitor 1632 also leads to significant reduction in MB growth through decreased cell cycle entry and increased apoptosis. In addition, HITOPK032 also demonstrates significant reduction in Group 3 MB cell proliferation at low micromolar concentration. We also demonstrate that HITOPK032 in combination with CDK 4/6 inhibition can additively inhibit proliferation of Group 3 MB cells. Our study establishes a critical role for the LIN28B-let-7-PBK pathway in Group3 MB and provides encouraging preliminary preclinical results for drugs that target this pathway.
CSIG-36. NOTCH3 DRIVES MENINGIOMA TUMORIGENESIS AND RESISTANCE TO RADIOTHERAPY
Authors: Cady Martha , Choudhury Abrar , Lucas Calixto-Hope , Phillips Joanna J , Palikuqi Brisa , Bush Nancy Ann Oberheim , Klein Ophir , Hervey-Jumper Shawn L , Dickinson Peter , Magill Stephen , Bhaduri Aparna , Crouch Elizabeth , Raleigh David
Published: November 2022

There are no approved targeted therapies for meningiomas and the cell types underlying meningeal tumorigenesis are incompletely understood. To address these limitations, we performed single-cell RNA sequencing of 57,114 cells from 8 human meningiomas and 54,607 cells from 3 canine meningiomas. Pseudotime, gene ontology, and copy number variant analyses revealed a population of pericyte-like meningioma cells that were conserved across human and canine tumors and were enriched in expression of Notch3 and other cancer stem cell genes. Deconvolution of cell types from bulk RNA sequencing and DNA methylation profiling of 200 human meningiomas integrated with immunohistochemistry (IHC), immunofluorescence (IF), and RNAScope demonstrated Notch3+ pericytes and Notch3 expression were enriched in high grade or Immune-enriched meningiomas, which were distinguished from other meningioma DNA methylation groups by genes driving vasculature development. IHC and IF of human meninges integrated with lineage tracing approaches using Notch3-CreERT2 ROSAmT/mG alleles in mice demonstrated Notch3 expression was restricted to the perivascular stem cell niche during meningeal development and homeostasis. Mice harboring Notch3-CreERT2 Nf2fl/fl alleles developed meningeal hyperproliferation. Overexpression of constitutively activated Notch3 (Notch3AICD) in Immune-enriched human meningioma cells increased the expression of cancer stem cell genes, driving clonogenic growth in vitro, limiting dilution tumor-initiating capacity in vivo, and resistance to radiotherapy in vivo. A selective Notch3 neutralizing antibody (αNRR3) blocked meningioma cell proliferation and expression of Notch3 target genes, inhibiting meningioma xenograft growth and prolonging overall survival. Single-cell RNA sequencing of 187,366 cells from meningioma xenografts after αNRR3 or radiotherapy treatment ± Notch3AICD overexpression revealed distinct meningioma cell-intrinsic or cell-extrinsic mechanisms driving responses to radiotherapy or αNRR3, respectively. Combined treatment with αNRR3 and radiotherapy additively blocked meningioma xenograft growth and extended survival benefit. In sum, these data shed light on a novel cell type, molecular mechanism, and therapeutic vulnerability in the most common primary intracranial tumor.
CSIG-39. PROSTAGLANDIN-SCULPTING; REPRODUCTIVE DRIVERS OF THE GBM TUMOR IMMUNE LANDSCAPE
Authors: Sharpe Martyn , Baskin Alexandra , Baskin David
Published: November 2022

Introduction

We have reported that GBM utilize sex-steroids and reproduction-specific proteins to hijack the granting of immune-privilege to male/partner-specific antigens/epitopes. We have extended upon this foundation to examine other examples of immunosuppressive tissue-mimicry mechanisms that GBM deploy. The generation of prostaglandins D2, E2 and F2 and reproductive proteins are used by GBM tumors to activate discrete immune-cell types and to drive vascularization and growth.

METHODS

Three GBM-transcriptome databases were mined and analyzed utilizing pathway, stratification, correlation and survival analysis.

RESULTS

PGD2 and PGF2 synthesis is driven by C3AR1 microglial signaling, in response to complement C3a activation by GBM expression of C3 and CFB. PGD2 is expressed in hypoxic tumors and PGF2 is expressed in normoxic ones. PGF2 drives the hematopoietic stem cell angiogenic pathway, via TPBG/CXCL12/CXCR4. This is the primary pathway promoting early placental vascularization and vascular development/repair of mucosal tissues. Microglial synthesized PGD2 drives the CCL5/CCR5 axis, a pathway central to cyclic vascularization of uterine tissues and in wound healing, via VEGFA. Generation of CCL5 also recruits CCR5-positive monocytes, which are then driven into M2-TAM phenotype. CCL5 also recruits and drive myeloid cells into MDSCs. SOX9 drives masculinization of embryonic gonads. GBM expression of SOX9 correlates with seminal heat shock protein expression. These reproductive HSPs are associated with neutrophil generation of PGE2 in GBM tumors, mirroring their role in the semenized female reproductive tract, where they support PGE2 synthesis and aid EGFR driven vascularization

CONCLUSIONS

The ability of GBM to modulate the anti-tumor response is central to their lethality. The discrete, cell-specific mechanisms revealed will allow personalized medicine using off-the-shelf drug therapy.
RADT-04. SINGLE SESSION GAMMA KNIFE RADIOSURGERY TO TREAT PATIENTS WITH 20 OR MORE BRAIN METASTASES
Authors: Wei Zhishuo , Luy Diego , Yavan Sila , Jose Shalini , Worrell Stephen , Belkhir J Raouf , Deng Hansen , Niranjan Ajay , Lunsford L Dade
Published: November 2022

BACKGROUND

Stereotactic Radiosurgery (SRS) has become a primary management option for brain metastases (BMs). This present study aims to review outcomes in patients with ≥ 20 BMs treated in a single session SRS and to identify predictors of local tumor control (LTC) and overall survival (OS).

METHODS

We identified 75 patients including 26 non-small cell lung cancer (NSCLC), 21 small cell lung cancer (SCLC), 14 breast cancer (BC), and 14 melanoma patients who underwent SRS for ≥ 20 BMs between 2014 and 2020. The median number of tumors was 24 (range 20 – 52), and the median cumulative tumor volume was 3.70 cc (0.13 – 62.49 cc). The median margin dose was 16 Gy (14 – 20 Gy). Median skull integral dose was 5492 mJ (range 1372 – 11243 mJ). The median treatment time for each session was 160 min. Outcome variables were assessed using univariate and multivariate analyses with p < 0.05.

RESULTS

Median OS after SRS was 5.8 months (range 0.1 – 73.2 months). Primary cancer type and concurrent immunotherapy were significant predictive factors for patient OS after SRS (p = 0.01, 0.05, and 0.02, respectively). LTC rate at 6 and 12 months after SRS was 95.7% and 83.7%, respectively. Thirty (40.0%) patients underwent additional SRS and 3 patients (4%) received post-SRS WBRT due to distant tumor recurrence. The median time to distant recurrence was 5 months (range 2-28 months). SRS-induced adverse radiation effects (ARE) events were observed in 3 patients (4.0%; 1 NSCLC, 1 SCLC, and 1 melanoma).

CONCLUSIONS

Our results suggest that patients with ≥ 20 BMs can be safely treated with SRS with an excellent LTC rate and a low risk of ARE. Newly developed BMs can be treated with repeat SRS. This single-session SRS allows patients to proceed with systemic cancer care without interruption.
RADT-06. SPARING OF MOTOR STRUCTURES IN ADJUVANT RADIATION THERAPY AFTER RESECTION OF BRAIN METASTASES: APPLICATION OF NTMS-DERIVED DTI-BASED MOTOR FIBER TRACKING IN ADJUVANT STEREOTACTIC RT TREATMENT PLANNING
Authors: Diehl Christian , Rosenkranz Enrike , Mißlbeck Martin , Schwendner Maximilian , Sollmann Nico , Eitz Kerstin , Bernhardt Denise , Ille Sebastian , Meyer Bernhard , Combs Stephanie , Krieg Sandro
Published: November 2022

BACKGROUND

Resection of brain metastases (BM) close to the motor cortex and the corticospinal tract (CST) bears a significant risk for treatment-related morbidity. Navigated transcranial mapping (nTMS) combined with diffusion-tensor-imaging (DTI) based fiber tracking (DTI-FTTMS) is a valuable tool to guide the neurosurgeon along the CST to preserve motor function. This study aims to proof the practicability of DTI-FTTMS in local adjuvant stereotactic RT planning in the management of BM. Method: Pre-surgical generated DTI-FTTMS-based CST reconstructions of 24 patients with 25 resected BM were incorporated into the RT planning system and elastic fused with planning imaging. The CST was delineated as the planning risk volume (PRV-FTTMS). Fractionated stereotactic intensity-modulated RT (IMRT) plans (7 x 5 Gy) were retrospectively calculated and then optimized to preserve PRV-FTTMS. Areas covered by the planning target volume (PTV) were not spared (overlap).

RESULTS

In regular plans mean dose (Dmean) of complete PRV-FTTMS was 5.4 ± 2.5 Gy. Regarding PRV-FTTMS portions within the 8.75 Gy (25% of prescription dose) isodose level Dmean was 18.2 ± 4.3 Gy and after plan optimization 13.1 ± 3.8Gy (-28.0%, p < 0.001). Within the 17.5 Gy (50%) isodose line PRV-FTTMS Dmean was reduced by 31.7% from 24.3 ± 3 Gy to 16.6 ± 4.8 Gy (p< 0.001). There was no decline of the effective treatment dose, PTV Dmean in regular plans was 36.9 ± 0.7 Gy vs. 37.7 ± 1.4Gy (p=0.013) after adaption. PTV coverage (V35Gy(%)*100) did not change with plan optimization: 0.99 vs. 0.99 (p=0.43). Dose constraints of organs at risk were all met both in regular and optimized plans.

CONCLUSION

DTI-FTTMS based motor tracts could be implemented in the adjuvant stereotactic RT planning of cavities after resection of BM. A significant dose reduction of motor structures within critical dose levels seems possible without reducing PTV treatment dose. However, the functional benefit needs to be investigated prospectively within clinical trials.
RADT-12. PRE- AND POST-OPERATIVE RADIATION TREATMENT PLANNING FOR PATIENTS RECEIVING STEREOTACTIC RADIOSURGERY FOR BRAIN METASTASES: A VOLUMETRIC ANALYSIS
Authors: Ho Cindy , Perlow Haley , Ritter Alex , Gokun Yevgeniya , Matsui Jennifer , Wang Joshua , Damante Mark , Blakaj Dukagjin , Beyer Sasha , Thomas Evan , Lonser Russell , Hardesty Douglas , Raval Raju , Palmer Joshua , Elder James
Published: November 2022

BACKGROUND

Pre-operative stereotactic radiosurgery (SRS) has emerged as a recent treatment option to treat large or symptomatic brain metastases. Compared to post-operative SRS, pre-operative treatment may reduce rates of radiation necrosis (RN) and meningeal disease through treating a smaller treatment volume and by preventing post-operative tumor seeding. We hypothesize that pre-operative radiation volumes will be smaller than post-operative volumes, which in turn may lead to a decreased treatment morbidity.

METHODS

A retrospective analysis was conducted and patients who had surgical resection and post-operative SRS or fractionated stereotactic radiosurgery (FSRT) for a posterior fossa brain metastasis were eligible for inclusion. Both pre-operative and post-operative MRIs were required to allow for accurate radiation target delineation. A pre-operative tumor volume was added for each patient, and the post-operative clinical treatment volume (CTV) used for radiation treatment was included. Pre-operative tumor and post-operative cavity volumes were compared using Wilcoxon signed rank test.

RESULTS

28 patients who received post-operative SRS or FSRT from 1/1/2016-12/31/2020 were included in this analysis. The mean pre-operative tumor volume was 14.9 ccs, and the mean post-operative CTV was 21.0 ccs (p < 0.01). 75% of patients had a smaller initial tumor size compared to the post-operative CTV used for radiation treatment planning. For patients with at least 4 follow up MRIs (n = 8), the size of the post-operative cavity progressively decreased with a mean initial cavity volume of 18.9 ccs and mean follow up volumes of 8.1, 7.1, 6.9, and 6.2 ccs.

CONCLUSIONS

In this study evaluating patients who received post-operative SRS, the pre-operative tumor volume was lower than the post-operative CTV for most patients. Previous studies including PROPS-BM have shown how pre-operative treatment may reduce the risk of RN because smaller radiation volumes are used. Pre-operative radiosurgery for patients with brain metastases requires prospective validation.
RADT-13. CLINICAL OUTCOMES COMPARING RADIOSURGERY TECHNIQUES FOR MANAGING LARGE BRAIN METASTASES
Authors: Kutuk Tugce , Kotecha Rupesh , Tolakanahalli Ranjini , Appel Haley , Hall Matthew , Wieczorek D Jay , Lee Yongsook , McDermott Michael , Ahluwalia Manmeet , Gutierrez Alonso , Mehta Minesh , Tom Martin
Published: November 2022

INTRODUCTION

Large brain metastases (BM) are associated with poor local control with single-fraction radiosurgery (SRS) alone. We sought to compare outcomes with various alternative management strategies to assess disease control rates.

METHODS

Consecutive patients diagnosed with BM ≥ 2 cm in maximum diameter between 3/2019-2/2021 and treated at a single tertiary institution were included. Primary endpoints included freedom-from-local-failure (FFLF) calculated on a per-lesion basis from the date of initial intervention to local failure, and overall survival (OS). Kaplan-Meier analysis and the log-rank test were used.

RESULTS

86 patients with 102 large BM met inclusion criteria. The median age was 66 years (range: 31-98), median KPS was 90 (50-100), and 57.8% were female. The most common primary tumor was lung in 40 (39.2%) lesions. The median tumor volume was 9.7 cm3 (2.1-35.5 cm3) and the median maximum tumor diameter was 3.3 cm (2.9-5.6 cm). 37 (36.3%) lesions were treated with staged-SRS, 31 (30.4%) with resection and postoperative-SRS, 21 (20.6%) with preoperative-SRS and resection, and 13 (12.7%) with fractionated-SRS (FSRS). Lesions treated with preoperative-SRS or postoperative-SRS were associated with higher rates of no- or stable-extracranial disease, and larger tumor volumes (preoperative-SRS: median 14.5 cm3 [4.2-33.1]; postoperative-SRS: 18.0 cm3 [2.5-35.5]; FSRS: 5.9 cm3 [2.1-24.6]; staged-SRS: 6.5 cm3 [2.2-27.8]).With a median follow-up of 15.6 months, 12 (11.8%) local failures and 42 (41.2%) deaths occurred. 1-year FFLF and OS for entire cohort were 85.6% (95% CI: 77.9-93.3%) and 64.4% (95% CI: 54.7-74.1%), respectively. The 1-year FFLF (p=0.542)/OS (p=0.043) rates were 94.1%/100% for preoperative-SRS, 84.0%/43.4% for staged-SRS, 81.8%/74.1% for FSRS, and 81.5%/63.4% for postoperative-SRS, respectively.

CONCLUSION

Although limited by patient numbers, selection bias, and high attrition rate, preoperative-SRS had the numerically most favorable outcomes, supporting this approach for large BM. Prospective evaluation is warranted to determine the optimal management strategy.
RADT-20. REPORT OF THE RESPECT-GBM™ PHASE I/IIA DOSE ESCALATION TRIAL OF RHENIUM-186 NANOLIPOSOME (186RNL) IN RECURRENT GLIOMA VIA CONVECTION ENHANCED DELIVERY (CED) & PLANNED PHASE IIB TRIAL
Authors: Brenner Andrew , Phillips William , Bao Ande , Hedrick Marc , LaFrance Norman , Michalek Joel , Patel Toral , Weinberg Jeffrey , Floyd John
Published: November 2022

A phase I/IIa dose escalation trial was initiated to determine the safety and recommended phase II dose (RP2D) of 186RNL in patients with recurrent glioma. Liposomal rhenium-186 (186RNL) is a source of high energy beta particles and gamma photons with attractive properties for brain CED.Patients with biopsy proven recurrent glioma had computerized treatment planning and placement of up to 4 intracranial catheter(s). Each patient received a single administration of 186RNL by CED. Whole body planar and SPECT/CT imaging from days 1-8 following treatment was performed. Patients were followed for safety, sufficiency of delivery and overall survival. Twenty-one patients across 6 dose escalation cohorts received 1.0-22.3mCi in a volume of 0.6-8.8mL. Mean tumor volume was 8.3mL, patients were heavily pretreated (mean 1.7 recurrences) with poor prognostic factors. There were no CED failures. Mean absorbed radiation dose to the tumor (MARDT) was 271Gy. No dose limiting toxicities were observed. Patients were stratified by MARDT. Those receiving > 100Gy MARDT (n=12) had a median and mean overall survival of 129.9 (95% CI 35.1 to 169.3) and 99.5 ± 19 weeks respectively with 3 patients alive. Patients receiving ≤ 100Gy MARDT (n=9) had a median and mean overall survival of 22.4 (95% CI 6.6 to 45.4) and 24.7 ± 4.8 weeks respectively, none are alive. Kaplan Meier analysis of overall survival for patients receiving MARDT greater than 100Gy vs. those with ≤ 100Gy showed a statistically significant difference in overall survival (p< 0.001).A single administration of 186RNL by CED in recurrent glioma patients is feasible, safe, and potentially effective in increasing overall survival when > 100Gy radiation is delivered to the tumor. A RP2D of 22.3mCi in 8.8mL was selected for patients with tumor size of ≤ 15mL in the planned phase 2b trial. The PIIb trial design and comparative survival data will also be presented.
RADT-23. MODALITY-SPECIFIC CNS INJURY FOLLOWING PROTON VS PHOTON BEAM RADIOTHERAPY IN GLIOMA
Authors: Winter Sebastian , Gardner Melissa , Parsons Michael , Grassberger Clemens , Bussière Marc , Ehret Felix , Kaul David , Boehmerle Wolfgang , Endres Matthias , Shih Helen , Dietrich Jorg
Published: November 2022

BACKGROUND

CNS injury following brain-directed radiotherapy (RT) is common and may mimic disease progression. Dosimetric advantages of protons (PRT) over photons (XRT) minimize radiation to healthy brain, potentially limiting radiotoxic sequelae. We characterized CNS radiotoxicity i.e., radiation-induced leukoencephalopathy (RIL), brain tissue necrosis (TN), and cerebral microbleeds (CMB), during progression-free survival (PFS) periods in glioma patients irradiated with PRT or XRT.

METHODS

34 patients (19 male; mean age = 40.10y) with grade 2/3 gliomas treated by partial cranial RT were stratified by RT modality [XRT(n = 17) vs PRT(n = 17)] and matched on 11 criteria [age, sex, tumor type/location/laterality, mutational status (IDH; 1p19q deletion), concurrent/adjuvant chemotherapy, radiation dose/fractions] for retrospective analysis. Radiotoxicity was characterized longitudinally until 3 years post-RT via analysis of serial MRI T2/FLAIR- (RIL), T1+Contrast- (TN), and Susceptibility (CMB)-weighted sequences. RIL was rated using a novel scoring system with embedded Fazekas scale (intraclass correlation coefficient > 0.9), at global (whole-brain) and hemispheric levels.

RESULTS

Analysis of delayed radiotoxicity at 3 years post-RT identified significant modality-specific differences. While both groups developed moderate-to-severe RIL [62% (XRT) and 72% (PRT)], XRT resulted in greater RIL injury dynamics (i.e., average % change between 1 and 3 years post-RT) in the contralesional hemisphere [F(1, 31) = 4.32, p < .05]. Conversely, PRT was associated with higher TN incidence [6%(XRT) vs 18%(PRT) z = - 2.22, p < 0.03, two-tailed]. Finally, while CMB incidence [76%(XRT) vs 71%(PRT)] and burden [mean #CMB: 4.3(XRT) vs 4.2(PRT)] were comparable, lesion-to-radiation field (RF)-correlation identified preferential CMB clustering at RF margins with PRT [X2(2, N =200)= 8.8, p < .02].

CONCLUSIONS

CNS radiotoxicity is common and progressive in glioma patients. Injury patterns suggest radiation modality specificity as RIL, TN, and CMB exhibit unique spatiotemporal differences following XRT vs PRT, likely reflecting dosimetric and biological differences between protons and photons. The impact of such sequelae on cognition is subject of current investigation.
RADT-30. RADIATION INDUCED MENINGIOMA IN BACKGROUND OF CHILDHOOD CRANIAL IRRADIATION: A CASE SERIES
Authors: Gupta Sunnia , Swampillai Angela , Brazil Lucy , Al-Salihi Omar
Published: November 2022

BACKGROUND

Cranial irradiation as part of prophylactic (PCI) or radical treatment for childhood malignancies can be associated with late consequences such as radiotherapy induced meningioma.

METHODS

We are reporting 5 such patients treated at our institute.

RESULTS

Case 1: 24y female received PCI for Acute Lymphoblastic Leukemia at the age of 2, and developed right frontal meningioma which was resected and pathology confirmed grade 2 atypical meningioma. It was treated with radiotherapy 60Gy/30fr and 2 year follow up scans remain stable. Case 2: 31y male received PCI as a child, and developed parieto-occipital meningioma which was excised multiple times. Pathology revealed Grade 2 atypical meningioma and was treated with radiotherapy 60Gy/30fr. Follow up scans 3.5 yrs later remain stable.Case3: 37y male received PCI at the age of 3, and developed multiple site meningiomas which were excised. Pathology showed likely Grade 2 meningioma. The sphenoid wing lesion progressed 2 years later, was re-excised and treated recently with radiotherapy 60Gy/30fr. Case 4: 52y female treated with radiotherapy for retinoblastoma at the age of 6-8 wks, developed left sphenoid wing meningioma which was resected and pathology revealed malignant meningioma. Radiotherapy 60Gy/30fr was recently completed.Case 5: 24y female treated with radiotherapy for medulloblastoma at the age of 5, developed meningiomas at multiple sites. Over the span of 10 years the frontal and clinoid lesions increased in size, and were treated with SRS/SRT recently.

CONCLUSION

All patients had background of cranial radiation and developed meningioma with latency period ranging 19 to 52 years. It is not possible to make an inference on gender, site of meningioma or craniaI dose correlation because of small number of cases and lack of data on dose. Further research is needed on how to prevent secondary malignancies in such patients and on standard of care for secondary meningiomas.
RADT-32. ADJUVANT RADIOTHERAPY VERSUS SURVEILLANCE FOR GRADE 2 INTRACRANIAL MENINGIOMAS: A MULTICENTER STUDY
Authors: Byun Hwa Kyung , Chang Won Ick , Kim Il Han , Lee Joo Ho , Park Chul-Kee , Kim In Ah , Kim Chae-Yong , Suh Chang-Ok , Cho Jaeho , Kim Eui Hyun , Chang Jong Hee , Kang Seok-Gu , Moon Ju Hyung , Yoon Hong In , Wee Chan Woo
Published: November 2022

BACKGROUND

To compare the outcomes between adjuvant radiotherapy (ART) and surveillance in patients with grade 2 intracranial meningiomas (MNG2s) after surgical resection.Materials and

METHODS

This multicenter study included 518 patients with newly diagnosed MNG2 who underwent resection between 1998–2018. Patients receiving ART with conventional fractionation (n = 158) were compared with those undergoing surveillance (n = 360). Progression-free survival (PFS) and progression/recurrence (P/R) rates were evaluated. Propensity score matching was performed to adjust for covariables (n = 43 in each group).

RESULTS

The median follow-up was 64.9 months. The median ART dose was 60 Gy in 30 fractions. Patients receiving ART had larger tumors (median, 5.0 vs. 4.5 cm, P < 0.001) and less frequent gross total resection (69.6% vs. 85.3%, P < 0.001). In multivariable analysis, ART was associated with significantly improved PFS (HR, 0.34; 95% CI, 0.22–0.53; P< 0.001) and P/R (HR, 0.29; 95% CI, 0.18–0.46; P< 0.001). In the propensity score matched cohort, the 5-year PFS rates were 80.8% vs 57.7% (P = 0.020) in the ART and surveillance group, respectively. Even in patients receiving gross total resection, the 5-year PFS (85.0% vs. 64.7%; HR, 0.50; 95% CI, 0.27–0.91; P = 0.023) and P/R rates (15.2% vs. 32.0%; HR, 0.50; 95% CI, 0.25–0.96; P = 0.038) were significantly improved by ART. Using recursive partitioning analysis in patients undergoing surveillance, we classified patients to low-, intermediate-, or high-risk of P/R based on surgical extent, tumor size, and Ki-67 index. The 5-year P/R rates in the low-, intermediate-, and high-risk groups were 18.6%, 37.9%, and 65.3%, respectively.

CONCLUSION

ART significantly improved PFS and P/R in MNG2s irrespective of surgical extent and should be recommended after both gross total and partial resection. A recursive partitioning analysis model for P/R may guide clinicians for decision making in resected MNG2s.
RADT-40. RADIATION-INDUCED CONTRAST ENHANCEMENT FOLLOWING PROTON RADIOTHERAPY FOR LOW-GRADE GLIOMA DEPENDS ON TUMOR CHARACTERISTICS AND IS RARER IN CHILDREN THAN ADULTS
Authors: Eichkorn Tanja , Bauer Julia , Deng Maximilian , Bahn Emanuel , Lischalk Jonathan , Eva Meixner , Elisabetta Sandrini , Regnery Sebastian , Held Thomas , Juliane Hoerner-Rieber , Alber Markus , Klaus Herfarth , Juergen Debus , Semi Harrabi , Laila Koenig
Published: November 2022

Proton beam radiotherapy (PRT) is used in the treatment of low-grade glioma (LGG) to mitigate long-term sequelae. Following PRT, increased rates of radiation-induced contrast enhancements (RICE) are suspected but poorly understood. We analyzed consecutive 227 patients (42 children and 185 adults) treated with PRT (54Gy RBE) for LGG from 2010 to 2020 and followed with serial clinical exams and magnetic resonance imaging for in median 5.6 years. Tumors were graded WHO 1 in a minority (n = 22, 12%) of adults, but a majority of children (n = 29, 69%). In contrast, tumors were graded WHO 2 in the majority (n = 160, 87%) of adults and a minority of children (n = 10, 24%). Five-year overall survival following PRT was 81% in adults and 91% in children. The risk of RICE was 5-fold more frequent in adults (25%) versus children (5%) (p = 0.0043). Also, within the adult cohort, RICE risk increases with age (p = 0,00128). In children and adults, RICE were symptomatic in 50% and 55% (n = 1 and 26) of cases with CTCAE grade 0 in 47% (n = 23), grade 1 in 25% (n = 12), 0% grade 2 (n = 0) and 29% grade 3 (n = 14), respectively. In adults, RICE risk was associated to WHO grading (8% in WHO grade 1 vs. 24% in WHO grade 2, p = 0.026), independent of age (p = 0.44) and irradiation dose (p = 0.005), but not independent of IDH mutational status. These data demonstrate effectiveness of PRT for LGG in both children and adults. The RICE risk is lower in children which are a main target group for PRT and differs with WHO grading.
CTIM-04. PHASE I STUDY OF IBRUTINIB WITH RADIATION AND TEMOZOLOMIDE IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Ahluwalia Manmeet , Patel Neha , Khosla Atulya , Rauf Yasmeen , Stevens Glen , Murphy Erin , Chao Samuel , Yu Jennifer , Suh John , Peereboom David
Published: November 2022

BACKGROUND

Glioblastoma is associated with dismal outcomes with a survival of 15-18 months. A major challenge in glioblastoma is the inability to effectively target glioma stem cells (GSCs) that have the capacity for self-renewal. GSCs are resistant to radiation and traditional chemotherapy agents. Ibrutinib is a first-in-class, potent, small-molecule tyrosine kinase inhibitor of Bruton’s Tyrosine Kinase (BTK) and Bone marrow X-linked (BMX). BMX nonreceptor tyrosine kinase activates STAT3 signaling to maintain self-renewal and tumorigenic potential of GSCs. Hence a combination of ibrutinib with radiation and temozolomide in Glioblastoma is a promising approach.

METHODS

Unmethylated MGMT GBM patients received ibrutinib daily with 60 Gy radiation over 6 weeks (Arm 1). MGMT methylated patients received Temozolomide at 75 mg/m2 in addition to Ibrutinib and radiation (Arm 2). Starting dose of Ibrutinib (level 1) was 420 mg daily, level 2 dose was 560 mg daily and dose level -1 was 280 mg. Patients received adjuvant Ibrutinib (Arm 1) and ibrutinib and temozolomide (Arm 2). The primary endpoint included the maximum tolerated dose (MTD) of Ibrutinib with radiation (Arm 1), and ibrutinib, radiation, and temozolomide (Arm 2). Progression-free survival and overall survival are secondary endpoints.

RESULTS

27 patients (15 males, 12 females), with a median age of 63 years (range, 34-77 years) were treated on two arms. Dose Limiting toxicity (DLT) in Arm 1 included grade 3 weakness, grade 4 transaminases, and grade 4 neutropenia. DLT in Arm 2 included grade 3 rash, grade 3 transaminases, grade 4 neutropenia, and thrombocytopenia. Ibrutinib was too toxic with radiation in Arm 1, MTD of 420 mg ibrutinib was confirmed in Arm 2.

CONCLUSION

MTD of Ibrutinib is 420 mg daily with Temozolomide and radiation. Efficacy outcomes (PFS and OS) will be presented.
CTIM-09. ENRICHED TCR/BCR VDJ REARRANGEMENTS CORRELATE WITH MRI AND SURVIVAL OUTCOMES IN PATIENTS WITH RECURRENT HIGH-GRADE GLIOMA TREATED WITH CAN-3110
Authors: Antonio Chiocca E , Nakashima Hiroshi , Mo Xiaokui , Solomon Isaac , Ling Alexander , Woods Jared , Bernstock Joshua , Villa Genaro , Piranlioglu Raziye , Landivar Ana Montalvo , Masud Nafisa , Triggs Daniel , Grant James , Wen Patrick Y , Lee Eudocia , Nayak Lakshmi , Chukwueke Ugonma , Batchelor Tracy , Krisky David , Aguilar-Cordova Estuardo , Aguilar Laura K , Fernandez Soledad , Matheny Christopher , Manzanera Andrea , Barone Francesca , Tak Paul Peter , Ligon Keith , Reardon David A
Published: November 2022

BACKGROUND

CAN-3110 (rQNestin34.5v2) is an HSV-1 oncolytic viral immunotherapy with one copy of the inflammatory ICP34.5 gene under transcriptional control of the Nestin glioma-specific promoter. We completed a phase 1 sequential dose-escalation trial of CAN-3110 in recurrent high-grade glioma (rHGG).

METHODS

CAN-3110 was injected intratumorally starting at 1x106 plaque forming units (pfu) and dose- escalated by half log up to 1x1010 pfu in biopsy confirmed rHGG. An expansion cohort of 12 patients was then accrued at 1x109 pfus. Blood and post-injection rHGG were collected.

RESULTS

41 rHGG patients were treated (42 separate interventions): median age 56 years (range 27-74); 21 females, 20 males; median baseline KPS 90 (range 70-100). CAN-3110 administration was well-tolerated with no dose limiting toxicities. Median overall survival (mOS) was 11.9 months. Histologic and molecular analyses showed significantly increased T cell infiltration in post treatment samples with elevated T cell and/or B cell receptor (TCR/BCR) transcripts which correlated with patient survival (HR 0.26 for patients with elevated TCR/BCR rearrangements as compared to patients with low). Volumetric analyses of MRI suggest a trend between reduction in the relative change in tumor growth, TCR/BCRs enrichment and survival in CAN-3110 treated patients.

CLINICAL IMPLICATIONS

Administration of CAN-3110 into rHGG was well tolerated. OS of CAN-3110 treated subjects compare favorably to historical controls. The association of increased TCR/BCR transcripts with survival suggests that CAN-3110 induces T cell responses against rHGG, supporting further clinical development of CAN-3110 viral immunotherapy.
CTIM-12. A PHASE I CLINICAL TRIAL ON THE INTRACRANIAL ADMINISTRATION OF INCREASING DOSES OF IPILIMUMAB PLUS FIXED DOSE NIVOLUMAB IN PATIENTS WITH RECURRENT GLIOBLASTOMA (RGB)
Authors: Geens Wietse , Schwarze Julia Katharina , Tijtgat Jens , Lescrauwaet Louise , Tuyaerts Sandra , Geeraerts Xenia , Stevens Latoya , Vanbinst Anne-Marie , Everaert Hendrik , Bruneau Michaël , Duerinck Johnny , Neyns Bart
Published: November 2022

BACKGROUND

Intra-operative intracerebral (iCE) administration of ipilimumab (IPI) and nivolumab (NIVO) after resection of rGB is safe and resulted in encouraging survival (NCT03233152J; Duerinck et al. JITC 2021).

METHODS

Eligible patients (pts) underwent a maximal safe resection followed by iCE administration of 5 mg IPI plus 10 mg NIVO and implantation of an Ommaya reservoir through which NIVO (10 mg) and IPI (cohort defined doses of 1-, 5- and 10 mg of IPI) were administered intracavitary (iCA) in combination with NIVO (10 mg) intravenously pre- and postoperatively and Q2w thereafter for up to 24w.

RESULTS

20 pts (13 male; median age 58y) were enrolled. One patient was excluded due to an intra-operatively diagnosed epidural bacterial infection. Respectively 4 pts were treated at the 1-, 4 pts at the 5-, and 11 pts at the 10 mg iCA IPI dose level. Median number and range of postoperative iCA administrations of IPI/NIVO was 2 (0-4) at the 1 mg dose level, 5 (1-10) at the 5 mg dose level, and pending for the 10 mg dose level. Most important treatment related adverse events were symptomatic aseptic neutrophilic pleocytosis (3 pts, all treated at the 10 mg IPI dose level), subacute cerebral edema necessitating corticosteroid treatment (5 pts), and bacterial colonization of the Ommaya reservoir (3 pts). There were no G5 AE. Nine pts have progressed and 4 pts died from progressive disease. Molecular-genetic characterization of rGB tissues, analysis of cellular and cytokine content, and NIVO/IPI concentrations in CSV samples are ongoing.

CONCLUSION

Repeated iCA administration of 10 mg NIVO plus 10 mg IPI resulted in treatment limiting aseptic neutrophilic pleocytosis. Safety of the presumed MTD of repeated 10 mg NIVO plus 5 mg IPI iCA will be further investigated.