bluuebunny/crossref_metadata_2025 huggingface dataset:
CSIG-09. RADIOTHERAPY WITH CONCURRENT INHIBITION OF CHEK2 ACTIVATES STING IN GLIOMAS
Authors: Chen Li , McManus Graysen , Arrieta Victor , Kim Kwang-Soo , Habashy Karl , Silvers Caylee , Najem Hinda , Gould Andrew , Ahmed Atique , Lukas Rimas , Heimberger Amy , Lee-Chang Catalina , Sonabend Adam , Dmello Crismita
Published: November 2023

Using an in vivo CRISPR screen approach, we demonstrated the contribution of glioma cell intrinsic checkpoint kinase 2 (Chek2) in the evasion of tumor cells from CD8+ T cell recognition. Genetic depletion or pharmacological inhibition of Chek2 with blood-brain-barrier permeable drugs that are being evaluated in clinical trials, in combination with standard of care radiotherapy and PD-1/PD-L1 blockade, led to survival benefit in multiple preclinical glioma models. Moreover, we observed that Chek2 inhibition or depletion is associated with activation of cytosolic DNA-sensing STING pathway in the glioma cells. A positive correlation was identified between STING pathway activity and T cell infiltration in the TCGA glioblastoma dataset. STING activation has been shown to promote robust immune response in glioblastoma. Building upon these results, we evaluated the impact of radiotherapy on Chek2 and STING signaling. After applying 2 Gy radiotherapy, a 20 fold increase of Chek2 activation was observed within the first hour in the in vitro grown glioblastoma patient derived cells, specifically GBM6 and GBM43 cells. Chek2 activation levels returned to the baseline within 6 hours in these cells. However, STING activation was moderate to absent at different time intervals within the first 48 hours post 2 Gy radiotherapy. Interestingly, when the in vitro-grown GBM6 cells were pretreated with Chek1/2 inhibitor prexasertib for 48 hours prior to the 2 Gy radiotherapy exposure, there was 10 fold reduction in the activation of Chek2 as compared to the radiotherapy alone group. Concomitantly, a 2-fold increase in the activation of STING was noted for up to 48 h in the pretreated group, as compared to the radiotherapy alone group. Our in vitro findings suggest an inverse relationship between the activation of Chek2 and STING. In conclusion, radiotherapy with concurrent inhibition of Chek2 offers a novel therapeutic combination to modulate STING activation in gliomas.
CSIG-10. SEX-DIFFERENCES IN NF-ΚB SIGNALING DRIVE SEX-BIASED RESPONSES TOWARDS SENESCENCE AND INFLAMMATION IN GLIOBLASTOMA
Authors: Wong Jason P , Tripp Lloyd , Reinhold Nicholas , Broestl Lauren , Luo Jingqin , Mitra Robi D , Rubin Joshua B
Published: November 2023

Male glioblastoma (GBM) patients have a higher incidence rate and worse median survival in comparison to females. The molecular mechanisms that drive these sex differences in incidence and survival are not well understood. Using a murine in vitro GBM model, we identified that male and female cells tend to segregate into two unique groups based on differential gene expression. Male-enriched processes included myc, E2F and G2-M checkpoint signaling. Female-enriched processes included epithelial-mesenchymal transition, interferon responses and TNF-α signaling by NF-κB. Reports from human GBM patients corroborate an increased enrichment for inflammatory and innate immune responses in females. Since the NF-κB pathway regulates senescence and its associated inflammatory response, the senescence-associated secretory phenotype, we examined if there are sex differences in NF-κB signaling as we have reported that female GBM cells undergo senescence more readily. We found that low levels of NF-κB activity were correlated with higher levels of senescence, and that cells from the female-enriched group correspondingly had lower levels of NF-κB activity. Interestingly, p-p65 S536 expression (a marker of increased NF-κB transcriptional activity) was negatively correlated with NF-κB activity in cells within the female-enriched group. Furthermore, female cells with low NF-κB activity responded more readily to TNF-α treatment. These results suggest that female cells can more readily modulate the NF-κB pathway in response to stimuli, thereby poising them towards a pro-inflammatory state. Since inflammation and senescence regulate therapeutic responses in GBM, and we have previously reported that female GBM cells undergo senescence more readily following radiation, these results suggest that further studies to understand the sex differences in NF-κB signaling may improve patient response to radiation and chemotherapy treatment.
CSIG-11. LIN28B EXPRESSION IN DIFFUSE MIDLINE GLIOMA
Authors: Knowles Truman , An Shejuan , Huang Tina , Qi Jin , Saratsis Amanda
Published: November 2023

INTRODUCTION

Diffuse midline glioma (DMG) is the most lethal of all childhood cancers. LIN28B is a RNA binding protein expressed in a variety of cancers, which suppresses the let-7 family of microRNAs, which in turn suppresses a plethora of oncogenes. However, the role of LIN28B in DMG has not yet been explored. Therefore, we sought to determine the pattern of expression and potential function of LIN28B in DMG using rare DMG cell lines.

METHODS

All studies were performed on DMG cell lines (n = 6) and controls (normal human astrocytes n = 1, human neural stem cells n = 1). RNA-Seq was performed using single-read sequencing at 50bp on the Illumina NextSeq 500 Sequencing System. Cells were then treated with DMSO or the LIN28B inhibitor, LI71, and submitted to functional in vitro studies, as well as RNA-Seq and Western Blot analysis. Functional pathways analysis was subsequently performed on resulting gene expression values with Ingenuity Pathways Analysis (Qiagen).

RESULTS

Differential LIN28B expression was demonstrated across cell lines, with DMG cells expressing greater LIN28B gene and protein levels compared to controls. LIN28B inhibition with small molecule inhibitor LI71 resulted in decreased cell proliferation and migration, in vitro. A total of 946 differentially expressed genes were identified between treatment groups (FC>2 or <-2, p< 0.05). Functional pathways analysis of differentially expressed genes implicated Cancer and Neurological Disease as the top disease processes, with Cellular Movement as the top molecular process in cell lines expressing LIN28B. Further, inactivation of Myc signaling was implicated in cells treated with LI71.

CONCLUSIONS

Our data demonstrates increased LIN28B expression in DMG cell lines compared with controls, with oncogenic effects on cell proliferation and migration. Further investigation of the LIN28B-let7 signaling axis is warranted in order to further explore LIN28B as a novel therapeutic target in DMG.
CSIG-12. GLIOMA MICROENVIRONMENT: FUNCTIONS, MOLECULAR MECHANISMS, AND THERAPEUTIC IMPLICATIONS
Authors: Bao Zhaoshi , Zhang Ying , Wang Peng , Zheng Chengjun , Wang Zhiliang , Fan Wenhua
Published: November 2023

Abstract Gliomas are the most common intracranial tumors in adults. The high mortality and disability rates place a heavy burden on society and the families of patients. The median survival of patients who have primary grade 4 glioma at the World Health Organization is only 14.6 months. Unlike primary glioblastoma (WHO grade 4, pGBM) which usually occurs in older adults, secondary glioblastoma (WHO grade 4, sGBM) with isotrate dehydrogenase (IDH) mutations typically progresses from low to high grades within 5-10 years of diagnosis. Although surgery, radiotherapy, and chemotherapy have almost become the standard treatment for gliomas, the prognosis of patients is still poor. In recent years, the immune microenvironment has gradually become a possible direction for tumor treatment, and treatment methods such as PD1/PDL1 inhibitors and tumor vaccines have emerged. Owing to the microenvironment around the intracranial tumor cells and the body tumor being different, the microenvironment cells have their specific characteristics, and there is a blood-brain barrier, immunotherapy for the glioma microenvironment has encountered a bottleneck. Here, we summarize the current tumor-associated microenvironment and the interactions between tumor and immune cells and introduce the current status of glioma-specific microenvironment and immunotherapy for glioma. Finally, we mentioned several recent microenvironment-related research advances by our team and looked forward to future glioma microenvironmental research.
CSIG-15. PTN-PTPRZ1 SIGNALING MEDIATES TUMOR-NORMAL CROSSTALK IN GLIOBLASTOMA
Authors: Kan Ryan , Ge Weihong , Yilgor Can , Bayley Nicholas , Tse Christopher , Tum Andrew , Patel Kunal , Nathanson David , Bhaduri Aparna
Published: November 2023

Glioblastoma (GBM) is the most devastating form of brain cancer with poor patient prognosis and high recurrence. An increasing body of literature suggests crosstalk between tumor and its surroundings, both molding the immune microenvironment and forming functional synapses with neighboring normal cells. Despite the high intra-tumoral and inter-patient heterogeneity, we have discovered PTN-PTPRZ1 signaling as the most significant and preserved communication pathway between GBM cells and their immediate neighboring cells. Through a novel tumor transplantation protocol onto cortical organoids, which are human embryonic stem cell-derived aggregates that faithfully mimic the human brain, we have seen evidence of tumor-normal crosstalk where PTN-PTPRZ1 is a key signaling axis. We hypothesize that PTN-PTPRZ1 signaling is pivotal to tumor growth and invasion, which ultimately leads to recurrence. Modulating PTN and/or PTPRZ1 levels on the cortical organoids via shRNA affects PTN and/or PTPRZ1 expression on the tumors, suggesting dynamic communication between tumor and normal cells via PTN-PTPRZ1 signaling. During the process of generating PTN knockdown cortical organoids, we have additionally discovered a pivotal role for PTN in the very early stages of cortical development. PTN and PTPRZ1 are signature markers of the outer radial glia in the developing human brain, which are absent in mouse models where the majority of PTN biology has been studied. By supplementing exogenous PTN to PTN knockdown organoids and withdrawing it at various timepoints, we have identified drastic phenotypes of neuron and radial glia survival and cell fate specification. With cortical organoids, we can interrogate the role of PTN in the early stages of neurodevelopment via a human-derived system.
CSIG-17. NICOTINAMIDE N-METHYLTRANSFERASE (NNMT) AS A POTENTIAL THERAPEUTIC TARGET FOR EGFRVIII-DRIVEN GLIOBLASTOMA
Authors: Li Ming , Chen Clark
Published: November 2023

Nicotinamide N-methyltransferase (NNMT) is an enzymatic catalyst involved in converting methyl groups from S-adenosyl-L-methionine (SAM) to nicotinamide (NAM), generating S-adenosine hyperblastoids (SAH) and 1-methylnicotinamide (MNA). Increased NNMT expression is frequently observed in various cancers and is associated with tumor progression, metastasis, unfavorable clinical outcomes, and drug resistance. Notably, NNMT stands out as one of the most up-regulated metabolism-related genes in glioblastoma, although the underlying mechanism for its overexpression remains elusive. Glioblastoma commonly exhibits genetic lesions in the epidermal growth factor receptor (EGFR) gene, including amplification or mutation, with EGFRvIII being the predominant mutant contributing to glioblastoma cell proliferation, invasion, therapeutic resistance, metastasis, and stemness. In this study, we demonstrate that activation of wild-type EGFR by EGF or the constitutively active mutant EGFRvIII promotes NNMT expression and enzyme activity in established glioblastoma cell lines and glioblastoma stem-like cells via the p38 mitogen-activated protein kinase pathway. Additionally, we identify STAT1 as a downstream transcription factor essential for EGFR/EGFRvIII-induced NNMT upregulation. RNA interference-mediated knockdown of NNMT in glioblastoma cells significantly inhibits EGFRvIII-promoted invasion and proliferation in vitro. Targeting NNMT effectively suppresses EGFRvIII-driven glioblastoma tumorigenicity and prolongs the survival of tumor-bearing mice. Clinically, NNMT is highly expressed and positively correlated with EGFR expression in human glioblastoma tumors. Collectively, these findings establish NNMT as a previously unrecognized downstream target gene of EGFR/EGFRvIII expression and highlight its potential as a therapeutic target for inhibiting EGFRvIII-driven glioblastoma.
CSIG-18. WNT SIGNALING MODULATES TUMORIGENIC FEATURES AND CELLULAR IDENTITY IN A MODEL OF LOW-GRADE GLIOMAGENESIS
Authors: Koch Marilin , Deo Minh , Hoetker Michael , Herold-Mende Christel , Wick Wolfgang , Turcan Sevin
Published: November 2023

RATIONALE: Isocitrate dehydrogenase (IDH)-1/2 mutations are known driver mutations for the development of low-grade gliomas (LGGs). However, secondary drivers are needed for tumor growth, and it remains unclear which co-factors and pathways are necessary to develop the LGG tumor phenotype. To identify additional players in IDH mutant-mediated oncogenesis, we investigated the effects of disrupting glioma-associated pathways in a tractable in vitro system of IDH-mutant malignant transformation. METHODS: A doxycycline-inducible IDHR132H expressing normal human astrocyte cell line was concomitantly treated with either a Wnt-activator/inhibitor (CHIR99021/IWP-2), TGF-β inhibitor (Repsox) or Notch inhibitor (YO-01027). IDH-associated CD171 marker expression changes were assessed with Flow cytometry, followed by transcriptional and proteomic analysis with RNA-Seq and mass spectrometry. Functional characterization entailed cell viability and clonogenic assays as well as cell cycle analyses. RESULTS: We observed significant IDH-related CD171 expression changes upon treatment with CHIR99021, Repsox and YO-01027. Wnt activation with CHIR99021 profoundly affected the IDH mutant-induced transcriptional landscape, leading to differential usage of LGG and stemness programs including altered expression of SOX4 and SOX11. On the protein level, Wnt activation additionally impacted pathways relevant for cellular architecture, specifically Rho-Rac-CDC42 signaling. This was also reflected by an altered cell morphology with small, rounded up cells, augmented clonal proliferation capacity and increased proportions of cell in S-phase. CONCLUSION: Wnt activation in a IDHR132H model system modulated LGG development, leading to differential expression of key LGG and stemness associated profiles, morphologic cell changes and increased replication capacity. While aberrant Wnt signaling is a common feature in glioblastoma, our data point to an effect also on low-grade gliomagenesis, therefore requiring further investigation.
CSIG-21. TITLE: INTEGRATIVE TRANSCRIPTOME PROFILING OF EXOSOME AND TISSUE IDENTIFIES PROGNOSTIC GENES AS THERAPEUTIC TARGETS OF GLIOBLASTOMA
Authors: Goel Pallavi , Roy Vijay Laxmi , Sadasivam Subhashini , Ghanekar Yashoda , Kaur Inderjeet , Sreegiriraju Vijay , Prathapa Kiran , Madiraju Surya , Ray Amit , Group Exsegen Neurosurgery
Published: November 2023

For glioma, molecular genetic analysis has grown in significant amounts for disease diagnosis and pathogenesis research. Due to limitations of tissue samples, liquid biopsy is being considered as a substitute for tissue biopsy which can be developed as a diagnostic technique. Studies have demonstrated that exosome-carrying molecules can foster a milieu that is favorable to cancer growth and therapy resistance. METHODS: In the present study the tumor tissue and serum of the same 80 patients were collected with a confirmed diagnosis of glioma with prior consent. Demographic details, pathology reports and survival data were also collected. RNA-seq analysis was performed in both tumor tissue and exosomal RNA. Fastq file with 100bp paired end reads were generated. Raw reads were trimmed using Trimmomatic (Version 0.39) to remove adapter sequences and low-quality reads. Reads mapping to ribosomal RNA were removed using SortMeRNA tool. Trimmed reads were then mapped to the human reference genome GRCh38.d1.vd1.fa using a two-pass method with STAR (2.7.10a). Differential gene expression was performed using DESeq2. The gene ontology and pathway analysis were performed using open source tool PANTHER. RESULTS: The differentially expressed genes shared between tumour tissue RNA and exosomal RNA experiments were selected for further analysis. Genes such as EGFR (tissue: Fold change (FC)[6.1], exosome: FC[7.2]; p-value< 0.001), PDFGRA (tissue: FC[3.7], exosome: FC[5.2]; p-value< 0.001), TTN (tissue: FC[12.6], exosome: FC[11.3]; p-value< 0.001) were found to be differentially regulated and were prominently associated with Integrin signaling pathway, Synaptic vesicle trafficking pathway, Wnt signaling and cellular proliferation. As per literature and clustering analysis, we found that these pathways and genes play an important role in the progression of tumors which can be further integrated into diagnostic platforms. CONCLUSION: This study will provide a reliable and effective way of diagnosis and management of glioma in patients with minimal invasion.
CSIG-29. CLINICAL AND TRANSCRIPTOMIC DATASET IDENTIFIES LARGE CHANGES IN IMMUNE AND HORMONAL SIGNALING AMONGST RECURRENT PATIENTS WITH CRANIOPHARYNGIOMA
Authors: Joshi Nikhil , Crowley Julia , Mccormack Shana , Malbari Fatema , Kraya Adam , Kline Cassie
Published: November 2023

INTRODUCTION

Craniopharyngioma is a low-grade suprasellar brain tumor that often produces deficiencies of pituitary hormones, including growth hormone. Although epidemiological data are reassuring that growth hormone does not lead to craniopharyngioma recurrence, the theoretical risk is cause for concern. To address this and other questions related to the care of individuals with recurrent craniopharyngioma, we analyzed gene expression in craniopharyngiomas in the context of clinical data. We envision insights that could guide decisions about hormone replacement and tumor-focused treatment alternatives.

METHODS

Clinical information was abstracted for a cohort of individuals diagnosed with craniopharyngioma at the Children’s Hospital of Philadelphia between 2016 - 2020. In parallel, tumor transcriptomic data for patients with craniopharyngioma were collected from the Children’s Brain Tumor Network (CBTN) and matched to clinical data where applicable. Bulk RNA-sequencing analysis, pathway analysis, and immune deconvolution (xCell) of samples was performed in R to identify transcript-level changes that distinguish recurrent from initial craniopharyngioma.

RESULTS

CBTN data was available for 54 initial tumor samples and 17 recurrent tumor samples, with matched clinical data available for 33 samples (26 initial, 7 recurrent). We did not find differences in clinical characteristics between individuals with versus without recurrence. Pathway analysis notably suggested altered levels of antigen presentation (NES: 2.97), Programmed cell death (NES: 2.34), WNT signaling (NES: 1.97), and Growth Hormone Signaling (NES: -1.277) amongst recurrent samples when compared against initial samples. Deconvolution of samples showed altered levels of M2-like macrophages (39.2% increased) and CD4+ T-helper-2 cells (-54.7% decreased) in recurrent samples compared against initial samples. Preliminary work is being completed to frame these results in the context of available clinical neuroendocrine data.

CONCLUSION

This work highlights marked changes in immune and hormonal signaling in samples from recurrent craniopharyngioma tumors. These insights have potential therapeutic implications that deserve further investigation.
CSIG-33. A 2ND GENERATION IDO1 PROTEIN DEGRADER TO OVERCOME NON-ENZYME-MEDIATED IDO1-DEPENDENT IMMUNE SUPPRESSION FOR GLIOBLASTOMA
Authors: Bommi Prashant , Monsen Paige , Lauing Kristen , Zhai Lijie , Barton Kevin , Borys Ewa , Anderson Douglas , Prabhu Vikram , Thakkar Jigisha , Lukas Rimas , Schiltz Gary , Wainwright Derek
Published: November 2023

Indoleamine 2,3-dioxygenase 1 (IDO1) is an immunosuppressive rate-limiting enzyme that metabolizes the essential amino acid, tryptophan (Trp), into the downstream catabolite, kynurenine. IDO1 is expressed in >90% of patient-resected glioblastoma (GBM). We recently validated that IDO1 can suppress the anti-brain tumor immune response and ablate immunotherapeutic treatment efficacy through non-metabolic IDO1 activity. To-date, most IDO1-targeted therapy has focused on inhibiting tryptophan metabolism. This class of drugs has failed to improve the overall survival of patients with cancer. To overcome this failure, we developed a therapeutic agent that inhibits both IDO1 enzyme- and non-enzyme-activities in the form of an IDO1-Proteolysis Targeting Chimera (PROTAC). We previously published the characterization of a 1st generation lead compound (Bollu et al., 2022; J. Med. Chem) with a DC50 for IDO1 of 0.329 µM in human GBM cells. In a more recent investigation, we discovered a 2nd generation IDO1-PROTAC, NU227326, with 30× more potency and a DC50 of 10.4 nM in human GBM cells. IDO1-expressing U87, U138, and patient derived xenograft (PDX) GBM43 were treated with either IDO1-PROTAC, IDO1-mutant-PROTAC, IDO1 enzyme inhibitor, or IDO1 siRNA. Transcriptomic analysis revealed differentially expressed genes that were commonly regulated after treatment with the IDO1-PROTAC as compared to treatment with the IDO1-mutant-PROTAC or IDO1 enzyme inhibitor groups in U87, U138, and GBM43 cells. Mass spectrometry discovered 34 unique proteins that were differentially expressed inside of human GBM cells and an additional 20 unique proteins that were identified in the supernatant of cultured human GBM cells after IDO1-PROTAC treatment. Meta-analysis of the transcriptomic and proteomic analyses identified a novel factor that was unique to IDO1-PROTAC treatment. IDO1-PROTAC treatment-enriched GO terms were associated with nucleoside kinase and metallocarboxypeptidase activities. This study discovered multiple new pathways that immunosuppressive IDO1 non-metabolically regulates in human glioblastoma cells.
RADT-04. DOSE PAINTING WITH THE GAMMA KNIFE LIGHTNING OPTIMIZER TO ESCALATE RADIATION DOSE TO RESIDUAL TUMOR WITHIN BRAIN METASTASIS RESECTION CAVITIES
Authors: Barbour Andrew , Gates Evan , Ford Eric , Phillips Mark , Halasz Lia
Published: November 2023

BACKGROUND

The novel Gamma Knife (GK) Lightning optimizer allows simultaneous automated optimization of multiple intracranial radiotherapy targets. We used this optimizer to create a dose-painting treatment plan where an escalated dose was prescribed to residual disease within a brain metastasis resection cavity. We validated this method by measuring dose-delivery accuracy using radiochromic film in an anthropomorphic phantom.

METHODS

A 15.7cc irregular contour was drawn to represent a brain metastasis resection cavity, a 2mm expansion contour created, and a 1.6cc contour drawn representing a nodule of residual disease. In GammaPlan v11.3.1, three targets were created with overlapping dose matrices. Targets were prescribed 3Gy (2mm expansion), 4Gy (resection cavity), and 5Gy (residual disease) in one fraction. On the GK Icon system, an occipital mold was made, an unexposed film placed in the phantom’s cranium, cone-beam coregistration conducted, and treatment delivered. The film was scanned and calibrated for absolute dosimetry. To evaluate dose-painting accuracy, global gamma index (GI) analyses were performed at various dose and distance tolerances, excluding points below 30% of the maximum dose.

RESULTS

An 18-minute treatment plan with 40 shots was created and delivered. Prescription isodose lines were 3Gy at 55% (2mm expansion, mean 4.8Gy), 4Gy at 69% (resection cavity, mean 5.2Gy), and 5Gy at 75% (residual disease, mean 6.1Gy). All target volumes had ≥ 99% prescription dose coverage and the maximum dose was 6.9Gy. Paddick conformality indices were 0.79 (2mm expansion), 0.74 (resection cavity), and 0.15 (residual disease). Gamma index pass rate/mean GI/median GI were 73%/0.68/0.55 at 1%/1mm tolerance, 85%/0.58/0.48 at 2%/1mm tolerance, and 97%/0.34/0.28 at 2%/2mm tolerance. An average of 17,883 points were evaluated per analysis.

CONCLUSIONS

We successfully performed GK dose painting with the Lightning optimizer, verifying dose delivery within clinically acceptable tolerances. Future work is needed to determine optimal dose levels for use in clinical practice.
RADT-06. IMPACT OF STATUS OF TUMOR PROGRESSION PRIOR TO STEREOTACTIC RADIOSURGERY ON LOCAL TUMOR CONTROL IN PATIENTS WITH TRIPLE-NEGATIVE BREAST CANCER BRAIN METASTASES TREATED WITH STEREOTACTIC RADIOSURGERY
Authors: Patel Reema , Xu Zhiyuan
Published: November 2023

INTRODUCTION

Prognosis in patients triple-negative breast cancer (TNBC) brain metastases remains poor owing to the lack of treatment targeting pathways. Furthermore, approaches–like surgical resection, stereotactic radiosurgery (SRS), and whole-brain radiation therapy–have variable efficacy depending on the degree of tumor burden. The cohort of patients benefit least to targeted therapy and immunotherapy, therefore, forming ideal candidates to evaluate the local tumor control attributed to SRS. This study aimed to characterize intracranial tumor response and clinical outcomes in the patient cohort. PATIENTS and

METHODS

This retrospective, single-center study included patients with confirmed TNBC brain metastases treated with SRS at the University of Virginia Health. Tumor response, new intracranial tumor development, and survival were investigated. 24 patients with 169 total treated lesions between 2007 and 2021 were assessed. The median age of patients at the initial treatment was 49.1 years.

RESULTS

One MRI within one month prior to SRS plus the treatment study MRI were evaluated. Tumor progression at the time of SRS led to worse local tumor control following the first SRS treatment (p < 0.0001). 15.1% of total treated lesions demonstrated a complete response, while 48.5% had a partial response. 25.7% of lesions remained stable and 13.5% progressed. Three patients did not have any follow-up imaging to assess initial tumor response due to mortality. For patients with tumor progression, the progression-free survival was 4.93 months. Additionally, new intracranial metastases developed in ten patients over their treatment course. Median overall survival following the first SRS session was 9.83 months (range 0.9 - 37.7 months), with a 1-year and 2-year survival of 54.5% and 22.7%, respectively.

CONCLUSION

Tumor control in patients with TNBC treated with SRS is unfavorable. Tumor progression prior to SRS might lead to worse tumor control. Further study is warranted to evaluate this phenomenon in a large cohort of patients.
RADT-10. BRAINSTEM METASTASES TREATED WITH STEREOTACTIC RADIOSURGERY: MASKED VS. FRAMED IMMOBILIZATION
Authors: Begley Sabrina , Goenka Anuj , Schulder Michael
Published: November 2023

BACKGROUND

Patients with brainstem metastases (BSM) have minimal surgical options due to high-risk anatomy. To review our efficacy treating BSM using Gamma Knife stereotactic radiosurgery (GK SRS), we compared results based on the utilization of mask-fixation (MF) or frame-fixation (FF).

METHODS

Data were retrospectively collected for 32 patients. Follow-up data for 49 lesions were analyzed for local control rate (LCR) and objective response rate (ORR).

RESULTS

Primary cancers included lung, breast, and melanoma; most lesions were pontine. MF was used in 18 patients. Average tumor volume was 0.99 cm3 (0.005 – 13.3 cm3). 39 lesions were treated with single fraction 16 Gy. 10 lesions were treated in 3-5 fractions with mean dose of 22.5 Gy. Mean follow-up was 14.2 months (1.2 - 48.2 months). 1-year LCR was 94.7%. ORR at last follow-up did not differ between MF vs. FF (p = .81). Average reduction of lesion volume at 6 and 12 months did not differ between MF vs. FF (64% vs 45%, p = .77; 70% vs 77%, p = .78). Failure occurred in a pontine colorectal cancer metastasis mask-immobilized for treatment with 14 Gy.

CONCLUSIONS

SRS for BSM achieved high LCR despite variability in tumor size and histology with no significant difference between MF vs. FF. Although trials have historically excluded patients with BSM, our data support SRS as a safe and efficacious treatment. This is the first study showing that MF provides equivalent, successful outcomes when compared to FF for patients with BSM.
RADT-20. STEREOTACTIC RADIOSURGERY FOR 15 OR MORE BRAIN METASTASES
Authors: Upadhyay Rituraj , Palmer Joshua , Perlow Haley , Schoenhals Jonathan , Ghose Jayeeta , Rajappa Prajwal , Blakaj Dukagjin , Beyer Sasha , Grecula John , Sim Austin , Hardesty Douglas , Elder J Bradley , Chakravarti Arnab , Thomas Evan , Raval Raju
Published: November 2023

BACKGROUND

Patients with ≥ 15 brain metastases(BM) continue to be treated with whole brain radiation therapy(WBRT), despite poor neurocognitive outcomes. We analyzed our institutional experience of treating these patients with stereotactic radiosurgery(SRS), with the aim of evaluating safety, cognitive outcomes, and survival.

METHODS

Patients who received SRS for ≥ 15 BMs in 1-5 fractions from 2014-2022 using the previously described single isocenter multi-target technique were included. Cognitive outcomes were objectively evaluated using serial Patient-Reported Outcome Measurement Information System(PROMIS) scores.

RESULTS

A total of 124 patients treated with LINAC-based SRS were included. The mean and median number of lesions treated per patient was 24.8 and 20, respectively (range 15 – 94). Most common primary histologies were lung(47.6%), melanoma(21.0%), and breast(14.5%). The median SRS dose was 24 Gy(range 18 – 30 Gy). The rate of any grade radiation necrosis (RN) and ≥ grade 3 RN were 15.3% and 3.2% respectively. New onset seizures were seen in 2.4% and alopecia in 2.4%. Median follow-up was 5.1 months(m). When cognitive data were available, 25 of 31 patients had a stable or improved PROMIS score. The 12m local control was 97.6% while overall intracranial control was 20.8%. One-year freedom from neurological death, leptomeningeal disease, and salvage WBRT were 85.6%, 87.6% and 71.7% respectively. Median overall survival(OS) from brain metastases diagnosis was 11.3m(95% CI 7.2m – 15.3m). On univariate analysis, no prior WBRT(p = 0.038), higher KPS(p = 0.002) and systemic therapy after SRS(p < 0.001) predicted for improved OS.

CONCLUSIONS

We present here the largest study evaluating SRS for patients with ≥ 15 BMs. We found that SRS was safe, had favorable cognitive outcomes, and comparable survival outcomes to contemporary studies evaluating WBRT in this patient population. Our study supports further randomized studies comparing SRS and memory avoidance WBRT approaches for patients with ≥ 15 BMs.
RADT-21. LINEAR ACCELERATOR BASED RADIOSURGERY WITH DYNAMIC CONFORMAL ARCS FOR PATIENTS WITH MULTIPLE BRAIN METASTASES: A PROSPECTIVE COHORT STUDY
Authors: Huang Shih-Ting , Liu Yen-Ting , Chu Kuan-An , Huang Tsu-Hsien , Chen Sin-Yin
Published: November 2023

PURPOSE

Linear accelerator (LINAC)-based stereotactic radiosurgery (SRS) is gaining popularity as an alternative due to its high delivery efficiency and improved accessibility. This study focuses on the radiosurgery protocol of a single institution, utilizing single-isocenter multi-target SRS treatment with an inverse-optimized dynamic conformal arc technique. Materials &

METHODS

A prospective cohort study was conducted from August 2020. The study protocol was approved by the Research Ethics Committee. Patients with brain tumors referred for SRS were treated based on the indications. Prescription doses were determined by target size and radiation oncologists. The protocol included a 1-2 mm expansion of tumors for the planning target volume (PTV), with a requirement of at least 85% PTV coverage. At least three non-coplanar arcs are needed. Competing risk survival analysis was used to assess the cumulative incidence of failure.

RESULTS

A total of 57 patients with 190 brain tumors underwent SRS in this study. 12 patients (21.1%) received at least 2 radiation courses for recurrent lesions. Tumor sizes ranged from 0.45 to 8.0 cm (median 1.41 cm). The maximal dose relation ranged between 71.5% and 91.4% (median 81.6). The conformal index ranged from 1.08 to 2.19 (median 1.19), and the dose gradient index ranged from 2.19 to 6.95 (median 3.59). The 1-year cumulative incidence of local failure and intracranial distant failure rates were 10.8% and 35.6%, respectively.

CONCLUSION

LINAC-based SRS using dynamic conformal arcs achieves optimal tumor coverage and a high dose gradient with ease. It demonstrates a low rate of local failure, effectively protects normal brain tissue, and allows for the postponement of whole brain radiotherapy, enabling patients to maintain a normal quality of life. In conclusion, LINAC-based SRS with dynamic conformal arcs may be a beneficial treatment option for brain metastases, even with a high lesion count, particularly in institutions equipped with LINAC.
RADT-23. STEREOTACTIC RADIOSURGERY FOR CYSTIC VESTIBULAR SCHWANNOMA - A SYSTEMATIC REVIEW
Authors: Torres Lisette , Mekonnen Mahlet , Furton Anna , Pandey Aryan , Vohra Sanah , Yang Isaac
Published: November 2023

BACKGROUND

Cystic vestibular schwannoma, also historically known as cystic acoustic neuroma, is a benign intracranial tumor that can form between the pons and the cerebellum in an area known as the cerebellopontine angle. These brain tumors can be treated with radiotherapy, surgical resection, or radiosurgery. However, there is no consensus on which treatment modality is the most effective with minimal to no complications.

METHODS

A comprehensive review of clinical articles reporting stereotactic radiosurgery treatment for cystic vestibular schwannoma was performed. PubMed, Web of Science, Cochrane, Scopus, and Embase were independently queried and the PRISMA guidelines were followed throughout the screening process. We identified high-quality studies representing data from 186 patients. We extracted patient demographics, tumor characteristics, type of stereotactic radiosurgery, dosage, tumor control rate, and follow-up time. All the available data points were used to evaluate the effect of stereotactic radiosurgery on tumor control rate for cystic vestibular schwannoma.

RESULTS

A total of 186 patients underwent stereotactic radiosurgery with Gamma Knife (n = 178) and CyberKnife (n = 8). The average tumor volume was 6.47 cm3 (range 4.82 – 8.4 cm3, SD ± 1.8). The average marginal and maximum doses were 12.8 Gy (12.5 -13 Gy, SD ± 0.25) and 24.9 Gy (23.8 - 26 Gy, SD ± 1.10), respectively. The average follow-up time was 63.5 months (53.5 – 74 months, SD ± 10.2). Following stereotactic radiosurgery treatment for cystic vestibular schwannoma across all studies, almost 92% of patients had tumor control at follow-up, (95%-CI: 91.4 - 91.6).

CONCLUSIONS

Our systematic review revealed that stereotactic radiosurgery can provide adequate tumor control for cystic vestibular schwannoma. Therefore, stereotactic radiosurgery is an effective treatment choice in patients with cystic vestibular schwannoma.
RADT-24. A PROSPECTIVE TRIAL EVALUATING THE EFFICACY OF REIRRADIATION TO BONY METASTASES WITH STEREOTACTIC BODY RADIATION THERAPY
Authors: Hammoudeh Lubna , Gunasti Lauren , Shin Kee-Young , Krishnan Monica , Hertan Lauren , Balboni Tracy
Published: November 2023

INTRODUCTION

Bone metastasis is common in advanced-stage cancer patients. While reirradiation of metastatic tumors offers significant symptom control, major limits exist on the possible dose delivered to previously irradiated disease sites. Stereotactic body radiation therapy (SBRT) offers the potential to avoid delivering toxic radiation doses to the spinal cord and other organs at risk by delivering large doses with steep dose gradients.

METHODS

We developed a prospective study including 44 patients with recurrent bone metastasis that were treated to assess the effectiveness of SBRT on local control at or before 6 months as a primary endpoint and local progression-free survival (LPFS), Progression-free survival (PFS), and overall survival (OS) as a secondary objective.

RESULTS

Patients median age was 62.5 years (22.7% female and 77.3% male). The majority of patients received reirradiation to a spinal lesion (29/44, 65.9%) of various primary disease sites predominantly prostate (13/44, 29.5%), lung (8/44, 18.2%), and renal cell (5/44, 11.4%). The most common dose prescriptions were 30 Gy in 5 fractions (24/44, 54.5%). Of the participants, 41 (93.2%) experienced local control at or before 6 months, with 3.6 median months to local progression for those who progressed. 48% and 36.5% of the cohort maintained LPFS at 2 years, and 3 years respectively with a local progression-free rate of 89.5% at 2 and 3 years. OS was maintained in 50.9% and 38.8% of patients at 2 years and 3 years respectively.

CONCLUSION

SBRT offers an effective and less toxic approach for the reirradiation of recurrent metastatic tumors as it can prevent associated toxicities to the surrounding normal tissues and maintain a local progression-free rate in a large percentage of patients. We believe that more clinicians should offer SBRT as an effective option for recurrent metastatic bone tumors especially involving the spinal vertebrae.
RADT-26. IMPROVING RADIATION TARGET VOLUME DEFINITION FOR GLIOBLASTOMA USING PREDICTIONS OF TUMOR RECURRENCE FROM MACHINE LEARNING AND PRE-RADIOTHERAPY ADVANCED MRI
Authors: Tran Nate , Luks Tracy , Ellison Jacob , Nair Devika , Li Yan , Jakary Angela , Liu Bo , Adegbite Oluwaseun , Villanueva-Meyer Javier , Butowski Nicholas , Clarke Jennifer , Chang Susan , Braunstein Steve , Lin Hui , Morin Olivier , Lupo Janine
Published: November 2023

INTRODUCTION

Standard-of-care (SOC) radiation therapy (RT) planning only utilizes a fairly 1.5-2cm uniform expansion of T2-weighted-FLAIR MRI lesion to generate a clinical target volume (2cm-CTV), without considering the spatial heterogeneity and infiltrative nature of glioblastomas. This study aimed to use multi-parametric MRI with 2 artificial intelligence (AI)-based approaches to predict regions of subsequent tumor progression and compare the resulting predictions to the 2cm-CTV, with the hypothesis that applying deep learning will lead to improved detection of subclinical disease that is under-treated, and more accurately delineate areas at higher risk for progression, than the uniform 2cm-CTV.

METHODS

We used normalized maps of anatomical, diffusion, and metabolic MRI post-surgical resection and before RT and chemotherapy from 72 patients newly-diagnosed with glioblastoma to train Random-Forest and deep-learning UNet models to identify voxels that later exhibit progression by either the contrast-enhancing-lesion (CEL) or T2-lesion (T2L). All models were trained/validated on 54 and tested on 18 patients after careful inter-exam alignment and normalization. Model performance was compared to the 2cm-CTV using a Progression-Coverage-Coefficient (PCC), a weighted Dice coefficient that accounts for tumor-size.

RESULTS

Random-Forest models were able to predict subsequent contrast-enhancing (CE) and T2 non-enhancing (NE) progression with an average respective test AUC of 0.88 and 0.82, with 15.6%/9.6% higher performance on patients who progressed early. The 2cm-CTV treatment plan achieved the highest sensitivity (0.833 vs 0.795) but also the lowest specificity (0.879 vs 0.935), over-treating normal-appearing-brain. Our deep learning model outperformed the 2cm-CTV in covering the progressed lesion, with the highest specificity (0.935 vs 0.879), PCC (0.741 vs 0.734), and had comparable sensitivity (0.795) to the 2cm-CTV, while sparing more normal brain compared to the 2cm-CTV.

CONCLUSION

This study demonstrates the potential benefit of using multi-parametric MRI with deep learning to assist in RT treatment planning to reduce excessive treatment of normal brain parenchyma.
RADT-30. PROTON THERAPY FOR RE-IRRADIATION OF RECURRENT GLIOMA
Authors: Barbour Andrew , Halasz Lia
Published: November 2023

BACKGROUND

Proton therapy may improve the side effect profile of re-irradiation for recurrent glioma by limiting the overlap with previous radiation dose received by the brain. Limited data exist regarding the outcomes or side effects after proton re-irradiation.

METHODS

We retrospectively reviewed the charts of 43 consecutive adult patients with glioma treated with uniform scanning or pencil beam scanning proton re-irradiation from June 2014-June 2022. Outcomes were estimated utilizing Kaplan-Meier analysis.

RESULTS

Median age of the cohort was 45 years (range 19-74). Initial histologic diagnosis was glioblastoma for 18 (42%), astrocytoma for 16 (37%), oligodendroglioma for 8 (19%) and diffuse glioma NOS for 1 (2%) patient. The median initial prescription dose was 60 Gy (range 54-61.2 Gy) with 86% receiving concurrent temozolomide. The median interval between initial radiation therapy (RT) and re-irradiation was 51 months (range 6-185 months). The median re-irradiation dose delivered was 37.5 cobalt gray equivalent (CGE) in 15 fractions (range 6-50.4 CGE in 2-28 fractions) with 34 patients receiving this dose fractionation. Concurrent systemic therapy included bevacizumab (8), chemotherapy (5), immunotherapy (2) or none (28). Overall, 40 (93%) finished the planned course and three stopped early given progression. Median survival was 11.5 months for the full cohort (95% confidence interval: 6.8-13.6 months). For patients with glioblastoma, median survival was 6.4 months (95%CI 5.0-13.5 months). For patients without glioblastoma, median survival was 11.6 months (95%CI 9.2-34.3 months). Twelve patients (28%) developed symptomatic pseudoprogression/radiation necrosis, with ten requiring increased steroids and four requiring bevacizumab.

CONCLUSIONS

Proton re-irradiation was well tolerated in patients with recurrent glioma, with 6.4 and 11.6 month median survival estimates for glioblastoma and non-glioblastoma histologies, respectively. Symptomatic pseudoprogression/radiation necrosis was common. Further study is needed to determine whether proton re-irradiation has improved tolerability compared to photons.
RADT-33. ANALYSIS OF PATIENTS DIAGNOSED WITH ATYPICAL TERATOID RHABDOID TUMOR OF BRAIN AT TERTIARY CARE CENTER
Authors: Shah Setu , Mehta Maitrik , Pandya Akash , Parikh Ankita
Published: November 2023

Atypical Teratoid Rhabdoid Tumor (ATRT) of brain is highly malignant neoplasm with incidence of 1-2% among all pediatric CNS tumors characterized by mutations and subsequent inactivation of SMARCB1 (INI1, hSNF5) gene with dismal prognosis of about 6-18 months. On retrospective analysis of patients between 2010-2021 from Medical Record Department, only five cases of ATRT brain were retrieved. All patients were of pediatric age group (6 yr/F, 2yr/M, 6yr/F, 4yr/F, and 1yr/M – Median 4 yrs). On radiological findings, in four patients lesion was primarily in brain and in one patient with diffuse leptomeningeal enhancement. Three patients underwent craniotomy and gross total excision, and, in 2 patients only biopsy was done. In molecular analysis immunohistochemistry (IHC) markers were as follows. In all patients Vimentin and Synaptophysin were positive. EMA was positive in 3 patients, GPAP was positive in 3 patients, CD99 was positive in 2 patients, AE1 was positive in 2 patients. A specific marker for ATRT (INI1 loss) was seen in 3 patients. In other patients INI1 assessment could not be done. In two patients CSF cytology was negative, and, in all patients bone marrow examination was normal. One patient (4yr/F) received local radiotherapy with concurrent Vincristine based chemotherapy and lost to follow up (after 1 year of treatment). One patient (6yr/F) received vincristine based chemotherapy and local palliative radiotherapy and expired (after 1 month of treatment). One patient (6yr/F) received St Jude HR/IRS III protocol chemotherapy and craniospinal irradiation (CSI) and is still on follow up (total follow up period – 9 years). Two patients did not take any kind of treatment in whom one patient expired, another lost to follow up. Looking at rarity of tumors and with the review of literature, multiagent chemotherapy and Craniospinal irradiation seems to be promising approach for treatment of ATRT brain.
RADT-38. DOSE ESCALATED RADIOTHERAPY IS ASSOCIATED WITH IMPROVED OUTCOMES FOR HIGH GRADE MENINGIOMA
Authors: Liang Zeng K , Soliman Hany , Myrehaug Sten , Tseng Chia-Lin , Detsky Jay , Chen Hanbo , Lim-Fat Mary-Jane , Ruschin Mark , Atenafu Eshetu G , Keith Julia , Lipsman Nir , Heyn Chris , Maralani Pejman , Das Sunit , Pirouzmand Farhad , Sahgal Arjun
Published: November 2023

BACKGROUND

The optimal modern radiotherapy (RT) approach after surgery for atypical and malignant meningioma is unclear. We present results of dose-escalation.

METHODS

Consecutive patients with histopathologic grade 2 or 3 meningioma treated with RT were reviewed. A dose-escalation cohort [≥ 66Gy equivalent dose in 2 Gy fractions using an a/b = 10 (EQD2)], was compared to a standard dose cohort (< 66Gy). Outcomes were progression-free survival (PFS), cause-specific survival (CSS), overall survival (OS), local failure (LF) and radiation necrosis.

RESULTS

118 patients (111 Grade 2, 94.1%) were identified; 54/118 (45.8%) received dose-escalation and 64/118 (54.2%) standard dose. Median follow-up was 45.4 months (IQR: 24.0 - 80.0 months) and median OS was 9.7 years (Q1: 4.6 years, Q3: not reached). All dose-escalated patients had residual disease vs. 65.6% in the standard dose cohort (p < 0.001). PFS at 3-, 4- and 5-years in the dose-escalated vs. standard dose cohort were 78.9%, 72.2% and 64.6% vs. 57.2%, 49.1% and 40.8%, respectively, (p = 0.030). On multivariable (MVA) analysis, dose-escalation (HR: 0.544,p = 0.042) was associated with improved PFS, whereas ≥ 2 surgeries (HR: 1.989, p = 0.035) and older age (HR: 1.035, p < 0.001) were associated with worse PFS. The cumulative risk of LF was reduced with dose-escalation (p = 0.016). MVA confirmed dose-escalation protective for LF (HR: 0.483, p = 0.019), whereas ≥ 2 surgeries prior to RT predicted for LF (HR: 2.145, p = 0.008). A trend was observed for improved CSS and OS in the dose-escalation cohort (p < 0.1). Seven patients (5.9%) developed symptomatic radiation necrosis (RN) with no significant difference between the two cohorts.

CONCLUSIONS

Dose-escalated radiotherapy with ≥ 66Gy for high grade meningioma is associated with improved local control and PFS with an acceptable risk of RN.