bluuebunny/crossref_metadata_2025 huggingface dataset:
RADT-15. PREOPERATIVE SINGLE FRACTION RADIOSURGERY VERSUS POSTOPERATIVE FRACTIONATED RADIOSURGERY FOR RESECTED BRAIN METASTASES: A BI-INSTITUTIONAL ANALYSIS OF SAFETY AND CLINICAL OUTCOMES
Authors: Prabhu Roshan , Shi Siyu , Dhakal Reshika , Soltys Scott , Burri Stuart , Asher Anthony , Gephart Melanie , Ward Matthew , Li Gordon , Heinzerling John , Pollom Erqi
Published: December 2020

BACKGROUND

Preoperative single fraction radiosurgery (SRS) and postoperative fractionated SRS delivered over 3–5 fractions have been shown to have favorable outcomes compared to postoperative single fraction SRS for resected brain metastases. No study has directly compared these 2 treatment approaches.

METHODS

Records for patients with resected brain metastases treated with either single fraction preoperative SRS or fractionated (3-5 fractions) postoperative SRS were reviewed. Preoperative SRS was 10-20% dose reduced compared to standard and surgery generally followed within 48 hours. Eligibility criteria included solid tumor metastases, 1 brain metastasis resected, and no previous cranial RT. Fine-Gray and Cox multivariable (MVA) and propensity score matched (PSM) analyses were used.

RESULTS

A total of 330 patients (137 preoperative; 193 postoperative) were included. Median dose was 15 Gy in 1 fraction and 24 Gy in 3 fractions, respectively. In MVA, preoperative SRS was significantly associated with higher risk of cavity local recurrence (LR, hazard ratio (HR) 2.04, p=0.002) and lower risk of leptomeningeal disease (LMD, HR 0.41, p=0.05). There was no difference in adverse radiation effect (ARE) or overall survival (OS) between groups. In the PSM analysis (65 matched pairs), 1-year outcomes for preoperative vs. postoperative SRS were as follows - cavity LR: 22.9% vs. 3.1%, p< 0.001, LMD: 4.2% vs. 15.5%, p=0.04, ARE: 3.2% vs. 7.9%, p=0.73, composite endpoint (cavity LR, symptomatic ARE, or LMD): 27.6% vs. 20.1%, p=0.33, OS: 56.3% vs. 62.3%, p=0.8.

CONCLUSIONS

Preoperative single fraction SRS and postoperative fractionated (3-5 fractions) SRS demonstrate distinct patterns of failure. Compared to postoperative SRS, preoperative SRS was associated with increased risk of cavity LR and lower risk of LMD in both multivariable and PSM analyses. There was no difference in risk of ARE or OS. Methods to reduce preoperative SRS cavity LR, such as with higher dose fractionated regimens, should be considered.
RADT-16. HYPOFRACTIONATED RADIOTHERAPY AND STEREOTACTIC RADIOSURGERY FOR VESTIBULAR SCHWANNOMAS: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Tosi Umberto , Guadix Sergio , An Anjile , Wright Drew , Brandmaier Andrew , Knisely Jonathan , Pannullo Susan , Christos Paul , Ramakrishna Rohan
Published: December 2020

BACKGROUND

Vestibular schwannomas (VS) are tumors of the cerebellopontine angle with significant morbidity, causing hearing loss, tinnitus, and trigeminal and facial nerve compromise. Surgical resection is complex and often results in comorbidities, with radiation therapy being used to achieve tumor control. Both single dose stereotactic radiosurgery (SRS) and, in recent years, hypofractionated stereotactic radiotherapy (hSRT), where a total 18-25 Gy dose is given in approximately 3-5 fractions, have been utilized. It remains unclear, however, how each of these approaches fares compared to the other.

METHODS

Ovid MEDLINE, EMBASE, CINAHL, and Cochrane Reviews were searched for studies either comparing hSRT with SRS or focusing on hSRT alone for the treatment of VS. Primary endpoints included tumor control, serviceable hearing, presence of tinnitus, and facial and trigeminal nerve symptoms. A random effects analysis was employed to compare pre- and post-treatment effects (hSRT alone) or SRS and hSRT outcomes (two-arm studies).

RESULTS

This analysis included 21 studies focusing on hSRT alone and 13 studies comparing SRS and hSRT. Significant heterogeneity was observed. Overall, when hSRT was analyzed alone, crude tumor control was achieved in 93% of 1571 patients at average follow-up of 49.9 months. There was no difference intra-group between pre- and post-treatment odds ratios (OR) of tinnitus, facial, or trigeminal impairment. However, serviceable hearing was diminished following hSRT (OR = 0.60, 95% CI: 0.44, 0.83, p = 0.002). Comparison with SRS showed no difference with respect to tumor control (p = 0.84), serviceable hearing (p = 0.65), trigeminal impairment (p = 0.96), or facial nerve impairment (p = 0.32).

CONCLUSIONS

hSRT achieved excellent tumor control and, with the exception of serviceable hearing, did not result in worse cranial nerve symptomatology. Analyzing two-arm studies showed that hSRT is a treatment modality comparable to SRS with respect to tumor control and cranial nerve comorbidities.
RADT-27. ASSOCIATION BETWEEN ADJUVANT RADIATION THERAPY AND OVERALL SURVIVAL IN PLEOMORPHIC XANTHOASTROCYTOMA
Authors: Khalafallah Adham , Rakovec Maureen , Mukherjee Debraj
Published: December 2020

Pleomorphic Xanthoastrocytoma (PXA) is a low-grade central nervous system (CNS) tumor with a generally favorable prognosis. However, due to its rarity, optimal adjuvant treatment guidelines have not been established by large scale studies. In this study, we investigated the effect of adjuvant radiation therapy (RT) on overall survival (OS) in adult patients with PXA to help address this unanswered question. The National Cancer Database (NCDB) was used to identify adult patients (age 18 years old) diagnosed with histologically confirmed PXA (2004-2016). Patient demographics, tumor characteristics, and treatment information were collected. Kaplan-Meier curves were generated to study OS, and factors that affected OS were identified using a multivariate Cox proportional hazards (CPH) model. A total of 546 patients were identified. The average age of patients at diagnosis was 36.6 years old, and overall median survival was 128.6 months. RT was used to treat 179 (33.3%) patients. Those who received RT had a shorter median OS (33.3 months) compared to those who did not (> 128.6 months, p < 0.001). Our multivariate model demonstrated receiving RT was independently associated with a significantly higher risk of death (hazard ratio [HR]=4.28, 95% confidence interval [CI] = 1.77-10.38, p = .0013). Patients ≥ 65 years of age also demonstrated significantly higher risk of death (HR = 2.20, CI = 1.54-4.16, p = 0.006) and had a decreased median OS (26.0 months). In adults with PXA, treatment with RT is independently associated with a significantly higher risk of mortality. The routine use of this modality in treating PXA warrants further study.
RADT-31. PATTERNS OF CARE IN THE USE OF ADJUVANT RADIOTHERAPY AND CHEMOTHERAPY IN LOW GRADE GLIOMA PATIENTS IN THE UNITED STATES FROM 2010-2016
Authors: Rehrer Warren , Odia Yazmin , Rubens Muni , Kalman Noah , Chuong Michael , Kotecha Rupesh , Mehta Minesh , Hall Matthew
Published: December 2020

PURPOSE

In 2016, RTOG 9802 reported an overall survival advantage with the addition of chemotherapy to adjuvant radiotherapy (CRT) in patients with high-risk low grade glioma (LGG). We used the National Cancer Database (NCDB) to measure trends in CRT use in LGG patients from 2010-2016, a period when no Level 1 evidence existed.

METHODS

The NCDB was queried for WHO Grade II glioma patients treated from 2010-2016 who met the inclusion criteria for RTOG 9802. Adjusted logistic regression was used to assess the association of treatment year with the annual percentage of patients who received adjuvant CRT. Relative percent change and average annual percentage change (AAPC) were compared to determine if a change (defined a priori as < 0.01) occurred in the use of adjuvant CRT in LGG patients during this period.

RESULTS

The analytic cohort consisted of 5,039 patients; 64.3% of patients were 40 years or older and 35.7% were under 40 with subtotal resection. Use of adjuvant CRT increased from 18.9% to 49.7% (p< 0.001) during 2013-2016, with no change observed before 2013. The AAPC in the use of CRT was +39.6% per year (p< 0.001). Corresponding declines in patients treated with surgery alone (p< 0.001) and surgery plus radiotherapy (p< 0.001) were observed during 2013-2016. Logistic regression demonstrated patients who were under 40 years old were significantly less likely to receive adjuvant CRT than patients 40 years or older (Odds Ratio 0.561, 95% CI 0.475-0.663, p< 0.001). Use of adjuvant CRT increased from 12.5% to 45.1% in patients with oligodendroglioma during 2013-2016 (p< 0.001).

CONCLUSIONS

During 2013-2016, an increasing number of patients with LGG were treated with surgery followed by adjuvant CRT. Future studies may characterize the use of single agent vs. multiagent chemotherapy in this population and the adoption of trimodality therapy by mutation status.
RADT-33. RADIOSURGERY VERSUS COMBINATION RADIOSURGERY-BEVACIZUMAB FOR THE TREATMENT OF RECURRENT HIGH-GRADE GLIOMA: A SYSTEMATIC REVIEW
Authors: Kulinich Daniel , Sheppard John , Nguyen Thien , Kondajji Aditya , Unterberger Ansley , Enomoto Adam , Patel Kunal , Gopen Quinton , Yang Isaac
Published: December 2020

BACKGROUND

High-grade gliomas (HGG) comprise the most common primary adult brain cancers and universally recur. Combination re-radiation therapy (reRT) and bevacizumab (BVZ) therapy for recurrent HGG is common, but its reported efficacy is mixed.

OBJECTIVE

To assess clinical outcomes after reRT±BVZ in recurrent HGG patients receiving stereotactic radiosurgery (SRS), hypo-fractionated (HFSRT), or fully fractionated RT (FSRT).

METHODS

We performed a systematic review of PubMed, Web of Science, Scopus, Embase, and Cochrane databases, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We identified studies reporting outcomes for patients with recurrent HGG treated via reRT±BVZ. Cohorts were stratified by BVZ treatment status and reRT modality (SRS, HFSRT, and FSRT). Outcome variables were overall survival (OS), and progression-free survival (PFS).

RESULTS

34 of 1,742 identified articles survived inclusion criteria (2%) and reported data on 954 patients receiving reRT alone and 445 patients receiving reRT+BVZ. All patients initially underwent standard-of-care therapy for their primary HGG. In a multivariate analysis that adjusted for median patient age, WHO Grade, RT dosing, reRT fractionation regimen, time between primary and reRT, and reRT target volume, BVZ therapy was associated with significantly improved OS (2.51 [0.11, 4.92] months, P=.041) but no significant improvement in PFS (1.40 [-0.36, 3.18] months, P=.099). Patients receiving BVZ also had significantly lower rates of RN (2.2% vs 9.5%, P < .001).

CONCLUSIONS

Combination reRT+BVZ may improve OS and reduce rates of RN in recurrent HGG, but further controlled studies are needed to confirm these effects.
RADT-40. TRENDS IN THE USE OF RADIATION FOR MENINGIOMA ACROSS THE UNITED STATES
Authors: Matani Hirsch , Abel Stephen , Xu Linda , Yu Alexander , Ranjan Tulika , Karlovits Stephen , Wegner Rodney
Published: December 2020

BACKGROUND

Meningiomas are tumors originating from arachnoid cap cells on the surface of the brain or spinal cord. Treatment differs by grade but can consist of surgery, radiation therapy or both. We utilized the national cancer database (NCDB) to compare trends in the use stereotactic radiosurgery (SRS) and external beam radiation therapy (EBRT) in the management of meningioma.

METHODS

We queried the NCDB from 2004-15 for meningioma patients (Grade 1-3) treated with radiation therapy, either SRS or EBRT. Multivariable logistic regression was used to identify predictors of each treatment and to generate a propensity score. Propensity adjusted Kaplan-Meier survival curve analysis and multivariable cox hazards ratios were used to identify predictors of survival.

RESULTS

We identified 5406 patients with meningioma meeting above criteria. Median follow up was 43 months. 45%, 44%, and 11% were Grade 1, 2, and 3, respectively. Predictors for SRS were distance from treatment facility and histology. Predictors of EBRT were tumor size and WHO grade 2 or 3 disease. Tumor size, treatment year, and receipt of chemotherapy were associated with improved survival. Five and ten year survival rates were 89.2% vs. 72.6% (p < 0.0001) and 80.3% vs. 61.4% (p = 0.29) for SRS and EBRT respectively. After propensity matching 226 pairs were generated. For SRS, 5 year survival was not significantly improved at 88.2% (p = 0.056)

CONCLUSIONS

In the present analysis, predictors of SRS utilization in management of meningioma include distance from treatment facility and histology whereas conventional EBRT utilization was associated with tumor size and grade 2 or 3 disease. Despite a possible survival benefit with SRS, inherent selection bias may confound interpretation of the apparent survival benefit reflected in our study.
RADT-42. ADJUVANT RADIATION THERAPY FOR SUBTOTALLY RESECTED CEREBELLAR LIPONEUROCYTOMA
Authors: McClelland Shearwood , Gardner Ulysses , Shah Mitesh , Watson Gordon , Shiue Kevin
Published: December 2020

INTRODUCTION

Classified as a benign glioneural tumor, cerebellar liponeurocytoma is a rare disease (fewer than 80 reported cases) and was upgraded from WHO grade I to grade II in 2007 due to its high recurrence rate. The authors report a case of definitive radiation therapy for recurrent subtotally resected cerebellar liponeurocytoma.

METHODS

An 80-year-old man having undergone seven resections for his left cerebellar liponeurocytoma without adjuvant therapy over the previous decade at outside institutions was referred for radiation therapy two months following his eighth resection, where gross total resection was limited by the lesion proximity to his brainstem resulting in a 2 cm residual left cerebellar lesion. Pathology revealed tumor cells strongly positive for synaptophysin and a Ki-67 labeling index < 1%. Due to the propensity of this disease to recur following resection, his entire resection cavity was treated with external beam radiation therapy (EBRT) to 46 Gy, followed by a 10 Gy boost to his residual disease yielding a total of 56 Gy to the residual disease.

RESULTS

Reimaging following the initial 46 Gy revealed the residual disease remained amenable (< 3 cm) to stereotactic radiosurgery (SRS), which was delivered via linear accelerator (10 Gy to the 80% isodose line) in a single fraction. Following EBRT + SRS, the patient responded well. At last follow-up, he has demonstrated no evidence of disease progression, brainstem-related morbidity or surgical incision-related morbidity.

CONCLUSIONS

The first reported case of SRS treatment of cerebellar liponeurocytoma as the culmination of a coordinated definitive plan beginning with EBRT supports the applicability and feasibility of this treatment strategy following subtotal resection. This case indicates that a radiation treatment plan similar to that for central neurocytoma may be an optimal strategy, and suggests that adjuvant radiation therapy following operative resection of this rare disease may be underutilized.
RADT-43. TREATMENT OF RETROPERITONEAL LEIOMYOSARCOMA BRAIN METASTASES WITH STEREOTACTIC RADIOSURGERY
Authors: McClelland Shearwood , Gardner Ulysses , Langer Mark , Shiue Kevin
Published: December 2020

INTRODUCTION

Retroperitoneal leiomyosarcoma is a relatively rare disease, with infrequent metastatic spread to the CNS. We present the first report of radiosurgical treatment of this disease.

METHODS

A 49-year-old woman developed leiomyosarcoma of the inferior vena cava and retroperitoneum with lung metastases on diagnosis. Following multiple courses of systemic and operative treatment, she developed a tender ulcerating mass in the left upper maxillary incisor associated with numbness along the upper gum, lip, and premaxillary area. CT revealed a 3.0 cm left posterior alveolar ridge gum lesion with bone invasion, for which she elected to undergo palliative radiation therapy (30 Gy in 10 fractions). Due to potential maxillary nerve involvement altering the intended radiation therapy treatment fields, an orbit/face MRI was performed to better delineate the lesion. On this MRI, two frontal lobe lesions were visualized; subsequent dedicated brain MRI revealed a total of five metastases (0.9 cm right superior frontal gyrus, 0.9 cm left middle frontal gyrus, 0.9 cm right postcentral gyrus, 0.7 cm right occipital, and 1.6 cm left occipital). Consequently, the decision was made to treat the brain metastases with linear accelerator (LINAC) stereotactic radiosurgery (SRS) to allow simultaneous treatment of the maxillary lesion and brain metastases.

RESULTS

A single CT simulation was performed for her intracranial and extracranial disease, using the Encompass face mask to allow for simultaneous head immobilization and optimal SRS targeting accuracy. LINAC SRS was delivered simultaneously during maxillary lesion radiation therapy to all five lesions (22 Gy to the 80% isodose line) in a single fraction with a 0.2 cm planning target volume (PTV) margin for each lesion.

CONCLUSIONS

The first reported case of metastatic retroperitoneal leiomyosarcoma brain metastases treated with SRS demonstrates the flexibility of LINAC (rather than Gamma Knife) SRS in allowing for simultaneous treatment of intracranial and extracranial metastatic disease.
RADT-45. EFFECT OF DIFFERENT RADIOTHERAPY TECHNIQUES ON HEMATOLOGICAL TOXICITY OF CRANIOSPINAL IRRADIATION
Authors: Zhang Yangqiong , Yang Huajun , Deng Guanhua , Luo Rishun , Zhang Ping , Cai Linbo
Published: December 2020

OBJECTIVE

To investigate the effect of different radiotherapy techniques on hematological toxicity of craniospinal irradiation.

METHODS

A retrospective study involving changes in hematology during craniospinal irradiation were conducted. 79 patients were divided into observation group and control group. 36 patients in observation group received intensity modulated radiation therapy and 43 patients in control group received three-dimensional conformal radiotherapy. The prescribed dose of PTV in the two groups are 28.8-36 Gy, and the single dose are 1.6-2.0 Gy. The hematological toxicity changes and bone marrow suppression stage of the two groups of patients before, during and after radiotherapy were recorded and analyzed.

RESULTS

90% of patients showed different bone marrow suppression stage during and after radiotherapy. During radiotherapy, the toxicity of hemoglobin in the observation group was more serious than that in the control group (z=-2.272, p=0.023). After radiotherapy, the toxicity of hemoglobin and white blood cells in the observation group was more serious than that in the control group (z=-3.053, p=0.002; z=-3.163, p=0.002).

CONCLUSION

We should closely observe the changes of hematological toxicity for craniospinal irradiation patient treated with IMRT and take corresponding preventive measures to avoid serious bone marrow suppression stage.
RBIO-02. COMBINING RADIOTHERAPY WITH PI3K ISOFORM-SPECIFIC INHIBITOR DECREASES RADIORESISTANCE AND SUPPRESSES TUMOR GROWTH IN GLIOBLASTOMA CELLS
Authors: Youn Seol Mi , Yoon Hong In
Published: December 2020

Glioblastoma (GBM) is the most malignant tumor that occurs within the brain and shows the dismal prognosis. The phosphoinositide 3-kinase (PI3K)-AKT signaling pathway plays a principal role in GBM. Also, Activated PI3K-AKT signaling by irradiation induces radioresistance. But, the pan-PI3K inhibitors cause side-effects in clinical trial. Different PI3K isoforms play non-redundant roles in brain tumor growth and regulating radioresistance. So it is expected that selective inhibition of PI3K isoforms decrease side effects. We demonstrated whether combining radiotherapy with the PI3K isoform inhibitor reduces radioresistance and tumor growth in GBM. Glioma261 expressed luciferase (GL261-luc) cell lines were used to investigate the synergistic effects of combining radiotherapy with the PI3K isoform inhibitors. GL261-luc were irradiated 1Gy with or without PI3K isoform inhibitors. GL261-luc irradiated by 1Gy was suppressed cell proliferation about 70% compared to control (p< 0.001). When irradiated with PI3K-isform inhibitor, each growth rate was about 18% (PI3K-pan, p< 0.00001), 25% (PI3K-alpha, p< 0.00001), 30% (PI3K-delta, p< 0.00001), 45% (PI3K-gamma/delta, p< 0.00001). Significant increase of DNA DSB and decrease of the migration ability were shown by combination radiotherapy with PI3K- isoform inhibitor. Especially, combining radiotherapy, PI3K-alpha inhibitor showed the effect similar to PI3K-pan inhibitor (In vitro). So, we analyzed combination therapy effects using PI3K-alphs inhibitor and radiotherapy in vivo. We demonstrated that combining radiotherapy with the PI3K-alpha isoform inhibitor markedly delayed tumor growth than radiotherapy only (p< 0.0001). Also, we confirmed that survival rate of intracranial GBM mouse was increased by combination therapy (p< 0.01). In addition, the expression of PD1, regulator of cancer immune system, in spleenocyte was increased by combination therapy (p< 0.001) (In vivo). Our results demonstrate that combining radiotherapy with the PI3K-alpha isoform improve radiosensitivity, which result in significant tumor growth delay and improved survival.
STEM-03. WAVE1 KNOCKDOWN ENHANCES THE ANTITUMOR EFFICACY IN PRIMARY GLIOBLASTOMA NEUROSPHERES
Authors: Namagiri Sriya , Thammegowda Shilpa , Sur Hannah , Vézina Amélie , Chowdhury Ashis , Maric Dragan , Gangaplara Arunakumar , Edwards Nancy , Jackson Sadhana , Ray-Chaudhury Abhik , Heiss John , Banasavadi-Siddegowda Yeshavanth Kumar
Published: December 2020

INTRODUCTION

Despite multi-model therapies that include maximal surgical resection, radiation, chemotherapy, and tumor treating fields, the median survival of Glioblastoma (GBM) patients is around 15 months. WASP-family verprolin homologous protein 1 (WAVE1) is a downstream effector that receives signals from small GTPases to regulate the actin cytoskeleton. WAVE1’s interaction with arp2/3 modulates critical roles, such as cell motility and morphologic changes. Expression of WAVE1 has been implicated in leukemia, ovarian, and prostate cancer. In this study, we tested the role of WAVE1 in GBM tumor biology.

METHODS

Expression of WAVE1 in normal brain and GBM tumor specimens was assessed by immunohistochemistry (IHC). The relevance of targeting WAVE1 for GBM therapy was evaluated in vitro by western blot, proliferation assay, cell cycle analysis, apoptosis assay, migration assay, and neurosphere formation assay using scrambled and target specific WAVE1-siRNA in patient-derived primary GBM neurospheres (GBMNS).

RESULTS

IHC data shows that the expression of WAVE1 is higher in GBM tumor samples than in low-grade gliomas and normal brain tissues. WAVE1 expression is upregulated in GBMNS compared to normal human astrocytes. WAVE1 knockdown significantly decreased the proliferation, migration, and self-renewal of GBMNS without affecting its cell cycle progression. Furthermore, WAVE1 depletion did not show any alterations in the apoptotic cell population, indicating that WAVE1 knockdown has a cytostatic effect on GBMNS.

CONCLUSION

Expression of WAVE1 positively correlates with GBM, and its knockdown imparts antitumor efficacy through cytostasis.
STEM-05. SINGLE CELL SEQUENCING CHARACTERIZES SPATIAL AND TEMPORAL RELATIONSHIPS OF ENHANCING AND NON-ENHANCING REGIONS IN HIGH-GRADE GLIOMA
Authors: Patel Kunal , Kawaguchi Riki , Alvarado Alvaro , Muthukrishnan Deepthi , Everson Richard , Liau Linda , Geschwind Daniel , Ellingson Benjamin , Kornblum Harley
Published: December 2020

INTRODUCTION

Treatments of high grade glioma focus on the contrast enhancing (CE) portion of the tumor. However, given the invasive nature of glioma, residual tumor cells responsible for recurrence likely exist in the non-enhancing (NE) region.

METHODS

In 3 patients undergoing surgery for malignant glioma, we used pre-operative magnetic resonance images to prospectively identify biopsy targets in the CE region and locations 0.5-2.0cm beyond the CE edge. We carried out single cell sequencing on image guided biopsy specimens to generate 12,528 RNA profiles.

RESULTS

In all samples, tumor cells clustered into three predominant groups: tumor cells with astrocyte markers (ASC-like), tumor cells with oligodendrocyte markers (ODC-like), and tumor cells with neither marker. This last group consisted of a small proportion of tumor cells and expressed putative stem cell markers (PROM1, NES, SLC1A3, A2B5, ID1). A trajectory analysis consistently positioned this group as branching off into either ASC-like or ODC-like cells. CE regions had different cellular compositions than NE regions, with higher proportions of tumor, endothelial cells, T-cells, and NK cells. Using location and cell density data, we modeled expected tumor burden, predicting tumor cells up to 1.5cm beyond the CE region of the tumor. There were significant differences in gene expression between CE and NE tumor cells, with increased inflammation and hypoxia in the CE region versus increased proliferative markers in the NE region. Tumor cells in the NE region were characterized by increased proliferation, markers of invasion, and markers of self-renewal.

CONCLUSIONS

Single cell sequencing illustrates multiple glioma cell types and suggests a hierarchical relationship between tumor cell types. CE and NE regions exhibit different tumor and non-tumor cell populations as well as different gene expression profiles within individual cell types. There remains a significant tumor cell burden in the NE portion of tumor, including actively proliferating cells.
STEM-10. LONG-LASTING TUMOR TREATING FIELDS (TTFIELDS) STIMULATION OF GLIOBLASTOMA PRIMARY CULTURE DAMAGES PREFERENTIALLY FULLY DIFFERENTIATED CANCER CELLS
Authors: Castiglione Stefania , Ranucci Matteo , Cannavale Gaetano , Cianci Francesca , Verduci Ivan , Mazzanti Michele
Published: December 2020

Glioblastoma (GBM) is the most aggressive among brain tumors. Radiotherapy and chemotherapy as adjuvant procedures after surgical removal of the tumor mass, are often accompanied by undesirable symptoms and result in an extremely poor prognosis. In the last twenty years, it has been demonstrated that the only treatment able to improve the life expectancy of patients with GBM has been Tumor Treating Fields (TTFields) application. However, despite different therapeutic actions, tumor relapse occurs inexorably in most of the patients. There is scientific consensus that tumor recurrence is due to a population of cells named GBM stem cells (GSCs). GSCs represent a restricted subpopulation in the tumor mass, which is mainly composed of bulk cells. The main characteristic of GSCs is their tumorigenic potential even if a small number of cells are left after surgery. Our working hypothesis is based on the evidence that TTFields destabilize the mitotic spindle of dividing cells. Thus, TTFields stimulation should preferentially target bulk cells because of their higher proliferation rate compared to GSCs. Preliminary experiments performed using GBM primary cultures obtained from patients’ biopsies confirmed the presence of two different cell populations. In GBM, primary cultures maintained in stem-cell permissive medium, more than 70% of cells do not show stemness properties. After 72 hours of TTFields stimulation, almost 50% of the cells die. The remaining cells were more than 50% positive for CD44, SOX2, OCT4, and Nanog stemness markers, suggesting an enrichment of GSCs within the population. Following long lasting stimulation (up to 288 hours), GSCs percentage further increased and, more importantly, cells restored their ability to proliferate. In conclusion, TTFields treatment demonstrated efficacy by delaying GBM expansion. However, to prevent GBM relapse, it is imperative to increase the inhibitory efficiency of TTFields, specifically on GBM stem cell growth.
STEM-13. FUNCTIONAL CHARACTERIZATION OF THE ZFHX4-CHD4 INTERACTION IN GLIOBLASTOMA CANCER STEM CELLS
Authors: Galdieri Luciano , Grinwald Mitchell , Gugala Zibi , Oates Edward , Chheda Milan
Published: December 2020

Glioblastoma stem cells (GSCs) they may be one reason for inevitable recurrence of GBM. We previously discovered that Zinc Finger Homeobox 4 (ZFHX4), a 450kD transcription factor, is required to maintain the GSC state. ZFHX4 interacts with CHD4, a core member of the nucleosome remodeling and deacetylase (NuRD) complex, which activates or represses gene expression via two distinct functions - histone deacetylation and ATP-dependent chromatin remodeling. CHD4 suppression phenocopies ZFHX4 suppression. The precise nature and function of the ZFHX4 interaction with CHD4 is not understood. Here we report that the ZFHX4-CHD4 interaction requires a single zinc-finger domain. An incremental truncation screen revealed that ZFHX4 amino acids 1838 to 2387, which contains zinc fingers 14 and 15, are required to bind CHD4. Disrupting the zinc coordination of zinc finger 14 impaired the ZFHX4-CHD4 interaction. Moreover, by overexpressing ZFHX4 amino acids 1838 to 2487, we decreased CHD4 recruitment to transcription regulatory regions of the stem cell genes SOX2 and SOX9, decreased transcription, and reduced clonogenic self-renewal. These results may provide the structural basis for new treatments to target GSCs and prevent recurrence in this devastating disease.
STEM-15. SMALL BUT FIERCE: THE ROLE OF EXTRACELLULAR VESICLES IN MESENCHYMAL TRANSITION AND THERAPEUTIC RESISTANCE IN GLIOBLASTOMA
Authors: Schweiger Markus , Li Mao , Fleming Renata , Tabet Elie , Würdinger Thomas , Tannous Bakhos
Published: December 2020

Glioblastoma (GBM) is a dismal disease and despite optimal treatment, long-term survival remains uncommon. Molecular classification revealed three distinct GBM subgroups and has helped to shine light on the tumor’s inter/intratumoral heterogeneity. Interestingly, recent evidence shows plasticity between these subtypes in which the proneural (PN) glioma stem-like cells undergo transition into the more aggressive mesenchymal (MES) subtype leading to therapeutic resistance. Extracellular vesicles (EVs) are considered a heterogeneous group of membrane-limited vesicles secreted by nearly every cell. In the context of GBM, these biological nanoparticles act as multifunctional signaling complexes and play an important role in intercellular communication allowing cancer cells to exchange information with each other, the tumor microenvironment, and distant cells. We show that MES cells derived EVs modulate PN cells to increase migratory potential, stemness, invasiveness, aggressiveness, and therapeutic resistance by inducing mesenchymal transition through NF-KB/STAT3 signaling. Furthermore, we shine light on the role of EVs derived from irradiated GBM cells and their potential impact on microglia and resulting treatment resistance.
STEM-21. CLINICAL RELEVANCE OF CANCER STEM CELL CYTOTOXICITY ASSAY IN GUIDING TREATMENT FOR GLIOBLASTOMA
Authors: Pier Paolo Claudio , Ranjan Tulika , Howard Candace , Yu Alexander , Xu Linda , Aziz Khaled , Jho David , Leonardo Jodi , Denning Krista , Valluri Jagan
Published: December 2020

BACKGROUND. The prognosis of glioblastoma (GBM) treated with standard-of-care regimens remains very poor with a median time to recurrence of 7-9 months, and a median survival of 15-18 months. GBMs contain a small, but resilient population of cancer stem cells (CSCs) that contribute to tumor initiation, maintenance, and therapy resistance. For these reasons, its is extremely important to determine the sensitivity of CSCs to chemotherapeutic agents, with the intent of identifying more effective treatment protocols which would then translate into improved clinical survival. METHODS. We have used a novel CLIA and CAP-accredited Cancer Stem Cell Cytotoxicity Assay (ChemoID) to guide treatment for 55 Grade III and Grade IV glioma patients with the most efficacious chemotherapy treatments from a panel of FDA approved drugs or their combinations. Patients were evaluated by MRI scans and response was assessed according to RANO criteria. RESULTS: We report here a prospective clinical investigation using the ChemoID assay to measure the sensitivity and resistance of CSCs and bulk of tumor cells cultured from 55 GBM clinical specimens challenged with several chemotherapy agents, which were also correlated to the clinical response of the treated patients, independently of other biomarkers. The median recurrence time was 15 months for patients with a sensitive (>40% cell kill) CSCs test versus only 6 months for patients with a resistant CSCs test. CONCLUSIONS. The data suggests that GBM patients treated with CSC Cytotoxicity Assay-guided responsive drugs have delayed time to recurrence and the assay has the potential to help tailor chemotherapy choices to improve clinical outcomes.
STEM-23. INHIBITING PROTEIN PHOSPHATASE 2A INCREASES THE ANTITUMOR EFFECT OF PROTEIN ARGININE METHYLTRANSFERASE 5 INHIBITION IN MODELS OF GLIOBLASTOMA
Authors: Kumar Banasavadi Siddegowda Yeshavanth , Sur Hannah , Otani Yoshihiro , Rachaiah Guruprasad , Namagiri Sriya , Chowdhury Ashis , Lewis Cole , Shimizu Toshihiko , Gangaplara Arunakumar , Wang Xiang , Vézina Amélie , Maric Dragan , Jackson Sadhana , Yan Yuanqing , Zhengping Zhuang , Ray-Chaudhury Abhik , Kumar Sachin , Chittiboina Prashant , Heiss John , Yoo Ji Young , Kaur Balveen
Published: December 2020

BACKGROUND: Despite multi-model therapy of maximal surgical resection, radiation, chemotherapy, and tumor treating fields, median survival of Glioblastoma (GBM) patients is less than two years. Protein Arginine Methyltransferase 5 (PRMT5) catalyzes the symmetric di-methylation of arginine residues and is overexpressed in GBM. Inhibition of PRMT5 causes senescence of immature GBM tumor cells. LB100, first-in-class small molecule inhibitor of Protein Phosphatase 2A (PP2A) can sensitize therapy-resistant tumor cells. Here, we tested the anti-GBM effect of concurrent PRMT5 and PP2A inhibition. Methods: Patient-derived primary GBM neurospheres (GBMNS), transfected with PRMT5 target-specific siRNA were treated with LB100 and subjected to in vitro assays including PP2A activity and western blot. The intracranial mouse xenograft model was used to test the in vivo antitumor efficacy of combination treatment. Results: We found that PRMT5-depletion increased PP2A activity in GBMNS. LB100 treatment significantly reduced the viability of PRMT5-depleted GBMNS compared to PRMT5 intact GBMNS. LB100 enhanced the G1 cell cycle arrest induced by PRMT5-depletion. Combination therapy also increased the expression of phospho-MLKL. Necrostatin-1 rescued PRMT5-depleted cells from the cytotoxic effects of LB100, indicating that necroptosis caused the enhanced cytotoxicity of combination therapy. In the in vivo mouse tumor xenograft model, LB100 treatment combined with transient depletion of PRMT5 significantly decreased tumor size and prolonged mice survival, while LB100 treatment alone had no survival benefit. Conclusion: Overall, combined PRMT5 and PP2A inhibition had significantly greater antitumor effects than PRMT5 inhibition alone.
STEM-28. NANOPARTICLES ENCAPSULATING A CONNEXIN43 MIMETIC PEPTIDE LIMIT GLIOMA STEM CELL SURVIVAL AND GLIOBLASTOMA PROGRESSION
Authors: Will John , Thompson Emily , Harrigan Megan , Smyth James , Sheng Zhi , Gourdie Robert , Sontheimer Harry , Foster Johan , Lamouille Samy
Published: December 2020

Glioblastoma (GBM) is the most common and aggressive primary adult brain tumor in the US. The current treatment regimen for GBM still retains an alarmingly poor prognosis, with median survival of only 14.6 months. Failure to generate more effective treatment strategies is due to the infiltrative nature of GBM tumor cells, which hinders complete surgical resection, and cellular heterogeneity within GBM tumors, with a sub-population of glioma stem cells (GSCs) resistant to irradiation treatment and chemotherapeutic agents including temozolomide. As a result, all treated GBM patients will experience tumor recurrence, highlighting the need for novel approaches in targeting such refractory tumor cell populations to successfully treat GBM tumors and prevent recurrence. Using super resolution localization microscopy, we have identified that increased interaction of connexin43 (Cx43) with microtubules in GSCs confers tumorigenic behavior to these cells. We employed a Cx43 mimetic peptide named JM2 (juxtamembrane 2) that encompasses the microtubule binding sequence of the Cx43 carboxy-terminus. This peptide drug efficiently and specifically disrupts the interaction of Cx43 with microtubules and limits GSC survival, proliferation, and migration, without affecting normal human astrocytes. Next, we implemented the therapeutic strategy of JM2 encapsulation within biodegradable polymeric nanoparticles (NPs) to reduce administration frequency and patient discomfort, and increase peptide stability and activity. We confirmed sustained release of JM2 from these poly(lactic-co-glycolic) acid biodegradable NPs, and JM2 bioactivity through disruption of Cx43 interaction with microtubules. Administration of JM2-NPs inhibits GSC-derived neurosphere formation in vitro and patient GBM-derived organoid growth ex vivo. Finally, using an orthotopic xenograft brain tumor mouse model, we demonstrate in vivo that JM2-NPs significantly decrease the number of GSCs within brain tumors, and inhibit the formation of highly invasive GBM tumors. Our findings on generation of JM2-NPs to target GSC survival lays the foundation for future clinical trials in newly diagnosed GBM patients.
STEM-30. NECROPTOTIC ASTROCYTES CONTRIBUTE TO MAINTAINING STEMNESS OF DISSEMINATED MEDULLOBLASTOMA THROUGH CCL2 SECRETION
Authors: Liu Hailong , Sun Youliang , Franco-Barraza Janusz , Wang Z John , Yu Xinguang , Feng Shiyu
Published: December 2020

Medulloblastoma (MB) with metastases at diagnosis and recurrence correlates with poor prognosis. Unfortunately, the molecular mechanism underlying metastases growth has received less attention than primary therapy-naïve MB. Though astrocytes have been frequently detected in brain tumors, their roles in regulating the stemness properties of MB stem-like cells (MBSCs) in disseminated lesions remain elusive. Effects of tumor-associated astrocytes (TAA)-secreted CCL2 on MBSCs self-renewal was determined by immunostaining analysis. Necroptosis of TAA was examined by measuring necrosome activity. Alterations in Notch signaling were examined after inhibition of CCL2. Progression of MBSCs-derived tumors was evaluated after pharmaceutical blockage of necroptosis. TAA, as the essential components of disseminated tumor, produced high level of CCL2 to shape inflammation microenvironment, which stimulated the enrichment of MBSCs in disseminated MB. In particular, CCL2 played a pivotal role in maintaining stem-like properties via JAK2/STAT3 mediated activation of Notch signaling. Loss of CCL2/CCR2 function repressed JAK2/STAT3-Notch pathway and impaired MBSCs proliferation, leading to a dramatic reduction of stemness, tumorigenicity and metastasizing capability. Furthermore, necroptosis-induced CCL2 release depended on RIP1/RIP3/MLKL activation in TAA, which promoted the oncogenic phenotype. Blockade of necroptosis resulted in CCL2 deprivation and compromised MBSCs self-proliferation, indicating MBSCs outsourced CCL2 from necroptotic TAA. Finally, CCL2 was upregulated in high-risk stages of MB, further supporting its value as a prognostic indicator. These findings highlighted the critical role of CCL2/CCR2 in Notch signaling activation in MBSCs, and revealed a necroptosis-associated glial cytokine microenvironment driving stemness maintenance in disseminations.
SURG-07. DETECTION OF GLIOMA INFILTRATION AT THE TUMOR MARGIN USING QUANTITATIVE STIMULATED RAMAN SCATTERING MICROSCOPY
Authors: Pekmezci Melike , Morshed Ramin , Chunduru Pranathi , Pandian Balaji , Young Jacob , Villanueva-Meyer Javier , Tihan Tarik , Sloan Emily , Aghi Manish , Molinaro Annette , Berger Mitchel , Hervey-Jumper Shawn
Published: December 2020

BACKGROUND

Differentiating neoplastic tumor tissues from normal brain at the infiltrative tumor margin remains challenging. Stimulated Raman scattering microscopy (SRM) is a rapid, label-free technique that provides microscopic imaging of unprocessed tissues. However, it has never been studied as a tool to enhance extent of resection.

METHODS

In this single center study, patients with WHO II-IV gliomas undergoing surgical resection were included. Margin samples were taken with corresponding stereotactic coordinates. Each tumor margin sample was analyzed using (1) H&E, (2) SRM, and (3) immunohistochemical (IHC) stains for IDH1-R132H or p53. Specimens were imaged fresh with SRM, inked for orientation and placed in formalin for routine processing. Stained slides were scored by 3-neuro-pathologists using a semiquantitative 2-tiered scoring system for the presence or absence of residual tumor. SRM microscopy images were segmented into cellularity. The intraobserver measure of agreement between modalities for each pathologist was calculated using Cohen’s kappa.

RESULTS

A total of 31 patients and 179 margin specimens were acquired. Postoperative MRI confirmed that 169 (94%) of glioma margin sample coordinates were indeed at the tumor margins (10 of 179 were not true margins). All 10 samples which were not true margins were identified as having residual tumor by SRM. IHC semiquantitative scoring of margin specimen confirmed 72 of 128 samples (56%) had residual tumor. Similarly, H&E-scoring confirmed 82 of 169 samples (49%) and 82 of 167 samples (49%) by SRM-scoring had residual tumor. Intraobserver agreements between all 3 modalities confirmed agreement: IHC-SRM was near perfect (K-0.84, CI-0.750-0.94); IHC-H&E substantial, (K-0.67 CI-0.54-0.80); SRM-H&E agreement substantial (K-0.72 CI-0.62-0.83). Margin samples with residual tumor demonstrated higher tissue cellularity when compared with samples without tumor (p< 0.0001).

CONCLUSIONS

SRM allows for identification of residual microscopic disease at the infiltrative tumor margin and therefore may be a promising tool to enhance extent of resection.
SURG-08. AWAKE CRANIOTOMY WITH BRAIN MAPPING FOR DIFFUSE LOW-GRADE GLIOMA: CASE REPORT OF INSTITUTIONAL EXPERIENCE IN OVERCOMING HURDLES IN A LOW-RESOURCE SETTING
Authors: Manigos Kirby , Ferraris Kevin Paul , Navarro Joseph Erroll , Seng Kenny , Alcazaren Jose Carlos
Published: December 2020

Maximal safe resection of low-grade gliomas located in functional areas of the cortex while avoiding postsurgical neurologic deficits can be achieved by awake craniotomy with brain mapping. The effectiveness of this surgical technique is fairly established in the developed world, however it remains to be routinely applied in low-middle income countries due to limited resources and lack of equipment. We present the case of a 44 year-old, right-handed male who had a 2-year history of focal aware motor seizures but was otherwise neurologically intact. Neuropsychological testing revealed no cognitive impairment. Cranial magnetic resonance imaging (MRI) revealed a non-enhancing, ill-defined tumor centered on the left insula and extending into the frontotemporal opercula, corona radiata, and posterior limb of the internal capsule—hypointense by T1-weighted sequence and hyperintense by T2-weighted sequence, thus radiographically consistent with diffuse low-grade glioma. Blood-oxygen-level-dependent functional MRI revealed left hemispheric language dominance in the cortex overlying the tumor, but with no motor cortex involvement. The patient underwent a protocol-driven awake craniotomy, intraoperative positive brain mapping using standard cortical stimulator, transsylvian and transcortical transopercular microsurgical approaches to achieve greater than 80% excision of the tumor. Postoperatively, the patient was seizure-free and with similar neurocognitive status prior to the surgery. The patient had been following up for standard adjuvant chemotherapy and radiotherapy. Avoidance of postsurgical neurologic deficits and maximal cytoreduction can still be achieved by awake craniotomy with brain mapping in settings with limited resources. Despite the lack of other perioperative tools and adjuncts such as diffusion tensor imaging, intraoperative ultrasonography, and even intraoperative MRI that are routinely available in high-resource settings, we illustrate in this case that comparable outcomes could be achieved by overcoming hurdles and aiming for the asymptote to the up-to-date and ideal neurosurgical treatment for diffuse low-grade gliomas.
SURG-19. EVALUATION OF SERUM NEURON SPECIFIC ENOLASE, INTERFERON-ALPHA, AND INTERFERON-GAMMA IN RESPONSE TO LASER ABLATION OF HIGH GRADE GLIOMAS
Authors: Bartlett Seamus , Nagaraja Tavarekere , Schultz Lonni , Ewing James , Brown Stephen , Knight Robert , Lee Ian
Published: December 2020

BACKGROUND

The blood-brain barrier (BBB) is a formidable obstacle in the treatment of gliomas. It has been speculated that the BBB may be temporarily disrupted in laser ablation, a relatively new treatment used for newly diagnosed and recurrent high grade gliomas (HGG). BBB disruption can be measured non-invasively through serum neuron specific enolase (NSE) levels. In addition to disrupting the BBB, laser ablation could trigger an immune response in brain that has yet to be studied. Interferon-alpha (IFN-α) and interferon-gamma (IFN-ɣ) are cytokines used as serum markers for an immune response.

OBJECTIVE

To measure NSE and IFN-α and IFN-ɣ as serum markers for BBB disruption and brain immune response activation, respectively, in patients undergoing laser ablation for recurrent high grade gliomas.

METHODS

Sixteen patients with recurrent HGG underwent laser ablation from 2/2017 to 12/2019. All 16 patients had gross total ablation of the contrast enhancing mass. Serum levels of NSE, IFN-α, IFN-ɣ were measured pre-operatively and at 24 hours, 2 weeks, and 8-16 weeks post-operatively, depending on adjuvant treatment received post-operatively.

RESULTS

Levels of NSE consistently increased 24 hours post-operatively (2.28±0.37 ng/ml) compared to pre-operative levels (1.62±0.29 ng/ml), p=0.032. Afterwards, NSE decreased and reached baseline by 2 weeks postoperatively (2 weeks- 1.67±0.29 ng/ml, 8 weeks- 1.85±0.91 ng/ml, 12 weeks- 0.81±0.33 ng/ml, 16 weeks- 1.23±0.93 ng/ml). Compared to their pre-operative levels, IFN-α and IFN-ɣ (85.46±35.29 and 1.62±0.47 pg/ml, respectively) did not display a significant difference in their serum levels (p=0.26-0.72 and 0.14-0.60, respectively, for IFN-α and IFN-ɣ) at any post-operative measurement time. Conclusions: Elevated NSE levels following laser ablation in HGG indicate a temporary disruption of the BBB that persists for approximately 2 weeks without eliciting an accompanying immune reaction in brain. Correlation studies with DCE-MRI are on-going.