bluuebunny/crossref_metadata_2025_split huggingface dataset:
NCOG-07. SURVIVAL BENEFIT OF RADIOTHERAPY AND SURGERY IN PATIENTS WITH LUNG CANCER BRAIN METASTASES WITH POOR PROGNOSIS FACTORS: A SINGLE-CENTER, RETROSPECTIVE, PROPENSITY SCORE MATCHING ANALYSIS
Authors: Liang Lun , Wang Zhenning , Duan Hao , Lu Jie , Jiang Xiaobing , Cui Run , Li Chang , Zhong Sheng , Guo Xiaoyu , Hu Hongrong , He Zhenqiang , Chen Likun , Mou Yonggao 
Published: November 2022

Abstract

PURPOSE
To investigate the effect of radiotherapy and surgery in patients with lung cancer brain metastases (BMs) with poor prognosis factors.

METHODS
We analyzed retrospectively 714 patients with lung cancer BMs. A 1:1 propensity score matching (PSM) was performed to balance potential confounders. Analyses of overall survival (OS) and risk factors for OS were assessed by log-rank test and Cox proportional hazard model.

RESULTS
Age ≥ 65 years, Karnofsky Performance Scale (KPS) score ≤ 70, anaplastic large-cell lymphoma kinase (ALK)/epidermal growth factor receptor (EGFR) wild type, extracranial metastases, non-surgery and non-radiotherapy led to poor prognosis. Patients were stratified according to these factors. Radiotherapy and surgery showed no survival benefit in patients with aged ≥ 65 years and pretreatment KPS score ≤ 70 before and after PSM. Before PSM,whole brain radiotherapy (WBRT) improved the OS and predicted good prognosis in patients with ALK/EGFR wild type or extracranial metastases. WBRT also predicted good prognosis in patients with non-surgery. Stereotactic radiosurgery (SRS) improved the OS and predicted good prognosis in patients with ALK/EGFR wild type or non-surgery. WBRT plus SRS improved the OS and predicted good prognosis in patients with extracranial metastases or non-surgery. WBRT plus SRS also predicted good prognosis in patients with ALK/EGFR wild type. Surgery improved the OS and predicted good prognosis in patients with non-radiotherapy. After PSM, SRS improved the OS and predicted good prognosis in non-surgery patients. WBRT plus SRS improved the OS and predicted good prognosis in patients with non-surgery or extracranial metastases. WBRT plus SRS predicted good prognosis in patients with ALK/EGFR wild type. Surgery improved the OS of patients with non-radiotherapy.

CONCLUSIONS
Radiotherapy has significant survival benefit in patients with lung cancer BMs with poor prognosis factors, including patients with ALK/EGFR wild type or extracranial metastases or non-surgery. Surgery only has significant survival benefit in patients with non-radiotherapy.
NCOG-45. DIFFERENTIAL AND DOSE-DEPENDENT EFFECTS OF CRANIAL IRRADIATION ON BRAIN STRUCTURES AND NEUROPSYCHOLOGICAL OUTCOMES IN CHILDREN WITH POSTERIOR FOSSA BRAIN TUMORS TREATED WITH DIFFERENT MODALITIES
Authors: Dhanani Sofia , O'Neil Sharon , Cho Scarlet , Shin Brandon , Nelson Marvin , Wong Kenneth , Olch Arthur , Tanedo Jeffrey , Biele Oliver , Rodman Jack , Lepore Natasha , Nelson Mary 
Published: November 2022

Abstract

BACKGROUND
Studies investigating dose-dependent effects of cranial irradiation (CRT) in children with posterior fossa brain tumors are limited by examining combined effects of surgery, chemotherapy, and radiation. We aimed to determine alterations in brain volume and microstructure, and neuropsychological outcomes in children with posterior fossa tumors treated with surgery alone, surgery and chemotherapy, and surgery, chemotherapy, and CRT combined. We explored the relationship of radiation dose to the thalamus, putamen, and hippocampus to outcomes of intelligence, processing speed, executive functions, memory, and social/emotional functioning.

METHODS
Forty-seven children with treated posterior fossa tumors (17 with surgery; 11 with surgery and chemotherapy; 19 with surgery, chemotherapy, and CRT) underwent neuroimaging and neuropsychological assessment a mean of 4.8 years after treatment, along with 17 healthy sibling controls (n=64). The putamen, thalamus and hippocampus were manually segmented on MRI, and structural mean radiation doses were calculated. Differences in demographics and medical history were evaluated using χ2 and t-tests. Linear regression examined differences in neuropsychological performance, structural volumes, and diffusion indices. Pearson correlation explored relationships of structural radiation doses to diffusion indices and neuropsychological outcomes.

RESULTS
All patients scored lower on Block Design than controls (p=0.01), and the surgery and chemotherapy group scored the lowest. There was no significant difference in mean fractional anisotropy (FA) values in the thalamus, hippocampus and putamen between the three patient groups and controls. Hippocampal volume and mean radiation dose approached significant correlation (r= -0.49; p=0.07). Right putamen FA correlated with mean radiation dose (r=0.56; p=0.02). When controlling for age, thalamic volume was lowest in the irradiated group (p=0.02).

CONCLUSIONS
Treatment of pediatric posterior fossa brain tumors with surgery, chemotherapy, and CRT impacts thalamic volume and may have a dose-dependent effect on the microstructure of the putamen compared to treatment with surgery/chemotherapy.
EXTH-32. SEQUENTIAL SUNITINIB AND AURANOFIN TREATMENT INDUCEDCYTOTOXICITY THROUGH ROS-MEDIATED MECHANISM IN GLIOBLASTOMA
Authors: Bagchi Monisha , Jamali Fatemeh , Martinez-jaramillo Elvis , Sabri Siham , Abdulkarim Bassam 
Published: November 2022

Abstract
Glioblastoma (GBM) displays aberrant expression of several receptor tyrosine kinases (RTKs) leading to worse prognosis. Despite aggressive treatment including surgery, radiation and the alkylating agent temozolomide (TMZ), GBM tumors counteract deleterious effects of treatment-induced reactive oxygen species (ROS) leading to resistance to standard treatment. Likewise, expression of the DNA repair protein O6-methylguanine-DNA-methyltransferase (MGMT) plays a key role in resistance to TMZ.We previously reported a potential link between MGMT expression and decreased angiogenesis in GBM. The differential expression of MGMT affected response to sunitinib, a multitargeted RTK inhibitor with anti-angiogenic properties FDA-approved in different cancer types. Notably, TMZ-resistant GBM MGMT-positive cells were more vulnerable to sunitinib treatment compared to isogenic MGMT-negative cells. We further provided evidence for a positive relationship between MGMT and the antioxidant enzyme, thioredoxin reductase 1 (TrxR1) in GBM. The TrxR1-targeting drug Auranofin, FDA-approved for rheumatoid arthritis generated ROS and induced more cytotoxic effects in GBM cells displaying low expression of MGMT and TrXR1. We hypothesized that sunitinib-induced anti-proliferative effects might sensitize GBM cells to Auranofin. We showed that MGMT-negative GBM cells, which displayed lower levels of TrxR1, were more vulnerable to Auranofin than MGMT-positive cells. The ROS scavenger N-acetylcysteine (NAC) reverted the cytotoxicity of Auranofin suggesting ROS-mediated cytotoxic effects. Conversely, Sunitinib exhibited ROS-independent anti-proliferative effects in MGMT-positive cells. Remarkably, sequential treatment using sunitinib pre-treatment (2 hours) followed by Auranofin (24 hours) significantly decreased cell viability, clonogenicity, increased ROS, decreased TrXR1 and MGMT expression and sensitized MGMT-positive GBM cells resistant to Auranofin. NAC reverted these synergistic effects, suggesting ROS-mediated mechanism. Our study provides new insights into the modulation of the cellular redox homeostasis using sequential sunitinib and Auranofin. This will enable repurposing Auranofin and sunitinib, two drugs with a known safety profile for an effective therapeutic strategy for GBM patients.
EXTH-34. ANTI-RETROVIRAL REPURPOSING FOR TREATMENT OF GLIOBLASTOMA
Authors: Rivas Sarah , Govindarajan Vaidya , Valdez Mynor Mendez , Heiss John , Shah Ashish 
Published: November 2022

Abstract
Glioblastoma (GBM) is a WHO grade IV glioma whose heterogeneous nature and stem-like features contribute to resistance to conventional chemotherapeutics. Previously, antiretrovirals have been proposed as anti-neoplastic agents, but their clinical efficacy is limited. With the advent of modern anti-retroviral and combinatorial therapy, we sought to repurpose FDA-approved anti-retroviral drugs for glioblastoma. Here, we performed an unbiased screen of 16 antiretrovirals in 40 glioma cell lines using DEPMap for drug repositioning. We identified six potential antiretrovirals among several drug classes with significant anti-glioma activity: abacavir (ABC), lamivudine (LMV), raltegravir (RLT), darunavir (DAR), indinavir (IND), and etravirine (ETV). We validated the effects of six antiretrovirals on patient-derived GBM neurospheres (GBM28 and GBM43) and established glioma cell line (A172). The non-nucleoside reverse transcriptase inhibitor (ETV) had the lowest effective IC50 in chemoresistant PDX GBM neurospheres (15uM) and A172 cells (2.7uM). Synergy assessment of ETV with standard of care temozolomide (TMZ) demonstrated that these drugs work independently of one another (Bliss score of -0.39 and -0.83 in GBM 28 and GBM 43, respectively). In addition, we investigated ETV effect on stemness features and human endogenous retroviral elements. Western blot, immunofluorescence and qPCR showed a decrease in the stemness markers, OCT-4, and HERV-K env expression. Reverse transcriptase levels decreased significantly after sublethal ETV treatment (5uM) for 48 hours in the stem-like GBMNS but not in adherent A172 cells. Overall, several antiretroviral drugs could be repositioned for glioblastoma therapy. Given its ideal therapeutic index and ability to penetrate the blood-brain barrier, ETV may be a promising candidate for future clinical trials in neuro-oncology.
EXTH-60. ONCR-GBM, A NOVEL ARMED ONCOLYTIC HSV-1 VECTOR ENGINEERED FOR EFFICACY AND SAFETY IN GLIOBLASTOMA
Authors: Strathdee Craig , Giovannoni Federico , Molgora Martina , Kong Lingxin , Floyd Michael , Teng Jian , Gyulakian Yulia , Grzesik Peter , Farkaly Terry , Denslow Agnieszka , Feau Sonia , Jacques Judith , Kennedy Edward , Lerner Lorena , Quéva Christophe , Colonna Marco , Quintana Francisco 
Published: November 2022

Abstract
Glioblastoma (GBM) is the most common type of primary brain tumor in adults, with a 5-year overall survival of only 7%. Oncolytic viruses are a promising and active area of research in GBM with the recent approval of an oncolytic HSV-1 vector, teserpaturev (Delytact, also known as G47Δ, Daiichi Sankyo) for recurrent GBM based on an overall survival of 92% at 1 year. G207, an HSV-1 vector more attenuated than teserpaturev, recently reported acceptable tolerability with evidence of responses in children with recurrent or progressive high-grade glioma. These vectors are not expressing any cDNA transgene that may enhance and prolong antitumor activity. We report here the development of ONCR-GBM, an oncolytic HSV-1 vector specifically engineered for safety using a microRNA attenuation strategy to limit viral replication in healthy cell type of the CNS. ONCR-GBM has been developed from a novel potently oncolytic strain of HSV-1 and optimized for infection of GBM tumor cells. Antitumor efficacy has been further enhanced through the expression of multiple payloads designed to modify the immunosuppressive tumor microenvironment of GBM. We previously reported that a vector expressing IL-12 and a PD-1 antagonist nanobody achieved &gt; 90% survival after a single injection in the GL261-Nectin1 orthotopic model. This vector promoted immune cell recruitment and activation in tumors and protected surviving animals from a subsequent tumor rechallenge. Additional payloads selected for interfering with the immune suppressive stroma in GBM have been evaluated for potentiating the response of IL-12 and anti PD-1 expressing HSV-1. We will present the outcome of the in vivo screen, and the selection of the optimal combination of payloads featured in ONCR-GBM clinical candidate.
EXTH-69. ASTROCYTOMA CELLS HARBORING MUTANT IDH1 ARE UNIQUELY SENSITIVE TO INHIBITION OF OXIDATIVE PHOSPHORYLATION
Authors: Gurjar Anagha , Colman Howard , Holmen Sheri 
Published: November 2022

Abstract

BACKGROUND
Diffuse gliomas are the most common primary brain tumor in adults, affecting ~20,000 people in the United States each year. Current treatment modalities, which include surgery, radiation, and chemotherapy, are relatively ineffective against these tumors and the prognosis is poor. Although most cancer cells rely on glycolysis to generate ATP, IDH1 mutant gliomas show enhanced dependence on oxidative phosphorylation. Thus, we evaluated the effect of IACS-010759, a potent and selective inhibitor of complex I that interferes with cellular respiration, in multiple patient-derived glioma cells.

METHODS
In the present study, we used six different patient-derived glioma cell cultures including four that are IDH1 wild type (wt) (GSC 20, GSC 23, LN 18 and SF 268) and two that are IDH1R132H mutant (BT142 & 21238-IDH1R132H). All cells were cultured as neurospheres to maintain glioma stem cell (GSC) culture conditions. The toxicity of IACS-010759 was also evaluated in immortal non-transformed mouse astrocytes. Neurospheres and astrocytes were treated with IACS-010759 (0.1 µM-100 µM) and cell viability was evaluated after 72 hours using CellTiter-Glo.

RESULTS
Inhibition of oxidative phosphorylation significantly reduced cell proliferation in all glioma cells evaluated. The IC50 of IACS-010759 ranged from 0.7 nM-100 µM but was lowest in IDH1R132H astrocytoma cells, supporting the hypothesis that IDH1 mutant astrocytoma cells have enhanced dependence on oxidative phosphorylation. Importantly, immortal, non-transformed astrocytes were relatively resistant to IACS-010759 suggesting that this strategy may have an effective therapeutic window in this disease.

CONCLUSION
In summary, IACS-010759-induced inhibition of oxidative phosphorylation elicited pronounced anti-neoplastic responses in vitro, especially in astrocytomas expressing mutant IDH1. IACS-010759 may be a promising therapy for both IDH1 wt and mutant gliomas, and we are currently evaluating the efficacy of this strategy in glioma mouse models.
EXTH-86. BH3 PROFILING IDENTIFIES ONC201/TIC10 AS A PROMISING PARTNER OF ABT-263 IN MEDULLOBLASTOMA IN VITRO
Authors: Spilz Antonia , Hajosch Annika , Seyfried Felix , Peraud Aurelia , Prabhu Varun V , Allen Joshua E , Westhoff Mike-Andrew , Siegelin Markus , Wirtz Christian Rainer , Karpel-Massler Georg 
Published: November 2022

Abstract

OBJECTIVE
Medulloblastoma represents one of the most common brain tumors in children. In this study, we identified by BH3 profiling that ONC201/TIC10 sensitizes for Bcl-xL/Bcl-2 inhibition in medulloblastoma and performed a preclinical testing of a combined treatment with ONC201/TIC10 and the Bcl-xL/Bcl-2 inhibitor ABT-263.

METHODS
BH3 profiling was performed to examine ONC201/TIC10-mediated dependencies on anti-apoptotic Bcl-2 family proteins. The combination treatment with ONC201/TIC10 and ABT-263 was tested in different medulloblastoma cells using MTT assays. Isobolograms were calculated to characterize the drug-drug interaction. Tumor spheroid and chorioallantoic membrane assays were used to examine the effects of the combination therapy in a 3D setting. Annexin V/PI staining and flowcytometry were used to detect pro-apoptotic effects. Western blot analyses and knockdown experiments with siRNA were performed for molecular analysis. Extracellular flux analyses served at examining effects on the tumor cell metabolism.

RESULTS
BH3 profiling showed that ONC201/TIC10 sensitizes medulloblastoma cells to Bcl-xL/Bcl-2 inhibition. In line with this finding, combined treatment with ONC201/TIC10 and ABT-263 led to a predominantly synergistic inhibitory effect on the cell viability of established (D425, D458, DAOY, HD-MB03), primary cultured (PC322) and stem-like (SC322) medulloblastoma cells in 2D and 3D models. The response towards the combination therapy was independent of baseline c-myc expression. On the molecular level, treatment with ONC201/TIC10 led to a dose-dependent decrease of Mcl-1. Moreover, the combination caused enhanced cleavage of caspases 9 and 3. On the metabolic level, the combination therapy led to a reduction in both, oxidative phosphorylation and the glycolytic rate and a reduced expression of respiratory chain proteins.

CONCLUSION
Combined treatment with ONC201/TIC10 and ABT-263 had a predominantly synergistic inhibitory effect on the cell viability of medulloblastoma cells. This effect was associated with downregulation of Mcl-1. Moreover, the combination treatment resulted in a metabolic reprogramming which likely creates a state of energy deprivation.
QLTI-08. SURVEY OF CANADIAN NEURO-ONCOLOGY CLINICIANS ABOUT THE TREATMENT OF ADULT MEDULLOBLASTOMA
Authors: Climans Seth , Cacciotti Chantel , Lim-Fat Mary Jane 
Published: November 2022

Abstract

BACKGROUND
Given the rarity of medulloblastoma in adults (fewer than 50 incident cases annually across Canada), the optimal chemotherapy strategy in this population is unknown. The management of adult medulloblastomas is thought to vary from institution to institution. Guidelines often omit suggestions for specific chemotherapy regimens, reflecting the lack of high quality evidence in this population. We sought to understand Canadian adult medulloblastoma practice patterns, hoping to inform future quality metrics and guidelines.

METHODS
In March 2022 a 30-question survey was sent out to 71 adult neuro-oncology clinicians on the Canadian Adolescent and Young Adult national rounds mailing list. Snowball sampling was permitted.

RESULTS
There were 25 responses (up to 35% response rate). Radiation oncologists (11), neuro-oncologists (8), medical oncologists (4), and neurosurgeons (2) responded from 6/10 Canadian provinces. They each treated on average 1.6 medulloblastoma patients per year. Most (61% of respondents) said that medulloblastoma molecular subgrouping was always done at their centre. Half (50%) indicated that cerebrospinal fluid testing was always done at diagnosis. The most common (64%) radiation regimen was 36 Gy (in 20 fractions) craniospinal irradiation + 18 Gy (in 10 fractions) boost. Concomitant chemotherapy was rarely given (75% of respondents included chemotherapy less than half of the time). Adjuvant chemotherapy was frequently administered (79% of respondents give it more than half of the time). The most common adjuvant chemotherapy was Cisplatin/Lomustine/Vincristine (57%), but other regimens included Cisplatin/Lomustine/Vincristine alternating with Cyclophosphamide/Vincristine (21%), Cisplatin/Cyclophosphamide/Vincristine (14%), and carboplatin-based regimens (14%). Respondents noted challenges prescribing chemotherapy in this population: drug toxicities, limited resources, and clinical uncertainty. There was support for standard of care adult medulloblastoma guidelines in 92% of respondents.

CONCLUSIONS
There is significant practice variation among Canadian neuro-oncology centres treating adult medulloblastoma. This variation can serve as an opportunity for quality improvement and clinical research.
QLTI-26. INTEGRATION OF NEURO-ONCOLOGY CLINICAL PATHWAYS IN PROVIDENCE SOUTHERN CALIFORNIA CLINICAL RESEARCH NETWORK
Authors: Bott Thomas , Bozoyan Nanor , Babcock Trisha , Cushman Kristen , Sharma Akanksha , Wagle Naveed , Carrillo Jose , Juarez Tiffany , Kesari Santosh 
Published: November 2022

Abstract

INTRODUCTION
ClinicalPath is an evidence-based oncology decision support and analytics tool for cancer care. ClinicalPath’s treatment recommendations are prioritized based on efficacy, toxicity, and cost by a nationwide committee of oncologists. The pathways are updated quarterly and are expected to speed the integration of new treatments into practice, standardize therapy, improve quality, and decrease cost. The pathway system also allows for local clinical trial mapping to promote clinical trial awareness and increase enrollment. ClinicalPath provides clinical pathways delivering personalized, evidence-based oncology guidance at the point of care. ClinicalPath’s network in North America serves more than 2,000 cancer physicians, within 54 practices in 31 states (15 academic medical centers, 29 hospital systems, and 9 community practices). Population: Our population is derived from multiple hospitals in Southern California within the Providence Health System. Methodology: Medical oncologists and Advanced Practice Providers received training on ClinicalPath before go-live. ClinicalPath was integrated into the Epic EHR in multiple Southern CA hospitals in a single month.

RESULTS
After 3 months of utilization within our Southern California region, 342 treatment decisions were made across all cancers, and 85.1% of cancer patients were treated on pathway. Of which, 7 treatment decisions were made within the neuro-oncology specialty, and 85.7% of those cancer patients were treated on pathway.

CONCLUSION
We successfully integrated and initiated ClinicalPath in a multiple hospital-affiliated community oncology clinical trial network. We are actively working across our Southern California Region to map locally available clinical trials to promote awareness and increase enrollment. Provider utilization and patient on-pathway rates are actively monitored and will be updated.
SURG-22. STAGED LASER INTERSTITIAL THERAPY (LITT) FOR THE SURGICAL TREATMENT OF INSULAR GLIOMA: A CASE SERIES WITH A NOVEL TREATMENT PARADIGM
Authors: Fadel Hassan , Pawloski Jacob , Haider Sameah , Robin Adam , Lee Ian 
Published: November 2022

Abstract

BACKGROUND
Insular gliomas pose a significant surgical challenge due to the insula’s delicate surrounding functional and vascular anatomy. Insular gliomas are conventionally treated with open surgical resection augmented by several surgical adjuvants. Despite advancements in technology and surgical techniques, surgical resection of insular gliomas has been associated with frequent and potentially severe morbidity. Laser interstitial thermal therapy (LITT) is a novel, cytoreductive, and less-invasive treatment option for glioma.

OBJECTIVE
We describe the first-ever series of patients with insular glioma treated with staged LITT with or without subsequent craniotomy.

METHODS
A retrospective institutional database identified patients with insular glioma who underwent staged LITT treatments. Clinical, histopathological, and volumetric lesional characteristics were obtained. Procedural characteristics, morbidity, overall survival (OS), and progression-free survival (PFS) were determined.

RESULTS
Between 2019-2022, 11 patients with insular glioma were treated in stages with a total of 21 LITT procedures with or without subsequent craniotomy. Four patients had Diffuse Astrocytoma (IDHmt/TP53+), one Gemistocytic Astrocytoma (IDHmt/TP53+), three Anaplastic Astrocytoma (IDHmt/TP53+), one Anaplastic Oligodendroglioma (IDHmt/1p19q codel), one secondary GBM (IDHmt/TP53+), and one GBM (IDHwt/TP53-). Six patients were treated with LITT alone, while five patients were treated with LITT followed by a craniotomy for complete resection. Patients had a median tumor volume of 31.5 cm3 (9.58, 97) and a mean extent of ablation±resection of 97.68% (S.D. 5.4). At a median follow-up of 12.59 months, patients had a median PFS of 12.88 months and an OS of 14.46 months. No patients had a change in KPS following LITT. Two patients had a decrease in KPS following surgery.

CONCLUSION
We present the first-ever reported series of insular glioma treated with staged LITT with/without subsequent resection. We found that staged treatment of insular gliomas with LITT is safe, effective, and a minimally invasive option that avoids the potentially significant morbidity associated with conventional surgery.