bluuebunny/crossref_metadata_2025_split huggingface dataset:
NCOG-19. PROGNOSTIC FACTORS IN ELDERLY PATIENTS WITH GLIOBLASTOMA: A RETROSPECTIVE INSTITUTIONAL SERIES OF 160 PATIENTS
Authors: Pellerino Alessia , Bruno Francesco , Pronello Edoardo , Mo Francesca , Franchino Federica , Rudà Roberta , Soffietti Riccardo 
Published: November 2021

Abstract

INTRODUCTION
Glioblastoma (GBM) prevails in elderly patients, who often suffer from other comorbidities that may affect the outcome. The aim of the study was to investigate clinical characteristics, comorbidities, and treatment-related complications that may impact the outcome of elderly patients with GBM.

PATIENTS AND METHODS
In this institutional retrospective study, we included GBM patients ≥ 65 years diagnosed with glioblastoma from 2015 to 2020. We retained information about comorbidities according to Charlson Comorbidity Index (CCI), Karnofsky prognostic score (KPS), MGMTp methylation, and clinical complications during treatment or follow-up.

RESULTS
We included 160 patients. Median age was 72 years (65-88). Median time of follow-up was 9.25 months. Median progression-free survival (mPFS) and overall survival (mOS) were 5.84 and 9.67 months. In a multivariate analysis, factors affecting survival were: KPS after surgery ≥ 70 (mPFS: HR 0.24, 0.13-0.44; mOS: HR 0.43, 0.24–0.76. 95% CI), partial vs gross total resection (mPFS: HR 2.15, 1.23–3.77; mOS: HR 2.61, 1.34–5.07. 95% CI), MGMTp methylation (mPFS: HR 0.35, 0.22–0.55; mOS: HR 0.37, 0.24–0.76. 95% CI), and complications after surgery (mPFS: HR 2.52, 1.39–4.55; mOS: HR 2.96, 1.63–5.40. 95% CI). Conversely, age and CCI were not significantly correlated with prognosis.

CONCLUSIONS
For elderly patients with GBM, CCI does not seem to predict the outcome. Other factors such as extent of surgery, MGMTp methylaton, postoperative KPS, and clinical complications after surgery retain a significant prognostic importance. Further studies are needed to standardize clinical prognostic scales specific for elderly GBM patients.
NCOG-20. LONGITUDINAL ASSESSMENT OF SUBJECTIVE COGNITIVE FUNCTION IN ADULTS WITH LOW GRADE GLIOMA TREATED WITH PROTON RADIATION THERAPY
Authors: Zarrella Giuliana , Parsons Michael , Sherman Janet , Dietrich Jorg , Shih Helen 
Published: November 2021

Abstract

INTRODUCTION
Our group previously demonstrated stability in neurocognitive function (NCF) over a 5-year period after proton radiation therapy (PRT) in low grade glioma (LGG) patients. Subjective cognitive function (SCF) had not been previously explored, nor had individual analyses of cognition, which can detect variability in trajectory. We used the newly derived Functional Assessment of Cancer Therapy-Brain Cognitive-Index (FACT-Br-CI) to examine SCF in LGG patients after PRT and compare longitudinal changes in SCF and NCF.

METHODS
20 LGG patients (M age =37.5) treated with PRT completed NCF tests and self-report measures annually for 5 years or until tumor progression. Group change in SCF was examined with paired t-test (baseline vs final FACT-Br-CI). Individual change scores were calculated for FACT-Br-CI and NCF tests (clinical trials battery composite; CTBC). Individual deterioration in NCF was defined by reliable change index (RCI) on CTBC, and in SCF was defined as decline of &gt;/=1 SD in FACT-Br-CI. Relationships between change in SCF and NCF were explored with correlations.

RESULTS
At the group level, no change was observed in FACT-Br-CI between baseline and last follow-up (t(19)=-.91;p=ns). Individual SCF analyses at last follow-up found the number of patients reporting decline=3 (15%), improvement=5 (25%), and no change=12 (60%). Individual changes were observed in SCF in 20% of patients at 3 months, 5.9% at 6 months, 12.5% at 12 months, 13.3% at 24 months, and 11.1% at 36 months. Median time to any deterioration in SCF was 36 months and for NCF was not reached. Correlation between CTBC and FACT-Br-CI change scores did not reach statistical significance (r=.41;p=ns).

CONCLUSION
Consistent with previous research, group analyses of LGG patients did not show cognitive decline after PRT. However individual analyses of SCF showed variability within the group: some patients experienced cognitive decline during follow up. Consideration of individual differences may yield additional information.
NCOG-22. RETROSPECTIVE ANALYSIS OF VISUAL OUTCOMES AFTER BEVACIZUMAB-BASED THERAPY IN OPTIC PATHWAY GLIOMA
Authors: Siegel Benjamin , MacDonald Tobey , Wolf David 
Published: November 2021

Abstract

BACKGROUND
Patients with optic pathway glioma (OPG) are vulnerable to debilitating visual impairment. Consequently, vision stabilization is a primary treatment goal. Bevacizumab has demonstrated promising effects on radiographic tumor burden, but less is known about its impact on vision. Our objective was to characterize visual outcomes associated with bevacizumab-based therapy (BBT) in OPG.

METHODS
This is a single-institution, retrospective review of patients treated with BBT for OPG from 2011 to 2020. Ophthalmologic and radiographic data were abstracted before and after treatment. Clinically significant visual acuity (VA) impairment was defined as logMAR &gt; 0.5 and change in VA was defined as change from baseline of logMAR ≥ 0.2.

RESULTS
Sixteen patients (13 sporadic OPG, 3 NF1-associated OPG) with evaluable vision outcomes were identified. Treatment indications were radiographic progression (N=15) and vision deterioration (N=4). Prior to BBT, 15 (94%) had failed at least one chemotherapy regimen. BBT regimens included bevacizumab/irinotecan (N=12), bevacizumab monotherapy (N=3) and bevacizumab/vinblastine (N=1). Nine patients (56%) had baseline VA impairment. Thirteen patients (81%) had stable or improved vision after BBT, including 8 of 9 with baseline VA impairment and all 4 patients with vision deterioration as a treatment indication. Eleven patients (69%) had radiographic progression following BBT (Median time-to-progression 66 weeks, IQR 27 weeks), 9 of whom had stable vision at time of progression. There were no associations between VA and age at treatment, NF1-status, histology, or BBT regimen.

CONCLUSIONS
BBT was associated with favorable visual outcomes for most patients with OPG in this modest retrospective cohort. Consistent with prior research, radiographic and ophthalmologic outcomes were discordant; a majority of patients experienced progressive disease despite stable vision. Next steps include (1) assessing visual field and optical coherence tomography outcomes in the same cohort and (2) comparing outcomes for BBT with other common therapies including carboplatin/vincristine and vinblastine.
NCOG-26. SOCIOECONOMIC FACTORS AFFECTING SURVIVORSHIP OF GLIOBLASTOMA PATIENTS IN THE PHILIPPINES: A RETROSPECTIVE COHORT STUDY
Authors: Hong Manilyn , Omar Abdelsimar , Khu Kathleen Joy 
Published: November 2021

Abstract

BACKGROUND
Glioblastoma (GBM) is the most common malignant primary brain tumor in adults worldwide. However, data on the survivorship of glioblastoma for low-middle income countries is sparse. We studied the clinical features, treatment, and survivorship of surgically managed GBM patients at a tertiary referral center in the Philippines over a 5-year period. We determined whether socioeconomic factors such as income level, employment status, marital status and educational attainment affected survival.

METHODS
A retrospective cohort study within a 5-year period (2015 to 2019) of surgically managed GBM patients in a single center was conducted using chart review and telephone interview.

RESULTS
A total of 48 cases met the inclusion criteria. Mean age of the cohort was 41 years, with a male predilection (62%). Mean duration of symptoms was 2.8 months. Majority of the tumors were were &gt;5 cm at the time surgery (90%), and involved more than one lobe (40%). Majority (73%) had preoperative KPS ≥70, and underwent subtotal resection (56%). Only 15% (n=7) had adjuvant chemoradiatherapy while another 23% (n=11) had radiotherapy alone. Median overall survival (OS) was 7.6 months (228 days). Most patients had rural residence (56%), low-income (83%), full time employment (79%), married status (73%) and secondary education (44%). Multi-variate analysis showed that only extent of resection (GTR p=0.0297 and STR p=0.0400) were associated with improved survival while widower status (p=0.0116) were significantly more at risk.

CONCLUSION
Many glioblastoma patients managed at our center in the Philippines presented at an advanced stage in their natural history, with larger tumors and more extensive distribution at time of presentation. After surgery, majority did not receive adjuvant treatment. As such, the median overall survival was less than that reported in published cohorts in developed countries. Extent of resection and marital status were significantly associated with survivorship.
NCOG-30. AWAKE CRANIOTOMY FOR MENINGIOMA RESECTION: A STUDY ON THE SAFETY AND TOLERABILITY
Authors: Bakhshi Saqib Kamran , Jawed Noyan , Shafiq Faraz , Enam Syed Ather 
Published: November 2021

Abstract
Resection of intra-axial brain tumors under scalp block improves safety of surgery, permitting preservation of neurological function and early recovery. However, limited data is available on employing this anesthesia technique for extra-axial tumors particularly meningioma, raising concerns that it may not be feasible due to dural attachment of tumor causing intractable pain and discomfort. We retrospectively analyzed 17 patients who underwent AC for resection of meningioma at our hospital during last 5 years, employing non-probability consecutive sampling. Variables for demographics, and details of diagnosis and surgical procedure were recorded. Eleven of these cases had grade I meningioma, and 6 had grade II meningioma. The mean age of these patients was 45.8 ± 10.5 years. Seizures were the most common presenting complain (n = 7; 41.2%). Eleven patients (58.3%) had convexity meningioma, 4 (33.3%) had parasagittal meningioma and 1 each had a parafalcine and anterior skull-base meningioma. The mean duration of surgery was 180.8 ± 36.2 minutes and the median estimated blood loss was 450 ml (IQR: 225 ml – 737.5 ml). The mean length of stay in the hospital was 3.1 ± 1.3 days. Only 1 patient had a prolonged hospital stay of 7 days because of post-operative seizures. Simpson grade I resection was performed in 6 (41.7%) patients, and grade II resection in 10 (50%) patients. Deterioration in pre-operative neurological exam was not seen in any patient, and no one required emergency intubation, conversion of surgery to general anesthesia, or re-operations. We propose that AC does not pose any significant risk of intra-operative or post-operative pain during meningioma resection, particularly convexity and parasagittal meningioma, and can make surgery possible for patients who are high risk for, or are not willing to undergo general anesthesia.
EXTH-23. PRECLINICAL EFFICACY OF A TARGETED, BRAIN PENETRANT INHIBITOR OF FATTY ACID DESATURATION IN GLIOBLASTOMA
Authors: Eyme Katharina , Sammarco Alessandro , Neustadt Rudolph , Mnatsakanyan Hayk , Tardiff Daniel , Chung Chee Yeun , Badr Christian 
Published: November 2021

Abstract
There is increasing evidence that targeting de novo fatty acid synthesis could be effective for the treatment of primary and metastatic brain tumors, but brain penetrant inhibitors of this pathway are still lacking. We have previously reported that Stearoyl CoA Desaturase (SCD), a desaturase enzyme which converts saturated fatty acids into their unsaturated counterparts is a therapeutic target in glioblastoma (GBM). We showed that SCD exerts a cytoprotective role by protecting GBM cells against lipotoxicity and is essential for maintaining self-renewal and tumor initiating properties in GBM stem cells (GSCs).
Using a panel of patient derived GSCs, mouse orthotopic GSC models, isogenic astrocytes models of gliomagenesis as well as in silico analysis, we report that in addition to SCD1, a second SCD isoform is also essential for GSCs maintenance. Further we demonstrate that while EGFR/PI3K/AKT signaling promotes lipogenesis, the activation of RAS/MEK/ERK signaling creates a metabolic vulnerability and sensitizes to SCD inhibitors. We tested a first-in-class, clinically relevant SCD inhibitor and showed that this compound effectively inhibits fatty acid desaturation in GSCs in a mouse orthotopic GSC model. Importantly, using different GSCs mouse models, we demonstrate that this SCD inhibitor can effectively increase overall survival as a monotherapy. Further, SCD inhibition impairs DNA-damage repair via homologous recombination thereby sensitizing to the standard of care therapeutics for GBM, ionizing radiation and temozolomide (TMZ). Consequently, combining this inhibitor with TMZ in mouse orthotopic GSC models leads to a significantly increased overall survival.
Altogether, our results provide a deeper understanding of de novo fatty acid dynamics in GBM and support the clinical testing of a new SCD inhibitor, with favorable pharmacokinetic and pharmacodynamic properties, in patients diagnosed with GBM.
EXTH-26. LAYER-BY-LAYER NANOPARTICLES DESIGNED FOR DUAL BLOOD-BRAIN BARRIER AND GLIOMA TARGETING
Authors: Straehla Joelle , Hajal Cynthia , Safford Hannah , Offeddu Giovanni , Wyckoff Jeffrey , Kamm Roger , Hammond Paula 
Published: November 2021

Abstract

BACKGROUND
While biologically diverse, high grade gliomas (HGGs) have a dismal prognosis in both adults and children. Promising therapeutics have been identified for HGGs based on common genomic alterations and aberrant signaling pathways, but achieving effective drug exposure at the tumor site remains a challenge largely due to the blood-brain barrier (BBB). HYPOTHESIS: A tunable nanocarrier platform can improve nanoparticle delivery across the (BBB) and into glioma cells.

METHODS
We synthesized layer-by-layer nanoparticles by coating anionic, fluorescent liposomes with nanometers-thick layers of oppositely charged polyelectrolytes, creating a library of organic, nontoxic drug carriers with varied surface chemistries. We characterized the library using dynamic light scattering and quantified interactions with a range of pediatric and adult glioma cell lines using flow cytometry. We used intravital two-photon microscopy to quantify nanoparticle trafficking across the intact BBB through a cranial window in anesthetized mice.

RESULTS
Nanoparticle surface chemistry strongly influences cellular trafficking in vitro, with two polymers identified as particularly high-performing across brain tumors lines: poly-L-aspartic acid (semi-synthetic) and hyaluronic acid (natural polysaccharide). The addition of the angiopep-2 targeting moiety onto these polymers improved nanoparticle uptake into brain microvascular endothelial cells in vitro without abrogating tumor affinity. We developed a new algorithm to quantify permeability of fluorescent compounds across the BBB in vivo and validated our method by measuring dextran permeability at varied molecular weights. In our initial study in non-tumor-bearing mice (n=12), we successfully quantified nanoparticle permeability across the BBB. In this study, surface functionalization did not increase BBB permeability above the control nanoparticle, though it did improve nanoparticle half-life in circulation and may still impart a therapeutic benefit when loaded with drug. Additional investigations in orthotopic tumor-bearing mice are ongoing. In summary, we report the development of layer-by-layer nanocarriers as a modular drug delivery platform with therapeutic potential for gliomas.
EXTH-44. SYSTEMIC CCL3 TREATMENT ENHANCES IMMUNOTHERAPY EFFICACY THROUGH IMPROVED DENDRITIC CELL MIGRATION
Authors: Hotchkiss Kelly , Batich Kristen , Janampalli Mrinaj , Norberg Pam , Sampson John 
Published: November 2021

Abstract

INTRODUCTION
Dendritic cell (DC) vaccines have shown marginal success in treating glioblastoma (GBM), with inefficient vaccine migration a major limitation. Prior evidence from our clinical trials demonstrated that tetanus diphtheria (Td) preconditioning produced greater DC migration to vaccine draining lymph nodes (VDLNs) and long-term survival. Greater DC numbers reaching VDLNs was also associated with long-term survival. We found from preclinical studies and our patients that increased DC migration was dependent upon the chemokine (C-C motif) ligand 3 (CCL3).

METHODS
The effect of systemic CCL3 treatment on DC vaccine migration (n=5), antigen-specific T cell responses (n=5) and efficacy against orthotopic GL261-OVA and SMA560 tumors (n=10) was studied in C57Bl/6 and VMdK mice. DCs were electroporated with OVA-mRNA or pulsed with ODC1 neoantigen peptide. Median overall survival (mOS) was measure in days (d) post-intracranial implantation.

RESULTS
Intravenous CCL3 at the time of intradermal DC vaccination resulted in a dose-dependent increase in migration to VDLN (10ug p=0.036, 20ug p&lt; 0.0001, 50ug p&lt; 0.0001). Mean migration levels following CCL3 treatment were similar to Td-preconditioning (p=0.52) but showed significantly less variability between mice. Combined CCL3 and DC vaccination generated more tumor antigen-specific CD8+IFNγ+ T cells 7 days compared to DC vaccine alone (p=0.0045). CCL3+OVA-DC treatment resulted in significantly greater survival compared to OVA-DC alone (mOS 37 vs 19.5 d; p=0.0174) in established GL261-OVA. CCL3 treatment increased survival in mice with established SMA560 tumors treated with neoantigen ODC1 peptide-pulsed DCs (Tumor alone mOS: 21d, DCvac: 25d, CCL3+DCvac: 48d, p=0.002).

CONCLUSIONS
These data combined with previous success of our DC vaccine clinical trials reflect the potency of CCL3 to enhance DC vaccine-specific migration, immune responses and survival. CCL3 is a novel and safe adjuvant to overcome prior limitations in DC vaccine therapy and may be translatable to increase heterogeneous tumor antigen presentation following vaccine-targeted tumor killing.
EXTH-66. ENHANCEMENT OF ANTI-PD-1 THERAPY WITH EXTENDED HALF-LIFE IL-2 IS INDEPENDENT OF MHC CLASS I RESTRICTED ANTIGEN RECOGNITION FOR TREATMENT OF EXPERIMENTAL GLIOMA
Authors: Tritz Zachariah , Ayasoufi Katayoun , Malo Courtney , Himes Benjamin , Khadka Roman , Fain Cori , Goddery Emma , Yokanovich Lila , Jin Fang , Hansen Michael , Parney Ian , Wang Chensu , Moynihan Kelly , Irvine Darrell , Wittrup Dane , Johnson Aaron 
Published: November 2021

Abstract
Glioblastoma (GBM) is the most common malignant brain tumor in adults, responsible for approximately 225,000 deaths per year. Despite pre-clinical successes, therapeutic interventions have failed to extend patient survival by more than a few months. Anti-PD-1 checkpoint inhibition monotherapy has had efficacy against some tumor types but not GBM. The aim of this study was to determine whether supplementing anti-PD-1 checkpoint blockade with an engineered extended half-life IL-2 could improve outcomes in a preclinical model of disease. Our enhanced checkpoint blockade (ECB) strategy reliably cures approximately50% of C57BL/6 mice bearing orthotopic GL261 gliomas and extended median survival even in the mice that eventually succumbed. This therapy generates robust immunologic responses, features of which include secondary lymphoid organ enlargement and increased activation status of both CD4 and CD8 T cells. Further, many of the characteristics of brain-tumor mediated peripheral immunosuppression, including MHC class II downregulation on APCs, are prevented by ECB combination therapy. This immunity is durable, with long-term ECB survivors able to resist GL261 rechallenge. Notably, ECB’s efficacy is independent of host MHC class I restricted antigen presentation, being equally efficacious in MHC class I and CD8 T cell deficient mice. Conversely, ECB combination therapy is reliant on CD4 T cells and their depletion abrogates the therapy’s survival benefit. Our data shows ECB combination immunotherapy to be efficacious against the GL261 glioma model through an MHC class I independent mechanism, enhancing its off-the-shelf translational appeal relative to strategies requiring extensive knowledge of tumor-specific antigens.
EXTH-68. DUAL METABOLIC REPROGRAMMING BY ONC201/TIC10 AND 2-DEOXYGLUCOSE HAS A STRONG ANTIPROLIFERATIVE EFFECT ON MEDULLOBLASTOMA CELLS
Authors: Dwucet Annika , Cao Qiyu , Pruss Maximilian , Westhoff Mike-Andrew , Wirtz Christian Rainer , Siegelin Markus D , Karpel-Massler Georg 
Published: November 2021

Abstract

BACKGROUND
Medulloblastoma represents one of the most common brain tumors in children. While the understanding of the molecular characteristics of this disease has very much advanced, more efficient and less toxic therapeutics are still in high demand. In this study we examined whether the imipridone ONC201/TIC10 affects the metabolic and proliferative activity of medulloblastoma cells alone and in combination with 2-Deoxyglucose in vitro.

METHODS
Extracellular flux (agilent seahorse) and Western blot analyses were performed to assess effects on tumor cell metabolism and the expression of proteins of the respiratory chain in established medulloblastoma cells. MTT assays and spheroid assays were performed to examine anti-proliferative effects in a 2-D and 3-D setting.

RESULTS
Treatment with ONC201/TIC10 has a strong inihibitory effect on the cellular viability of different medulloblastoma cells independent of c-Myc expression. While ONC201/TIC10 decreases the oxidative consumption rates in D458 (c-Myc high) and DAOY (c-Myc low) cells, extracellular acidification rates experienced an increase in D458 and a decrease in DAOY cells. Treatment with ONC201/TIC10 in combination with the glycolysis inhibitor 2-Deoxyglucose synergistically inhibited the cellular viability of medulloblastoma cells and impaired the growth of spheroids.

CONCLUSION
Overall, ONC201/TIC10 profoundly inhibits the proliferative activity of medulloblastoma cells in a c-Myc-independent manner. Additional treatment with the glycolysis inhibitor 2-Deoxyglucose synergistically enhances the anti-medulloblastoma activity of ONC201/TIC10. This promising approach warrants further investigations.
EXTH-69. FUNCTIONAL GENOMICS UNCOVER GENETIC DEPENDENCIES IN ATRTS
Authors: Merk Daniel , Hirsch Sophie , Tsiami Foteini , Walter Bianca , Haeusser Lara , Babaei Sepideh , Admard Jakob , Casadei Nicolas , Roggia Cristiana , Spohn Michael , Schittenhelm Jens , Singer Stephan , Schüller Ulrich , Piccioni Federica , Persky Nicole , Root David , Claassen Manfred , Tatagiba Marcos , Tabatabai Ghazaleh 
Published: November 2021

Abstract
Brain tumors are the leading cause of cancer-related deaths in children. Embryonal brain tumors including medulloblastoma and atypical teratoid rhabdoid tumors (ATRTs) account for 15% of all primary brain and CNS tumors under the age of 14 years, with ATRTs being most prevalent in infants. Despite intensive research efforts, survival estimates for ATRT patients stay relatively low as compared to other tumor entities with a median survival of around 17 months. We here describe genome-wide CRISPR/Cas9 knockout screens in combination with small-molecule drug assays to identify targetable vulnerabilities in ATRTs. Based on functional genomic screening revealing ATRT context-specific genetic vulnerabilities (n = 671 genes), we successfully generated a small-molecule library that shows preferential activity in ATRT cells as compared to a broad selection of other human cancer cell lines. Of note, none of these drugs differentially affect ATRT cells from distinct molecular subgroups, suggesting that top candidate inhibitors might serve as pan-ATRT therapeutic avenues. CDK4/6 inhibitors, among the most potent drugs in our library, are capable of inhibiting tumor growth due to mutual exclusive dependency of ATRTs on either CDK4 or CDK6. Our approach might serve as a blueprint for fostering the identification of functionally-instructed therapeutic strategies in other incurable diseases beyond ATRT, whose genomic profiles also lack actionable alterations so far.