bluuebunny/crossref_metadata_2025_split huggingface dataset:
EXTH-24. FC-ENHANCED ANTI-CTLA-4 IMMUNE CHECKPOINT BLOCKADE AND ITS COMBINATION WITH ANTI-PD-1 WITH CONCOMITANT DOXORUBICIN AND ULTRASOUND-MEDIATED BBB OPENING: A NOVEL IMMUNOTHERAPY FOR GLIOBLASTOMA
Authors: Kim Kwang-Soo , Habashy Karl , Gould Andrew , Najem Hinda , Zhao Junfei , Amidei Christina , Saganty Ruth , Arrieta Victor , Dmello Crismita , Chen Li , Zhang Daniel , Castro Brandyn , Billingham Leah , Levey Daniel , Morin Benjamin , Muzzio Miguel , Canney Michael , McCortney Katy , Horbinski Craig , Zhang Peng , Miska Jason , Rabadan Raul , Heimberger Amy , Stupp Roger , Chand Dhan , Lee-Chang Catalina , Sonabend Adam 
Published: November 2023

Abstract
Despite the recent success of immune checkpoint blockade in various cancer types, glioblastoma (GBM) remains resistant to immunotherapy due to its immunosuppressive features and the poor penetration of systemic agents across the blood-brain barrier (BBB). Recent clinical trials demonstrated the unprecedented efficacy of Fc enhanced anti-CTLA-4, an anti-CTLA-4 antibody with enhanced affinity to Fcγ receptors (FcE-aCTLA-4), against immunologically inactive (‘cold’) tumors. This agent exhibits a high affinity for FcγRIIIA regardless of its polymorphic variants of FcgRIIIA that are known to influence the binding affinity and efficacy of conventional anti-CTLA-4 antibodies. We observed robust expression of FcγRIIIA in tumor-associated macrophages/myeloid cells (TAM) of human GBM, which was most pronounced in newly diagnosed GBM. FcE-aCTLA-4 demonstrated high-affinity binding to FcγRIV, the mouse ortholog of human FcγRIIIA, which was highly expressed on TAMs in mouse gliomas. We evaluated the efficacy of the murine homologous FcE-aCTLA-4 antibody as monotherapy and in combination with other treatments in several murine glioma models. FcE-aCTLA-4 selectively depleted CTLA-4 expressing intra-tumoral regulatory T cells (Tregs) via antibody-dependent phagocytosis by TAMs while spearing peripheral Tregs and other CD4+ T cell populations. In a cohort of 4 GBM patients, doxorubicin delivered with low-intensity pulsed ultrasound and microbubbles (LIPU/MB), a procedure that temporarily opens the BBB, upregulated FcγRIIIA expression on TAMs. Treatment of immunotherapy-resistant murine gliomas with a combination of FcE-aCTLA-4, anti-PD-1, and doxorubicin with concomitant LIPU/MB resulted in over 90% cure rates, which correlated with increased infiltration of activated CD8+ T cells in the brain, and complete rejection upon subsequent tumor rechallenge. Our findings indicate that FcE-aCTLA-4 exhibits a novel immunomodulatory function in GBM, and its therapeutic potential is significantly improved when combined with anti-PD-1, doxorubicin, and delivered by LIPU/MB. This therapy warrants further evaluation in clinical trials.
EXTH-42. PRECLINICAL INVESTIGATION OF A NOVEL BRAIN PENETRANT MEK INHIBITOR TO TARGET BRAIN METASTASIS
Authors: Yamazawa Erika , Nayyar Naema , Ijad Nazanin , Torrini Consuelo , De Sauvage Magali , Migliarese Christian , Summers Elizabeth , Marion Braxton , Lee Catherine , Suriben Rowena , Perez Michelle , Powell Ben , Miller Nichol , Grandinetti Brooke , Wakimoto Hiroaki , Brastianos Priscilla 
Published: November 2023

Abstract
Melanoma is one of the most common cancers with a high rate of brain metastases, with up to 75% of cases showing brain metastases upon autopsy. BRAF mutations are common in melanoma and found in up to 50-55% of melanoma brain metastases. Despite the clinical success of BRAF/MEK inhibitors for the treatment of advanced melanoma, dabrafenib and vemurafenib have limited intracranial overall response rates of 42-50% and median progression-free survival of 3.6-5.5 months. This limited efficacy is in part attributed to minimal blood-brain barrier penetration of the current available inhibitors. The goal of this study was to characterize a novel MEK inhibitor KIN-7136 as a potential therapeutic agent for brain metastasis driven by aberrant BRAF-MEK signaling, such as BRAF-mutant melanoma, using in vitro assays and an in vivo model of metastasis. KIN-7136 showed improved rodent brain exposure compared to conventional agents; the brain-to-plasma concentration ratio (Kp) of KIN-7136 was &gt;1.0, much higher than comparators binimetinib and mirdametinib. In vitro cell viability assays showed potent cytotoxic effects of KIN-7136, with IC50s ranging from 15.4 to 204.9 nM in models of MAPK dysregulation including A375 (melanoma, BRAFV600E), NCI-H2405 (lung adenocarcinoma, BRAFΔNVTAP), HMVII (melanoma, BRAFG469V), and LN001 (patient derived lung adenocarcinoma, KRASG12V). Western blotting for phospho-ERK confirmed KIN-7136-mediated on-target downstream suppression in the A375 cell line. In vivo, daily oral treatment with KIN-7136 was well tolerated and produced a significant extension of overall survival compared to the vehicle control (p=0.0289, log-rank test) in the A375 intracranial tumor model in athymic mice. These preclinical data confirm activity of KIN-7136 in BRAF-mutant melanoma brain metastases models and support further research to advance its clinical progression.
EXTH-74. TUMOR PHARMACOKINETICS AND PHARMACODYNAMICS IN PATIENT-DERIVED XENOGRAFT MODELS OF GLIOBLASTOMA TREATED WITH THE PRMT5 INHIBITOR SKL27969
Authors: Tien An-Chi , Margaryan Tigran , Molloy Jennifer , McNamara James , Knight William , Hon Raymond , Opachich Zorana , Melendez Ernesto Luna , Elliott Mackenna , White Connor , Sanai Nader , Tovmasyan Artak , Mehta Shwetal 
Published: November 2023

Abstract
Epigenetic regulation plays a key role in the development of several cancers, including glioblastoma (GBM). Protein arginine methyltransferase 5 (PRMT5) has recently emerged as a promising therapeutic target for GBM. PRMT5 is the primary type II methyltransferase that catalyzes symmetric arginine dimethylation in multiple proteins. In this study, we evaluated the pharmacokinetics, pharmacodynamics, and radiation sensitization properties of SKL27969, a highly selective PRMT5 inhibitor, in orthotopic patient-derived xenograft (PDX) models of GBM. Mice with intracranial tumors were randomized to 50 mg/kg (oral) SKL27969 vs. placebo for two cycles either alone or in combination with radiation. SKL27969 levels in plasma and contrast-enhancing tumor tissue were measured by liquid chromatography tandem mass spectrometry (LC-MS/MS). Unbound fractions were determined by equilibrium dialysis. Immunohistochemistry was performed to assess levels of SDMA, phospho-Histone H3, pH2AX, and cleaved caspase 3 (CC3). For survival studies, mice with intracranial tumors were randomized into four cohorts – vehicle, radiotherapy, SKL27969 monotherapy, and SKL27969 plus radiotherapy. The median brain-to-plasma and tumor-to-plasma partition coefficients of unbound SKL27969 were 1.8 and 2.9, respectively – indicating favorable brain and tumor penetration ability of SKL27969. A decrease in SDMA (+) cells (54% vs. 0.1%, p &lt; 0.001) indicated PRMT5 inhibition and was accompanied by an increase in CC3 (+) cells (0.7% vs. 1.2%, p = 0.01). SKL27969 is well tolerated, achieves pharmacologically relevant unbound concentrations in GBM PDX models, and is associated with significant target modulation. Ongoing studies are evaluating in vivo survival benefit from combining PRMT5 inhibition with radiation therapy.
EXTH-76. TRANSLATIONAL BARRIERS IN 5-ALA PHOTODYNAMIC THERAPY FOR GLIOMAS: A SYSTEMATIC REVIEW OF THE IN VIVO LANDSCAPE AND FUTURE DIRECTIONS FOR CLINICAL APPLICABILITY
Authors: Bhanja Debarati , Wilding Hannah , Baroz Angel , Trifoi Mara , Shenoy Ganesh , Slage-Webb Becky , Hayes Daniel , Soudagar Yasaman , Connor James R , Mansouri Alireza 
Published: November 2023

Abstract

INTRODUCTION
Photodynamic therapy (PDT) is an emerging investigational therapeutic for gliomas marked by variable success. Several strategies to increase its efficacy have been attempted, and although promising, challenges that have hindered translational progress persist. The objective of this study was to analyze translational barriers through a systematic review and appraisal of the in vivo literature. Method: PRISMA guidelines were utilized to identify studies that reported translational in vivo data of 5-aminolevulinic acid (5-ALA) PDT in murine glioma models. Databases were searched from inception to 2022, using the terms: “photodynamic therapy” AND (“5-ALA” OR “ALA” OR “PPIX”) AND “in vivo” AND (“glioma” OR “glioblastoma” OR astrocytoma”). Study design parameters were appraised, and mechanistic and translational outcomes across all studies were evaluated and compared. Result: Eight studies (2002-2019) were included. The most common animal model used was immunosuppressed rats orthotopically implanted with glioma cells. Only two studies used syngeneic models. No studies validated findings in external cohorts or patient-derived xenografts. Experimental light power densities ranged widely from 0.5-100mW/ cm2. Only three studies utilized a longitudinal delivery strategy, and all found significantly decreased tumor volume and increased survival compared to high-dose single-session PDT. For mechanistic endpoints, only one study investigated the impact of PDT on the immune response, finding increased TME CD8+ T-cell infiltration in the experimental group. Safety endpoints, including hemorrhage, elevated intracranial pressure (ICP), and off-target cortical damage, were measured in only three studies, in which high power densities were associated with increased hemorrhage and elevated ICP.

CONCLUSION
While in vivo evidence for 5-ALA PDT is compelling, this appraisal uncovers discrepancies in power densities, lack of validation in putative translational models, and limited understanding of PDT impact on the immune response and TME. Future preclinical investigations that address these barriers will offer distinct and necessary steps toward effective clinical translation.
QLTI-10. STANDARD WORK FOR ORAL CHEMOTHERAPY IMPROVES SAFETY WITHOUT INCREASING DELAYS
Authors: Balakrishnan Samantha , Nagpal Seema , Dugala Anisia , Coffey Gwen , Pena Justine 
Published: November 2023

Abstract

Purpose
Oral chemotherapy in the outpatient setting does not have the same level of oversight as chemotherapies delivered in an infusion treatment area. This project aimed to create a standardized process to prescribe outpatient oral chemotherapy to improve patient safety. The primary process-measure was laboratory data review prior to ordering therapy, with primary outcome-measure being number of days between approval to administer therapy and actual administration. A secondary process-measure was documentation quality, and counterbalance-measure was delay in ordering due to lab review.

METHODS
A Failure Mode Effects Analysis was performed. Standard work was developed for each step of prescribing and roles and responsibilities were assigned for each step in the process. A checklist was developed within the medical record to review and document essential steps in the process allowing for greater visibility. Fifty-three patient encounters were reviewed prior to intervention and 39 post-intervention.

RESULTS
FMEA identified 7 high-risk points. For the primary process measure, prior to intervention, 34/53 (64%) encounters had laboratory data review prior to chemotherapy order. After intervention, 38/39 (97%). The change did not delay ordering; we observed a mean 2-day delay between laboratory data review and chemotherapy order (significant difference from zero [p = 0.001]) pre-intervention. After intervention, there was no statistically significant delay (mean -0.74 days, p = 0.376). Documentation improved after intervention; 23/53 (43%) chemotherapy encounters contained complete data pre-intervention, and 36/39 encounters (92%) post-intervention.

CONCLUSIONS
As part of our standardized process, we developed a new chemotherapy checklist and flowsheet in the medical record. While the fraction of patients with zero delay in chemotherapy administration after approval did not change, patient safety improved with more patients having laboratory review prior to chemotherapy order. This review did not increase delays in ordering therapy. Documentation quality also improved. Having a standard process increases patient safety while prescribing outpatient oral chemotherapy.
QOL-01. VARIABILITY IN ANXIETY AND DEPRESSION SYMPTOMS AFTER ELOQUENT GLIOMA RESECTION IS ASSOCIATED WITH CHANGES IN FUNCTIONAL CONNECTOMIC PROPERTIES
Authors: Noll Kyle , Chen Henry , Bradshaw Mariana , Wefel Jeffrey , Sullaway Catherine , Thomas Ashley , Kumar Vinodh , Prabhu Sujit , Liu Ho-Ling 
Published: November 2023

Abstract
Little is known regarding how treatment-related changes in cerebral networks relate to symptoms of anxiety and depression in patients with glioma. Fifteen patients with left perisylvian glioma underwent resting-state fMRI and neuropsychological evaluation before and 1 month after resection. Symptoms of depression and anxiety were characterized with Beck Depression Inventory-II (BDI) and Beck Anxiety Inventory (BAI) Total scores and rates of clinically significant symptom burden. Change scores and reliable change classifications were also examined. Graph theoretical analysis was applied to fMRI connectivity matrices to calculate brain network properties. Comparison of pre- and postoperative measures were performed with Wilcoxon tests. Correlations between changes in anxiety and depression symptom measures and network properties were examined. Pre- and postoperative Total scores did not significantly differ though postoperative symptom burden trended toward reduction [Change: BDI=-1.93(5.73), BAI=-5.80(8.19)] with considerable interindividual variability noted [Change: BDI range=-12 to +6; BAI range=-18 to +6]. Preoperatively, at least mild symptoms were found in 27% of patients on BDI and 60% on BAI. Postoperatively, rates were the same for BDI while BAI was 33%. Using reliable change criteria, improvement was found in 13% of patients on BDI and 33% on BAI without any significant worsening. Significant postoperative connectivity decreases were observed in betweenness centrality [Change = -5.56(12.07), p = .031] and assortativity [Change=-.062(.096), p = .027]. Strong associations were found between pre- to postoperative differences in betweenness centrality and assortativity and changes in BDI [ρ(13)=.58 and .67, p&lt; .02] and BAI Total scores [ρ(13)=.62 and .68, p&lt; .01]. Anxiety and depression symptoms vary considerably postoperatively, though most patients do not show significant worsening. Variability in symptom change appears related to alterations in functional connectomics, with those showing increases in certain connectomic properties exhibiting worse postoperative anxiety and depression symptoms. Surgically-induced connectomic changes may coincide with or potentially contribute to psychological symptom differences in the postoperative setting.
QOL-02. MONITORING GBM PATIENT HEALTH-RELATED QUALITY OF LIFE AND QUALITY ADJUSTED LIFE MONTHS DURING INDIVIDUALIZED MULTIMODAL IMMUNOTHERAPY USING EQ-5D-5L
Authors: Van de Vliet Peter , Makalowski Jennifer , Kampers Linde , Sprenger Tobias , Schirrmacher Volker , Stuecker Wilfried , Van Gool Stefaan 
Published: November 2023

Abstract
DC vaccination emerges as effective treatment for patients with GBM. Besides overall survival, Health-Related Quality of Life (HRQoL) during and after treatment is an important qualitative assessment. We explored the usability of the self-reporting EQ-5D-5L instrument (), available in 14 languages, to determine the Health Utility Index (HUI) and calculate Quality Adjusted Life Months (QALM) in GBM patients during individualized multimodal immunotherapy (IMI). Selection criteria for this retrospective analysis were the start of IMI between 15 October 2021 and May 2023, and availability of at least 5 HRQoL measurements with EQ-5D-5L. Nineteen GBM patients (9 females, 10 males) met these criteria. Median age at diagnosis was 52 years (range 21-67). Median Karnofsky performance index was 80 (60-100). The HUI at time of first diagnosis was unknown. The median HUI at start of immunotherapy was 0.868 (1-0.346). Fifteen patients received IMI as part of first-line treatment. Four patients were treated at time of relapse. Patients received in median 2 IO-Vac® vaccines (0-3) and 6 immunogenic cell death immunotherapy courses (4-12). Sixteen patients were still alive in median 11 months (6-48) after first diagnosis. Three patients died respectively 11, 16, 34 months after diagnosis. The patient response rate to the EQ-5D-5L instrument was high. A median of 7 HRQoL measurements were registered per patient (5-15). One patient did not appropriately answer the EQ-5D-5L questionnaire due to active refusal. The median life time between start of IMI and last time point for measurement of HRQoL was 12.5 months (7.8-47.5). The Quality Adjusted life time between each time point was calculated based on the HUI for each patient. The life time reduction was -0.9 months (-4.2-0), resulting in a median QALM of 12 months (6.3-45.9). EQ-5D-5L can be used to determine the QALMs as qualitative basis for cost-effectiveness calculations for innovative treatments like IMI.
QOL-06. HEALTH RELATED QUALITY OF LIFE INFLUENCES ON OVERALL SURVIVAL IN GLIOBLASTOMAS
Authors: Nakajima Riho , Kinoshita Masashi , Okita Hirokazu , Nakada Mitsutoshi 
Published: November 2023

Abstract

BACKGROUND
Currently, in treatment of glioblastomas (GBM), emphasis is placed not only on prolonging prognosis but also on maintaining quality of life (QOL). The purpose of this study was to investigate the relationship between health related QOL and prognosis in GBMs and to examine factors that influence on QOL. Method: Participants were 34 patients with GBMs who underwent surgery (mean age, 56.4 years). All patients assessed Karnofsky performance status (KPS), several kinds of neurological and neuropsychological functions, and SF-36 for QOL. In SF-36, we calculated three summary component scores: physical, mental, and role/social component score (PCS, MCS, RCS, respectively). Cox-regression analysis was used to analyze relationship between QOL and progression-free survival (PFS) and overall survival (OS). To examine clinical and functional factors and brain regions associated with QOL, multiple regression analysis and the Voxel-based lesion symptom mapping (VLSM) were utilized. Result: When association between PFS/OS and QOL (PCS, MCS, and RCS) were analyzed, significant correlation was found only between OS and PCS (p = 0.039). Then, we investigated factors influencing on PCS. Using univariate analysis, the clinical factors associated with PCS were lesion location and KPS at 6 months (p = 0.037, p = 0.030, respectively). As for brain functions, visuospatial cognition and paralysis were significantly associated with PCS (p = 0.012 and p = 0.0056, respectively). Among these significant factors in univariate analyses, only visuospatial cognition and paralysis were associate with PCS via multiple regression analysis. Result of VLSM revealed that patients who resected the right medial superior frontal gyrus and deep part of the middle frontal gyrus showed significantly low PCS. Patients with VLSM positive region resected were more likely to have paresis and/or visuospatial cognitive deficit (p = 0.0013).

CONCLUSION
Health related QOL was associated with OS in GBMs. Factors influencing on QOL were visuospatial cognition and paresis, that may cause by lesion of the right frontal lobe.
QOL-07. RESISTING DECLINES IN FUNCTIONAL FITNESS: PRELIMINARY FINDINGS FROM THE RESIST TRIAL
Authors: Keats Melanie , Blanchard Chris , Fowles Jonathon , Grandy Scott , Langley Jodi , LeBlanc Alex , Neyedli Heather , Weeks Adrienne , MacNeil Mary 
Published: November 2023

Abstract
Few studies have evaluated the efficacy of exercise (EX) in mitigating the functional decline experienced by glioblastoma patients receiving steroids. Here we report preliminary findings on the impact of a tailored ~12-week circuit-based resistance training (CRT) program on functional fitness in glioblastoma patients on treatment. Patient accrual, adherence, and safety was evaluated throughout. Functional status (Short Physical Performance Battery) and grip strength were assessed at baseline and post-study. Depending on the treatment protocol, EX participants completed 3-6 weeks of in-person training followed by 6-9 weeks of home-based, Zoom facilitated training (3-4, 25–30-minute sessions/week). From March 2022 to May 2023, 33 glioblastoma patients were screened and met eligibility criteria, 24 expressed interest, and 15 subsequently agreed to participate (45% accrual). Participants were randomly allocated to either the EX (n = 7) or wait-list control (CON = 8) group. Ten participants (EX = 5; CON = 5) have completed the study with 1 CON ongoing (27% attrition; 2 withdrawn; 2 died) and incomplete fitness data for 1 EX participant. Three serious, unrelated adverse events were recorded, including 2 disease related deaths and 1 hospitalization. Adherence to in-person EX sessions was 96%. While not significant, preliminary efficacy data suggests that EX participants were more likely to maintain or mitigate losses in lower body function (CON (Mchange=-1.0, SD = 2.6); EX (Mchange = 0; SD = 1.3), t(7)=0.943, p &gt; 0.05, d = 0.49) and grip strength (CON (Mchange=-5.94kg, SD = 9.15; EX (Mchange = 0.4kg, SD = 5.75), t(7)=0.269, p &gt; 0.05, d = 0.83). Findings show that glioblastoma patients on active treatment are willing and able to safely engage in CRT. Participants were adherent to in-person CRT sessions, however self-reported home-based CRT was low, with many participants disengaging from EX. While this may be attributed to declining health and worsening fatigue related to ongoing treatments, additional study is needed to explore strategies to improve adherence to home-based EX sessions as in-person sessions are not always feasible.