bluuebunny/crossref_metadata_2025_split huggingface dataset:
CTIM-34. EFFECTS OF NEOADJUVANT IMMUNE CHECKPOINT INHIBITION ON PEDIATRIC AND ADULT HIGH-GRADE GLIOMAS
Authors: Keren-Gill Hadar , Herrera Gilbert , Baisiwala Shivani , Markus Lauren , Sun Lu , Everson Richard , Oren Michal Yalan , Govender Dinisha , Margol Ashley , Chi Susan , Prados Michael , Kline Cassie , Mueller Sabine , Davidson Tom Belle , Prins Robert 
Published: November 2024

Abstract
High-grade gliomas (HGG) are lethal tumors with few long-term survivors affecting adult and pediatric patients. Studies investigating immune checkpoint inhibition (ICI) suggest administration of neoadjuvant anti-PD1 blockade (neo-aPD1) enhances local and systemic anti-tumor responses. This data is supported by increased T cell density in the tumor and proportion of cytotoxic T cells in peripheral blood. In a previous randomized clinical trial, neo-aPD1 improved survival in adult with recurrent glioblastoma. In this study, we utilized multiplex immunofluorescence (mIF), and single-cell RNA sequencing (scRNA-seq) to investigate the effects of neoadjuvant ICI on the TME and compare between pediatric and adult populations. Tissue samples from adult patients with recurrent GBM treated with neo-aPD1 (n=22) or adjuvant only therapy (n=5) were obtained from our UCLA off-label neo-PD1 study. Tissue samples were also obtained from pediatric patients with recurrent/progressive HGG treated with neoadjuvant ICI from the ongoing Pediatric Neuro-Oncology Consortium study PNOC19. Samples included diagnostic tissue from two patients and on study surgery tissue from four patients. All tissue samples were subjected to mIF and underwent imaging analysis to assess immune cell infiltration by quantifying lymphoid and myeloid cell densities across the two treatment groups. Our preliminary findings elucidated a trend of higher T cell infiltration in adult neoadjuvant compared to adjuvant-only treated patients (median density 58.11 vs 15.15 T-cells/mm2). Compared to their adult counterparts, neoadjuvant ICI treated pediatric patients had even more robust total T cell infiltration (median density 268.10 vs 58.11 T-cell/mm2, pediatric vs adult respectively). scRNA-seq analysis revealed a greater enrichment of monocytic macrophages in the pediatric population compared to tissue resident microglia in the adults. This early data requires analysis of additional samples to better understand differences in the anti-tumor immune response between adult and pediatric recurrent/progressive HGG patients.
CTNI-34. A RANDOMIZED PROSPECTIVE TRIAL OF POST-OPERATIVE FLUID RESTRICTION TO DECREASE THE INCIDENCE OF DELAYED HYPONATREMIA AND READMISSION AFTER TRANSSPHENOIDAL SURGERY
Authors: Silverstein Julie , Mok Shinghei , Klaassen Doriann , Hwang Jenie , Blount Sydney , Williams Kelley , Fong Brendan , Luo Chongliang , Kim Albert 
Published: November 2024

Abstract

BACKGROUND
Delayed hyponatremia (hypoNa) is the leading cause of readmission following transsphenoidal surgery (TSS). Some institutions have adopted post-operative fluid restriction (FR) protocols based on retrospective studies. We present results of a prospective randomized controlled trial evaluating post-TSS FR.

METHODS
300 participants scheduled for TSS (2016-2023) at a single institution were included. Patients with CKD, CHF, AVP deficiency on postoperative day (POD) 3, chronic hypoNa, untreated adrenal insufficiency/hypothyroidism, and those for whom FR was felt unsafe were excluded. Patients were randomly assigned to control (CON, n=94) or moderate FR (FR1, n=39). Participants in CON group were instructed to drink ad lib. Participants in FR1 were FR to 1.8 liters/day (2 liters/day if &gt; 100 kg) from POD3-14. Based on interim analysis suggesting a trend toward reduced hypoNA, FR was changed to strict FR (FR2, n=62) of 1 liter/day (1.2 liters/day if &gt; 100 kg). Serum sodium (Na) was monitored inpatient and on POD 3, 7, 10, and 14, and readmissions evaluated. Fluid intake and thirst were assessed.

RESULTS
In the intention-to-treat analysis, incidence of hypoNa (Na &lt; 135 mEq/L) was 31.9% CON, 28.2% FR1, and 21% FR2, and severe hypoNa (Na &lt; 125 mEq/L) 7.4% CON, 5.1% n FR1 and 0% FR2. Readmission for hypoNa occurred in 6.4% (n=6) CON, 7.7% (n=3) FR1 and 1.6% (n=1) FR2. Severe hypoNa occurred more frequently in CON vs. FR2 (P=0.04), and nadir Na was higher in FR2 vs. CON (P=0.02). Although thirst scores were similar among groups, an individual’s thirst score correlated with compliance

CONCLUSION
Results of this randomized study show a reduction in severe hypoNa and readmission for hypoNa in patients on FR from POD3-14 after TSS vs. patients instructed to drink ad lib. This provides strong evidence that post-TSS FR decreases rate of delayed hypoNa and related readmission.
CTNI-48. A PHASE 1 STUDY OF ERAS-801, A POTENT, SELECTIVE, AND CENTRAL NERVOUS SYSTEM (CNS)-PENETRANT EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) INHIBITOR, FOR PATIENTS WITH RECURRENT GLIOBLASTOMA MULTIFORME (GBM)
Authors: Wen Patrick , Ahluwalia Manmeet , Odia Yazmin , McKean Meredith , Snyder James , Colman Howard , Lobbous Mina , Nghiemphu Leia , Chong Robert , Yang Jennifer , Patel Hina , Vecchio Daniela , Lokku Armend , Brail Les , Mellinghoff Ingo 
Published: November 2024

Abstract
EGFR is among the most common targets for genetic alterations in GBM. Changes in EGFR gene amplification and the extracellular domain result in receptor overexpression or constitutive activation, and enhanced oncogenic signaling. ERAS-801 is a potent, selective, and highly CNS-penetrant EGFR inhibitor being developed for the treatment of GBM, with a focus on tumors harboring EGFR genetic alterations. THUNDERBBOLT-1 is the first-in-human phase 1 dose escalation and expansion trial evaluating ERAS-801 monotherapy for patients with recurrent GBM. ERAS-801 is administered orally once daily for continuous 28-day cycles. As of April 10, 2024, a total of 52 patients were treated across 7 dose cohorts: 20 mg (n=3), 40 mg (n=5), 80 mg (n=3), 160 mg (n=6), 240 mg (n=25), 280 mg (n=4), or 320 mg (n=6). Key patient characteristics were median age of 60 years, 67% male, mostly one prior therapy, and 81% tumors with alterations. The MTD was 240 mg. Dose-limiting toxicities were observed at 320 mg (n=2, Grade 2 QT prolongation, Grade 3 rash and Grade 3 dermatitis acneiform), 280 mg (n=3, Grade 3 QT prolongation), and 240 mg (n=1, Grade 3 QT prolongation) doses. The most common treatment related adverse events (TRAEs), in &gt;10% of patients, were dermatitis acneiform, diarrhea, and nausea. Electrocardiogram QT prolongation occurred in 11.5% of patients and was not associated with clinical findings. ERAS-801 showed rapid absorption; peak plasma concentration was generally achieved within 6 hours post dose. PK exposure increased in a dose-dependent manner over the doses evaluated. Across all doses there was a confirmed partial response (using mRANO) in 1 patient and 6 patients achieved a PFS of 6 months. ERAS-801 shows well behaved PK with substantial CNS penetration, preliminary safety, and tolerability in patients with recurrent GBM. The TRAEs were reversible, manageable, and consistent with known toxicities of EGFR inhibitors.
CTNI-63. RHENIUM (186RE) OBISBEMEDA (RHENIUM NANOLIPOSOME,186RNL) FOR THE TREATMENT OF LEPTOMENINGEAL METASTASES (LM): SUMMARY OF THE PHASE 1 DOSE ESCALATION STUDY AND PHASE 2 ADMINISTERED DOSE SELECTION
Authors: Brenner Andrew , Youssef Michael , Kumthekar Priya , Bao Ande , Michalek Joel , Phillips William , Patel Toral , Floyd John , Hedrick Marc , Juverdianu Leonardo , Blouw Barbara , LaFrance Norman , Moore Melissa 
Published: November 2024

Abstract

BACKGROUND
Leptomeningeal metastases (LM) is a devastating systemic cancer complication most often seen with breast, lung, and melanoma, with limited treatment options and poor survival. Rhenium (186Re) Obisbemeda (186RNL) provides the combination of effective therapeutic beta radiation, simultaneous gamma-decay for imaging, and ~90-hour physical half-life for optimal radiation delivery. A summary of the Phase 1 dose escalation study, expected to be completed, will be presented.

METHODS
ReSPECT-LM is a Phase 1 dose escalation study for patients with LM from any primary cancer. Adult patients are given a single dose of 186RNL via intraventricular catheter (Ommaya reservoir) in an outpatient setting to determine the maximum tolerated/feasible dose (MTD/MFD), safety, and tolerability. Seven administered dose cohorts in a 3 + 3 design, from 6.6 mCi to 109.96 mCi, were anticipated.

RESULTS
For the first 5 cohorts, doses were well-tolerated; most AEs were Grade 1 and 2 with 1 DLT (Cohort 5) at time of abstract submission. CSF tumor cell enumeration assays were performed with a maximum reduction over baseline seen at Day 28. Radiation absorbed doses were calculated for the ventricles, cranial subarachnoid space, and spinal fluid and showed a linear increase with administered dose, with liver and spleen remaining low. Neurological symptoms were reported to improve. We expect the Phase 1 conclusion and the RP2D to be determined for conference reporting; additionally, based on duration of benefit seen during the Phase 1, a multidose paradigm will be initiated to extend benefit.

CONCLUSION
A single dose of 186RNL for patients with LM has been well-tolerated, with high absorbed doses to the treatment area, acceptable organ doses, and promising clinical improvement and reductions in tumor cell count. Phase 2 is expected to begin enrollment by Q4 2024. Additionally, based on these data, a Phase 1 multidose study is planned to be initiated this year.
CTNI-66. IDH-MUTANT GLIOMA PATIENTS TREATED WITH VORASIDENIB: ONGOING DATA FROM THE VORASIDENIB EXPANDED ACCESS PROGRAM
Authors: Cloughesy Timothy , Peters Katherine , Colman Howard , Taylor Jennie , Mellinghoff Ingo , Shih Helen , Chacar Christelle , Dewey Jonathan , Wen Patrick 
Published: November 2024

Abstract

BACKGROUND
Vorasidenib (VOR) is an oral, brain-penetrant dual inhibitor of mutant isocitrate dehydrogenase 1/2 (mIDH1/2) demonstrating clinical efficacy and safety in patients with mIDH1/2 glioma in the phase 3 INDIGO study (NCT04164901). Servier launched an expanded access program (EAP, NCT05592743) in November 2022 designed to provide access to VOR for patients with mIDH1/2 glioma. Early clinical outcomes of patients treated in this EAP are presented.

METHODS
Eligible participants were aged ≥12 years with mIDH1/2 glioma and, in the opinion of the treating oncologist, would potentially benefit from treatment with VOR. Safety assessments occur every two weeks for the first two 28-day cycles, then monthly for the duration of treatment.

RESULTS
As of the March 31, 2024 data cutoff, 71 participants have initiated treatment with VOR. Mean (SD) age was 42.7 (14.8) years; 39 (55%) were male; and 34 (48%) with astrocytoma. mIDH mutation status was 46 (65%) mIDH1. One participant had separate tumors with either mIDH1 or mIDH2 identified. The majority of participants had grade 2 gliomas (n=51 [72%]) and non-contrast–enhancing disease (n=49 [69%]). As of the data cutoff, 62 (87%) participants remain on treatment, with the majority initiating treatment within the past 6 months (n=49 [69%]). Nine (13%) participants have discontinued treatment due to: radiographic progressive disease (n=3); clinical progressive disease (n=4); adverse event (AE) unrelated to treatment (n=1); or other reason (n=1). Three participants have died (disease progression [n=2], unrelated infection [n=1]). At least one AE of any grade was seen in 35 (49%) participants, with 4 (6%) experiencing unrelated serious AEs. Eight (11%) patients had AEs of special interest (defined as grade 2 or higher ALT/AST elevations). Ten (14%) patients had AEs that led to dose interruption and one (1%) patient had dose reduction. Additional treatment duration and various subgroup analyses will be presented.
DNAR-16. TARGETING APOBEC CYTIDINE DEAMINASES TO ENHANCE RADIOSENSITIVITY IN GLIOMA
Authors: Marin Bianca M , Gujar Amit , Kocakavuk Emre , Johnson Kevin C , Amin Samirkumar B , Verhaak Roel G W 
Published: November 2024

Abstract
Glioma is the most common and aggressive primary adult brain tumor. Radiation therapy (RT) is a critical part of glioma treatment, but radioresistance severely limits its therapeutic efficacy. To better understand how radioresistance develops, we analyzed 212 paired primary and recurrent gliomas from the Glioma Longitudinal Analysis Consortium. We found a significant increase in mutational signatures associated with the activity of the Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) family of cytidine deaminases in RT-treated recurrent gliomas (p&lt;0.001, paired Wilcoxon signed-rank test). Further analysis of post-treatment mutations showed that RT increased APOBEC mutational signatures independent of other factors (p&lt;0.001, multivariable log-linear regression), suggesting that APOBEC proteins become activated by radiation. However, their role in promoting tumor evolution and treatment resistance is currently unknown. Further analyses of extended signature contexts and expression data nominated APOBEC3B (A3B) and APOBEC3G (A3G) as candidates for creating these mutational signatures. To investigate their roles in RT response, we knocked out (KO) A3B and A3G individually in patient-derived glioma cell lines before RT. Compared to Control cells, irradiated A3B-KO and A3G-KO cells acquired significantly fewer APOBEC mutational signatures by whole genome sequencing (p&lt;0.05, Kruskal–Wallis test) and exhibited enhanced radiosensitivity in vitro. Interestingly, the KO cells displayed a significant decrease in mutational signatures associated with Non-Homologous End-Joining (NHEJ), one of the main pathways for repairing the RT-induced DNA damage (p&lt;0.05, Kruskal–Wallis test), suggesting that APOBEC deletion impaired DNA repair. This was further supported by persistent gH2AX DNA damage foci 48h post-RT and reduced autophosphorylation of DNA-dependent protein kinase (DNA-PK), a vital component of the NHEJ pathway, particularly in A3G KO cells. Overall, our results identify APOBEC proteins as potential targets for radiosensitizing gliomas and highlight the clinical utility of using mutational signatures to predict and monitor response to treatment.
DDEL-13. ENHANCING THE EFFICACY OF THE BBB-PENETRANT PEPTIDE-DRUG CONJUGATE PT(IV)-M13 WITH THE KINASE INHIBITOR BIA TO IMPROVE INTRA-TUMORAL DELIVERY AND INHIBIT DNA REPAIR
Authors: Vaughn-Beaucaire Philippa , Macias Jorge Luis Jimenez , Miller Edward , Pentelute Bradley , Lawler Sean 
Published: November 2024

Abstract
The blood-brain and blood-tumor barriers (BBB and BTB) constitute major obstacles to effective GBM therapy. These barriers impede the penetration of the great majority of pharmacological agents into brain tumors. This study introduces a dual-modality approach aimed at enhancing drug delivery to GBM through manipulating BTB permeability and facilitating targeted drug delivery through a novel BBB penetrant drug conjugate. First, we investigated the effects of the broad specificity kinase inhibitor 6-bromo-indirubin-3’-acetoxime (BIA), a derivative of the natural medicinal indirubin, on BTB integrity. These studies revealed that BIA diminishes trans-endothelial electrical resistance and reduces the expression of VE-cadherin in human cerebral microvascular endothelial cells (hCMEC/D3), indicating a loosening of tight junctions. This effect was also observed in mouse GBM models, suggesting a BIA-induced increase in BTB permeability, enhancing the intra-tumoral accumulation and efficacy of non-brain-penetrant therapeutic agents in murine GBM models. Secondly, we have developed Pt(IV)-M13, a perfluoroaryl stapled variant of the cell-penetrating peptide TP10 conjugated to Pt(IV), a prodrug form of cisplatin. This conjugate demonstrates an ability to penetrate the BBB, enhancing drug delivery while limiting exposure to healthy brain tissue, Pt(IV)-M13 exhibits a promising cytotoxic effect on GBM cells, sparing non-tumorous cells, and increases the survival of GBM tumor-bearing mice significantly compared to controls. Our data includes quantitative analysis of platinum accumulation in tumor tissues versus non-targeted regions, highlighting the specificity and potential of this approach. Furthermore, we have found that BIA synergizes with Pt(IV)-M13 in vitro, via inhibition of DNA repair, and are currently investigating the safety and efficacy of administering BIA in conjunction with Pt(IV)-M13 in vivo. This novel strategy holds potential to significantly impact the clinical management of GBM, emphasizing the importance of targeting the BTB in future therapeutic strategies.
DDEL-17. INTRA-TUMORAL CONVECTION ENHANCED DELIVERY OF DEXAMETHASONE REDUCES INFLAMMATORY SIGNATURES AND EXTENDS SURVIVAL IN GBM MODEL
Authors: Dadario Nicholas , Teasley Damian , Lei Liang , Rolfe Nathaniel , Winans Nathan , Kotidis Corina , Khoury Nadine , Yoh Nina , Furnari Julia , Sperring Colin , Upadhyayula Pavan , Ifediora Nkechime , Humala Nelson , Mahajan Aayushi , Zhao Wenting , Gill Brian , Sims Peter , Canoll Peter , Bruce Jeffrey 
Published: November 2024

Abstract
Dexamethasone is the most widely utilized drug for glioblastoma (GBM). However, systemic delivery of dexamethasone in GBM patients is associated with significant side effects and increasing doses with worse survival. Convection-enhanced delivery (CED) can deliver high doses of immunotherapy directly into the tumor microenvironment (TME) while avoiding systemic toxicity. Here, we report that high doses of dexamethasone can be delivered locally by CED without side effects and increase survival in a GBM model along with reduced inflammatory myeloid signatures. We investigated CED of dexamethasone treatment on survival(n=40), adverse side effects, and the immunological TME through peripheral analyses, liquid chromatography–mass spectrometry, and histology in a preclinical syngeneic mouse model. Additionally, we assessed the transcriptional responses of human GBM slices and stem-cell-derived human microglia after steroid treatment through bulk and single-cell RNA sequencing. We found that 7-day treatment with CED of dexamethasone produced a significant survival advantage in glioma-bearing mice compared to non-treated control(p=0.03). Systemic dexamethasone achieved low levels of drug in the TME and caused dysregulated blood glucose, blood counts, and peripheral organ weights, while high CED doses avoided these side effects(p&lt; 0.05 each). Steroid treatment of acute GBM slices and lipopolysaccharide-activated microglia in-vitro both reversed inflammatory myeloid signatures associated with poor survival and recurrence on RNA sequencing analyses. We demonstrate the preclinical efficacy of delivering high local doses of dexamethasone in a GBM model through CED and observed prolonged survival along with reduced adverse inflammatory myeloid signatures. No side effects were demonstrated after chronic CED treatment of dexamethasone while systemic delivery achieved poor tumor penetration and caused known hematologic and metabolic side effects supporting the potential to optimize the clinical use of this therapy. CED of dexamethasone provides us a new treatment paradigm to locally control inflammatory signatures in the glioma TME in a controlled fashion.
DDDR-20. CLINICAL EFFICACY OF PYROTINIB COMBINING WITH STEREOTACTIC RADIOSURGERY IN HER2-POSITIVE BREAST CANCER BRAIN METASTASES
Authors: Zhen Juanjie , Bashir Shoaib , Yang Yanying , Wang Hui , Lai Mingyao , Cai Linbo 
Published: November 2024

Abstract

BACKGROUND
Up to 50% of patients with breast cancer (BC) and human epidermal growth factor receptor 2 (HER2) positive present with disease progression in brain metastases (BM). Pyrotinib, an oral irreversible pan-HER receptor tyrosine kinase inhibitor, has shown efficacy in active central nervous system (CNS) metastases. However, clinical efficacy of pyrotinib combining with stereotactic radiosurgery (SRS) in BCBM is unclear.

METHODS
This retrospective, observational study collected data from 52 HER2+ BC patients with brain metastasis who received pyrotinib-based therapy in Guang dong Sanjiu brain hospital from 2019 to 2023. Among these patients, 36 received pyrotinib-based therapy combining with SRS concurrently, or within 1 months. Age, stage at diagnosis, dates of BM, primary tumor subtypes, prior systemic therapy, CNS-directed local therapy, the objective response and survival status were collected. The assessment of adverse effects was based on CTCAE 4.0.

RESULTS
34 patients were evaluable for efficacy (median age: 51.5). With a median follow-up duration of 19.6 months, 1 patient (0.3%) achieved CR, while 27 patients (79.4%) had PR, resulting in an ORR of 82.3%. The median CNS PFS was 13.2 months (95% CI, 4.9-21.7). Median overall survival (OS) was 22.6 months (95% CI, 17.5-27.6). The most common grade 3 or worse treatment-emergent adverse event was diarrhea (6 [17.6%]).

CONCLUSIONS
Our results suggest that pyrotinib combining with SRS is associated with promising efficacy and a satisfactory safety profile for Her2+ breast cancer brain metastases.
DDDR-22. USE OF BIOPSY-DERIVED TUMOR ORGANOIDS FOR PERSONALIZED DRUG TESTING IN RECURRENT GLIOBLASTOMA
Authors: Herold-Mende Christel , Woellner Amelie , Warta Rolf , Cao Junguo , Paul Adrian , Aquilla Maddalena , Jungwirth Gerhard , Wick Wolfgang , von Deimling Andreas , Unterberg Andreas , Krieg Sandro , Jakobs Martin 
Published: November 2024

Abstract
To date, there are no effective systemic treatment options for recurrent glioblastoma (GBM). Furthermore, often surgical resection is not possible and tumors have acquired an increased chemo- or radioresistance. Patient-derived tumor organoids (PDTOs) provide a new exciting tool to test individual treatment responses. Aim of this study was to assess the feasibility of a personalized PDTO-based drug testing even from rare material such as stereotactic biopsies. PDTOs were prepared based on single cell suspensions from tumor material obtained either from open GBM resections (reference data set, n = 37) or from stereotactic biopsies (n = 8). Drug response curves (6-9 doses) were performed for 9 drugs including commonly used drugs such as temozolomide, lomustine, etoposide and temsirolimus. Viability was measured using CellTiterGlo (Promega) to assess half-maximal inhibitory concentrations (IC50). Medical records were reviewed for survival and molecular information such as the MGMT methylation status. Drug testing on PDTOs from open resections allowed to adjust the test range for each drug. Additionally, a significant association between increased temozolomide sensitivity of PDTOs and both, MGMT methylation and increased survival was observed. However, in 59% of the cases, no sensitivity to any of the drugs was seen, and only 17% were highly sensitive to more than one drug. Subsequent drug testing on PDTOs from biopsies of recurrent GBM revealed sensitivity in 3/8 cases against one (n=2) or two (n=1) of the drugs. However, sensitivity against drugs varied substantially in a patient-individual manner. We successfully developed a workflow to test drug sensitivity on PDTO even from low starting material obtained from stereotactic biopsies. Association of clinical outcome and MGMT methylation with temozolomide sensitivity corroborated the strength of this approach. Furthermore, patient-individual treatment responses strongly suggest for a future personalized drug testing.