bluuebunny/crossref_metadata_2025_split huggingface dataset:
CTNI-31. TREATMENT BENEFIT IN PATIENTS AGED 80 YEARS OR OLDER WITH BIOPSY-PROVEN AND NON-RESECTED GLIOBLASTOMA IS DEPENDENT ON MGMT PROMOTER METHYLATION STATUS
Authors: Weller Jonathan , Katzendobler Sophie , Niedermeyer Sebastian , Harter Patrick , Herms Jochen , Trumm Christoph , Niyazi Maximilian , Thon Niklas , Tonn Joerg-Christian , Stoecklein Veit 
Published: November 2023

Abstract

PURPOSE
Glioblastoma is associated with especially poor outcome in the elderly. It is unclear if patients aged ≥ 80 years benefit from tumor-specific therapy as opposed to receiving best supportive care (BSC) only.

METHODS
Patients with IDH-wildtype glioblastoma (WHO 2021), aged ≥ 80 years, and diagnosed by biopsy between 2010 and 2022 were included. Patient characteristics and clinical parameters were assessed. Uni- and multivariate analyses were performed.

RESULTS
76 patients with a median age of 82 (range 80–89) and a median initial KPS of 80 (range 50–90) were included. Tumor-specific therapy was initiated in 52 patients (68%). 22 patients (29%) received temozolomide monotherapy, 23 patients (30%) were treated with radiotherapy (RT) alone and 7 patients (9%) received combination therapies. In 24 patients (32%), tumor-specific therapy was omitted in lieu of BSC. Overall survival (OS) was longer in patients receiving tumor-specific therapy (5.4 vs. 3.3 months, p&lt;0.001). Molecular stratification showed that the survival benefit was owed to patients with MGMT promoter methylation (MGMTpos) who received tumor-specific therapy as opposed to BSC (6.2 vs. 2.6 months, p&lt;0.001), especially to those with better clinical status and no initial polypharmacy. Patients with unmethylated MGMT promoter (MGMTneg) did not benefit from tumor-specific therapy (3.6 vs. 3.7 months, p=0.18). In multivariate analyses, better clinical status and MGMT promoter methylation were associated with prolonged survival (p&lt;0.01 and p=0.01).

CONCLUSION
Benefit from tumor-specific treatment in patients with newly diagnosed glioblastoma aged ≥ 80 years might be restricted to MGMTpos patients, especially to those with good clinical status and no polypharmacy.
CTNI-43. A PHASE 1/2 STUDY OF LOW DOSE FRACTIONATED RADIATION THERAPY AS A CHEMOPOTENTIATOR OF SALVAGE TEMOZOLOMIDE FOR HIGH-GRADE GLIOMA
Authors: Lin Timothy , Ke Suqi , Hu Chen , Mukherjee Debraj , Weingart Jon , Kleinberg Lawrence , Huang James , Assadi Ryan , Holdhoff Matthias , Grossman Stuart , Ahmed Mansoor , Redmond Kristin 
Published: November 2023

Abstract
Cell-survival curves demonstrate low-dose radiation hypersensitivity, with steepest cell kill at 0.3-0.5 Gy/fx. This phase 1/2 study assessed the safety/efficacy of low-dose fractionated radiotherapy (LDFRT) as a chemopotentiator of TMZ in recurrent glioblastoma or anaplastic astrocytoma (AA) patients. Patients with recurrent glioblastoma/AA following standard-of-care therapy, &gt; 12 months from prior RT and &gt;2 months from prior TMZ were eligible for 0.5 Gy RT twice daily x10 fractions with concurrent TMZ (150-200 mg/m2), both delivered in 5 days of a 28-day cycle up to 6 cycles, followed by 6 cycles of adjuvant TMZ. In phase 1, hematologic toxicity was assessed 1 month after initiating therapy. Brain MRIs were obtained every 2 months, or monthly when concerned for progression (defined by RANO criteria). Pseudoprogression consisted of MRI changes irrespective of clinical deterioration/steroid use that stabilized/reversed without oncologic intervention. The primary endpoint, 1-year overall survival (OS), would be considered for future investigation with a lower bound of 80% CI &gt; 28%, chosen from historical data. Secondary endpoints included rates of pseudoprogression and hematologic toxicity. 31 patients were enrolled/analyzed. Grade 3-4 acute hematologic toxicity was observed in 8(27%) patients. Median follow-up was 9.5(range:0.1-66.3) months. Median OS was 9.6(95%CI 7.0-15.4) months. 1-year OS was 34.5%(95%CI 20.9%-57.0%; lower bound of 80%CI = 24.8%). 77% of patients experienced pseudoprogression, with a median time from start of LDFRT of 1.9(95%CI 1.7-4.4) months and median duration of 3.6(95%CI 1.6-Not estimable) months. Patients with pseudoprogression had improved OS vs. those without (N = 6; median 10.6 vs 3.9 months, HR = .12[95%CI .03-.40];P &lt; .01). LDFRT for recurrent glioblastoma/AA was safe. High pseudoprogression rates were observed at low RT doses, with improved OS amongst patients with pseudoprogression. LDFRT with TMZ may elicit low-dose RT hypersensitivity in patients with glioblastoma/AA. Further study is needed to optimally apply this radiobiological property to improve clinical outcomes.
CTNI-47. DOSE ESCALATION OF ASTX727 IN ADULT PATIENTS WITH RECURRENT/PROGRESSIVE NON-ENHANCING IDH MUTANT GLIOMAS
Authors: Arrillaga-Romany Isabel , Miller Julie , Dietrich Jorg , Plotkin Scott R , Gerstner Elizabeth , Jordan Justin T , Forst Deborah , Lee Eudocia , Wen Patrick , Reardon David , Nayak Lakshmi , Batchelor Tracy , Chukwueke Ugonma , Rivera Miguel , Agar Nathalie , Cahill Daniel , Bernstein Bradley 
Published: November 2023

Abstract

BACKGROUND
IDH mutant gliomas typically display a hypermethylation pattern known as the glioma CpG island methylator phenotype (G-CIMP) which results in gene activation that promotes gliomagenesis. This study aims to reverse this methylation signature and disrupt tumor growth via treatment with an oral demethylating agent.

METHODS
This is 2-stage clinical trial investigating oral ASTX727 (decitabine + cedazuridine, a cytidine deaminase inhibitor, as a combination tablet) in patients with recurrent primarily non-enhancing IDH mutant gliomas. The Dose Escalation Stage consisted of a single arm 3 + 3 design. The primary objective was to establish the MTD and assess safety in this patient population.

RESULTS
Eleven pts (F = 45%, M = 55%) with a median age of 44 yrs (range 26-61 yrs) were enrolled. Two DLTs (grade 4 neutropenia for &gt;72 hrs) were observed in 5 pts enrolled at the starting dose (35 mg decitabine/ 100 mg cedazuridine for 5 consecutive days). Six additional patients were enrolled at dose level -1 (35 mg decitabine/100 mg cedazuridine for 4 consecutive days). There were no DLTs at dose level -1 and this was declared the MTD. Grade ≥ 3 AEs included neutropenia (5 pts), leukopenia (1 pt), lymphopenia (1 pt), hyponatremia (1 pt) and increased ALT (1 pt). Best treatment response was SD in 11 patients. At the time of last follow-up (5/15/23) 10 pts have discontinued treatment (8 for PD, and 2 based on physician decision), 2 pts (18%) have died due to disease progression, 8 pts remain alive and in follow-up, and 1 patient remains on treatment. Median duration on treatment was 212 days (range 36 days – not reached).

CONCLUSIONS
ASTX727 was well tolerated in patients with recurrent non-enhancing IDH mutant glioma at dose level -1 with no DLTs . A surgical expansion cohort is currently enrolling to confirm drug target engagement and explore pharmacodynamics.
CTNI-49. RHENIUM-(RE-186)-OBISBEMEDA [RE-186-NANOLIPOSOME] (186RNL) PHASE 2 FOR RECURRENT GLIOBLASTOMA (RGBM) VIA CONVECTION ENHANCE DELIVERY [CED]
Authors: Brenner Andrew , Michalek Joel , Moore Melissa , Hedrick Marc , Bao Ande , Phillips William , Patel Toral , Weinberg Jeffrey , Floyd John 
Published: November 2023

Abstract

BACKGROUND
The Phase 1 ReSPECT-GBM trial observed a relative improvement in overall survival(OS) in rGBM with absorbed doses &gt;100 Gray[Gy] compared to lower doses and historical controls. Statistical modeling was employed to understand the dose response relationship in planning the Phase2 trial.

METHODS
Phase1 data from cohorts1-6 of the 3 + 3 dose-escalation trial[N = 21] were utilized. Longitudinal MRI and SPECT/CT imaging were performed to assess treatment outcomes. SPECT/CT images were used to find the treatment volume. Variation in survival significance was assessed with log rank tests and an accelerated failure time (AFT) model. All statistical testing was 2-sided with a 5% significance level.

RESULTS
MTD/DLT was not reached in the first 6 cohorts. The 3 + 3 dosing (ml&mCurie) by cohort was 1: 0.66&1.0, 2: 1.32&2.0, 3: 2.63&4.0, 4: 5.28&8.0, 5: 5.28&13.4, 6: 8.8&22.3. Unadjusted for covariate information, median OS was 11.0 months(m) [95% Confidence Interval (CI) 5.0 m to 17 m]. Median OS varied significantly with absorbed dose; &lt; 100 Gy: n = 9, median OS = 6.0 m, 95% CI 1.0m to 11m), ≥100 Gy: n = 12, median OS = 17.0 m (95% CI 8.0 m to 35.0 m), p &lt; 0.001. After adjustment for age, baseline ECOG performance status, and baseline tumor volume, the AFT model predicted the OS to fold increase by 1.3 (95% CI 1.1 to 1.5)/100Gy increase in the absorbed dose (p &lt; 0.001) and by 1.28 (95% CI 1.21 to 1.35 m)/10% increase in the treated to total tumor volume ratio (p &lt; 0.001). The phase 2 trial, utilizing Cohort6 administered dose 22.3mCi in 8.8mL for tumor volumes ≤20mL [average absorbed dose of 374.5Gy], is ongoing--n = 5 accrued as of May 2023.

CONCLUSION
186RNL therapy resulted in a dose and volume dependent impact on OS without significant toxicity. Based on these data, the Cohort 6 non-DLT dose advanced to Phase 2. Study progress will be reported.
CTNI-53. ESTABLISHING A PHASE I AND RANDOMIZED PHASE II TRIAL OF SELINEXOR AND TEMOZOLOMIDE IN GLIOBLASTOMA
Authors: Chow Frances , Berens Michael , Tamir Sharon , Landesman Yosef , Walker Christopher , Palmer Joycelynne , Porter Alyx , Piccioni David , Ney Douglas , de la Fuente Macarena , Kizilbash Sani H , Bojanowski-Hoang Kimberly , Lipinski Lindsay , Strowd Roy , Giglio Pierre , Hrachova Maya , Mantica Megan , Schiff David , Gore Steven , Portnow Jana 
Published: November 2023

Abstract

BACKGROUND
Selinexor (SEL) is a first-in-class XPO1 inhibitor with potent antitumor activity via tumor suppressor protein nuclear localization and reactivation, oncoprotein translation suppression, and DNA repair inhibition. As a single agent, SEL has demonstrated adequate brain penetration and clinically relevant responses in glioblastoma. We seek to enhance the effect and benefit of SEL by priming with temozolomide (TMZ).

METHODS
We developed in vitro and in vivo studies to rationally design a phase I/II trial to evaluate the safety and efficacy of the sequential combination of SEL+TMZ. Sequential treatment of U87 cells and intracranial mouse xenografts demonstrated superior DNA damage (ɣH2A.X, cleaved PARP) and overall survival compared to combination or single-agent therapy (HR 0.25 [95% CI, 0.07-0.84]; p = 0.01, log-rank). We used the top-scoring pair method to identify a 6 gene-pair RNAseq signature associated with response to SEL.

RESULTS
Based on preclinical findings, we developed and opened a multi-institutional phase I/II clinical trial in October 2022. Eligibility includes histologically confirmed 1st recurrent MGMT promoter methylated glioblastoma. Primary objectives are safety and preliminary efficacy. Secondary objectives are overall response rate, efficacy, and prospective validation of a molecular signature of response. Phase I dose finding by IQ 3 + 3 (n = 12) involves TMZ 150mg/m2 on days 1-5 of a 28-day cycle plus SEL on days 8 and 15. Phase II will involve randomization (n = 72) to the RP2D of SEL+TMZ versus monotherapy TMZ. Using proportional hazards regression, RHR 0.5 with p &lt; 0.1 will demonstrate sufficient efficacy. We have enrolled 3 participants in dose level 1 (SEL 60mg) with no dose-limiting toxicities (DLTs) observed. Additional preliminary results will be presented.

CONCLUSION
Preliminary results suggest that a sequential dosing regimen of SEL+TMZ is feasible and initial dose is well-tolerated and may minimize the cumulative toxicity of SEL. The trial is currently enrolling nationwide (NCI #10505, NCT05432804).
CTNI-78. EVALUATION OF POST-PROGRESSION TREATMENTS AFTER VAL-083 IN RECURRENT AND NEWLY DIAGNOSED GBM MGMT-UNMETHYLATED PATIENTS
Authors: Kamiya-Matsuoka Carlos , Weathers Shiao-Pei , Yung W K Alfred , Loghin Monica , Majd Nazanin , Brown Dennis , Langlands John , Schwartz Richard , Knight Stephanie , Puduvalli Vinay , de Groot John , O'Brien Barbara 
Published: November 2023

Abstract
Almost all GBM patients experience recurrent disease following up-front standard of care treatment, with a median survival of 3-9 months after recurrence. Challenges with salvage therapies include the potential for side-effects, which may limit further treatment. VAL-083 is a bi-functional DNA-targeting agent which rapidly induces inter-strand DNA cross-links at N7-guanine inducing double-strand breaks causing cell death independently of MGMT DNA repair and DNA mismatch repair deficiency. VAL-083 was evaluated in an open-label two-arm biomarker-driven phase 2 trial in MGMT-unmethylated bevacizumab-naïve GBM patients with either recurrent (Group 1) or newly diagnosed GBM requiring adjuvant therapy after chemo-radiation with TMZ (Group 2). Post-progression, patients were followed for survival status, and any post-VAL-083 treatments. Here we review treatments received by patients following participation in this clinical trial, and their outcomes. Patients were excluded from the review if no data had been collected or if they had undergone subsequent surgery. Group 1(n=42) and Group 2(n=31) who received 30 mg/m2 VAL-083 (days 1-3 of 21-day cycle) were evaluated. In Group 1 and Group 2, 17/42 (40.5%) and 20/31 (64.5%), respectively, received an alkylating agent post-VAL-083. Receiving more than the median number of cycles of VAL-083 in either group didn’t limit patients from receiving alkylating agents such as CCNU and TMZ after VAL-083. No hematologic complications were identified. Furthermore, receiving ≥5 cycles of adjuvant TMZ prior to VAL-083 in Group 1 didn’t affect patient’s ability to receive alkylating agents. For both groups, mOS and OS-6 from the last dose of VAL-083 were greater for those receiving alkylating agent post VAL-083, compared to those who didn’t. These data demonstrate that alkylating agents may be administered safely to patients who have progressed following therapy with VAL-083, and patients who have received an alkylating agent after VAL-083 therapy have a better outcome compared to those receiving other treatments.
CTNI-80. INTUITT-NF2, AN ADAPTIVE PLATFORM-BASKET TRIAL FOR NF2-RELATED SCHWANNOMATOSIS PATIENTS WITH PROGRESSIVE SCHWANNOMAS, MENINGIOMAS, AND EPENDYMOMAS: PRIMARY OUTCOME OF THE BRIGATINIB TREATMENT ARM
Authors: Plotkin Scott R , Babovic-Vuksanovic Dusica , Dinh Christine , Fell Geoffrey , Merker Vanessa , Nghiemphu Phioanh , Trippa Lorenzo , Yohay Kaley , Blakeley Jaishri 
Published: November 2023

Abstract

INTRODUCTION
NF2-related schwannomatosis (NF2-SWN) predisposes affected individuals to vestibular schwannomas (VS), non-vestibular schwannomas (NVS), meningiomas, and ependymomas. The rarity of NF2-SWN and the presence of multiple tumor types has impeded clinical trials. We conducted a multi-center, adaptive, platform-basket trial to screen multiple drugs against progressive NF2-SWN tumors. We report the final analysis of the first treatment arm with brigatinib, an oral ALK inhibitor that inhibits multiple tyrosine kinases.

METHODS
This study enrolled participants ≥ 12 years with NF2-SWN and progressive target tumors (baskets: VS, NVS, meningioma, or ependymoma Radiographic response (RR) was defined as ≥ 20% decrease in target tumor volume from baseline. The primary outcome was RR rate. Secondary outcomes included safety, hearing response, and RR in non-target tumors. Tumor response was evaluated by MRI every 3 months in year 1 and every 6 months thereafter. In stage 1, 20 participants received brigatinib 180 mg daily. Interim analysis suggested activity in NVS and meningioma. Thus, an additional 20 participants with progressive meningioma or NVS were enrolled in stage 2.

RESULTS
Forty participants (median age 26 years, 12 pediatric, 28 female) were treated. Prior treatment included surgery (90%), radiation therapy (20%) and chemotherapy (55%). Target tumors included 10 VS, 9 NVS, 19 meningiomas, and 2 ependymomas. Overall RR rate was 10% for all target tumors (22% for non-VS, 11% for meningioma, 0% for VS, and 0% for ependymomas). There were no grade 4 or 5 treatment-related adverse events (AEs). The most common AEs were diarrhea (63%), nausea (40%), muscle cramps (33%), increased LDH (35%), increased AST (33%), and increased ALT (23%).

CONCLUSION
Brigatinib treatment was associated with RR in NVS and meningiomas in a heavily pretreated cohort of participants with progressing NF2-SWN tumors. This novel design provides unique ability to assess treatments for hereditary syndromes with multiple primary tumors.
DNAR-01. PAR-MEDIATED DNA DAMAGE SIGNALING IN IDH MUTANT GLIOMAS: COMBINING PARG INHIBITION AND RADIATION FOR SELECTIVE CYTOTOXICITY
Authors: Kitagawa Yosuke , Nasser Ali , Chang Chia , Melamed Lisa , Miller Julie , Wakimoto Hiroaki , Cahill Daniel 
Published: November 2023

Abstract
Isocitrate dehydrogenase (IDH) 1 or 2 mutant gliomas have unique metabolic characteristics and DNA damage response. Radiotherapy and chemotherapy have been proven to be effective treatments for IDH mutant gliomas. Poly (ADP-ribose) (PAR) mediates DNA damage response and is regulated by opposing enzymes: poly (ADP-ribose) polymerases (PARPs) synthesize PAR, while poly (ADP-ribose) glycohydrolase (PARG) breaks it down. Combining PARG inhibitor (PARGi) and Temozolomide (TMZ) in IDH mutant cells leads to imbalanced NAD sequestration into PAR, causing metabolic lethality. This study characterizes the combination of PARGi and radiation. PARGi monotherapy showed no difference between IDH mutant and wild-type cells. However, we found that combining PARGi with radiation significantly increased cytotoxicity in IDH mutant glioma models, similar to PARPi and radiation. (Wang et al, ACi.Adv. 2020) Our findings showed that unlike TMZ+PARGi, PARGi and radiation did not consume and deplete NAD. Cytotoxicity was partially reversed by IDH inhibitor, highlighting the contribution of PAR-mediated DNA damage signaling in IDH mutant contexts. This convergence of vulnerabilities in IDH mutant cells identifies PAR-mediated DNA repair mechanisms that operate independently of NAD metabolism. IDH mutant enzyme generates 2 hydroxyglutarate (2HG), which is critical early in tumor development. However, the effect of 2HG on radiation sensitivity varies across cellular contexts. In this study, we found that IDH1 mutation and 2HG production enhance radiosensitivity in glioma cells both in vivo and in in vitro models, facilitated by PAR-dependent mechanisms. This augmentation of radiosensitivity is associated with S-phase blockage of the cell cycle, unveiling a vulnerability in the replication process of these cancer cells. In summary, this study demonstrates that the combination of PARGi and radiation regulates DNA repair pathways, augmenting cytotoxicity specifically in IDH mutant gliomas. Targeting PAR during radiation holds promise for treating IDH mutant gliomas, tailoring therapy to maximize durability while minimizing impact on normal cells.
DNAR-04. MICRORNA DEGRADATION ENHANCES GLIOBLASTOMA INTRA-TUMORAL HETEROGENEITY TO AUGMENT ACQUIRED TEMOZOLOMIDE RESISTANCE
Authors: Ramakrishnan Valya , Singh Gatikrushna , Xu Beibei , Ackers Johnny , Chen Clark 
Published: November 2023

Abstract

INTRODUCTION
O6 methyl-guanine methyltransferase (MGMT) restores alkylated DNA to its undamaged form and dictates clonal evolution in response to chemotherapy. As such, MGMT is a major determinant of glioblastoma resistance to the standard-of-care chemotherapy temozolomide. miR-181d is a MGMT suppressing microRNA, whose expression inversely correlate with survival expectation after temozolomide treatment. Here, we characterize the expression of miR-181d and MGMT in response to temozolomide treatment. Method: Laboratory characterization, single cell analysis, and murine modeling

RESULTS
Treatment of glioblastoma cells with temozolomide (TMZ) induced a feed-forward cascade resulting in an ataxia telangiectasia and Rad3 (ATR) and polyribonucleotide nucleotidyl transferase 1 (PNPT1) dependent degradation of miR-181d. Single-cell analyses revealed such miR-181d degradation: 1) increased mean level of MGMT expression in a cell population and 2) enhanced cell-to-cell variability in MGMT expression to increase intra-tumoral heterogeneity in DNA repair capacity. This increased intra-tumoral heterogeneity enhanced glioblastoma resistance to temozolomide through a mechanism distinct from lowering the mean MGMT expression of the tumor population. Suppression of this heterogeneity by exogenous miR-181d over-expression enhanced the tumoricidal activity of temozolomide against glioblastomas.

CONCLUSION
We identified an interface between DNA damage response and miRNA degradation that mediate intra-tumoral heterogeneity and subsequent temozolomide resistance. This resistance mechanism is distinct from modulation of the mean MGMT expression of the population.
DDEL-09. SATURATED FATTY ACID EMULSION OPENS THE BLOOD-BRAIN BARRIERS AND ENHANCES DRUG DELIVERY
Authors: Sung Kyoung Su , Cho Won-Ho , Kim Hak Jin 
Published: November 2023

Abstract

PURPOSE
To evaluate whether saturated fatty acid (SFA) emulsion affects the BBB and whether drug delivery is promoted with the aid of SFA in the brain.

MATERIAL AND METHODS
Each SFA (butyric, valeric, caproic, enantic and caprylic acid) emulsion was infused into the right common carotid artery in a rat model. Trypan blue staining for qualitative and semiquantitative analysis of the BBB opening was performed. A transmission electron microscopic (TEM) exam with the contrast media for morphologic evaluation of the tight junction was obtained. Delivery of doxorubicin in the brain was determined by fluorometric analysis. Delivery of temozolomide (TMZ) through the BBB was studied by desorption electrospray ionization (DESI)-MS imaging.

RESULTS
The ipsilateral hemisphere revealed positive trypan blue staining in all five SFA emulsion groups. Ratios of the ipsilateral to the contralateral hemisphere of in trypan blue permeability with hue analysis was above 1.0. As the carbon number in the used SFA increased, the ratio of trypan blue permeability increased and was statistically significant (P &lt; 0.05). The tight junction and neural interstitium were filled with the contrast media in all five SFA emulsion groups. Delivery of doxorubicin (P &lt; 0.05) and TMZ were significantly high in the ipsilateral hemisphere compared to the contralateral hemisphere. In the caprylic acid group, the BBB opening and drug delivery were highest among the five SFA groups.

CONCLUSION
SFA emulsion with intraarterial infusion opened the BBB and drug delivery was enhanced consequently. Thus, SFA emulsion might be another strategy for the research of BBB opening and promotion of drug delivery in the brain.