bluuebunny/crossref_metadata_2025_split huggingface dataset:
CTNI-42. PHASE I CLINICAL TRIAL OF PEPOSERTIB PLUS RADIATION IN NEWLY DIAGNOSED MGMT-UNMETHYLATED GLIOBLASTOMA
Authors: Majd Nazanin , Yeboa D Nana , Weathers Shiao-Pei , Yuan Ying , Robichaux Christine , Anssari Haider Al , Gachimova Evguenia , Loghin Monica , Kamiya-Matsuoka Carlos , O'Brien Barbara , Aaroe Ashley , Patel Chirag , Yung W K Alfred , Wintermark Max , Gule Maria , Ferguson Sherise , Puduvalli Vinay , de Groot John 
Published: November 2023

Abstract

BACKGROUND
DNA-dependent protein kinase (DNA-PK) is a pivotal component of DNA damage repair (DDR) pathways and is an attractive target in glioblastoma because its expression renders tumors less vulnerable to radiotherapy. Peposertib is a small molecule DNA-PK inhibitor that has been shown to potentiate radiotherapy and regress glioblastoma tumors pre-clinically. We conducted a two-stage phase I trial of peposertib plus radiation in newly-diagnosed MGMT-unmethylated glioblastoma (NCT04555577). Method: In stage 1, patients received peposertib plus standard-of-care radiotherapy to determine the maximum-tolerated dose (MTD) based on the Bayesian Optimal Interval design (maximum n = 24). Stage 2 is a window-of-opportunity expansion cohort and will include 5 surgical patients to evaluate tumor drug concentration. Both groups receive adjuvant temozolomide for 6-cycles.

RESULTS
Fifteen completed the 10-week dose-limiting toxicity (DLT) period; 3-50mg, 3-100mg, 3-200mg, 6-300mg. One DLT (G3 radiation necrosis [RN] at 300mg) was observed. Most notable toxicity was 3 patients with transient G3 dermatitis of the scalp (not DLT per protocol) (2-200mg, 1-300mg). Therefore, radiation dose constrains to the skin were incorporated and subsequent patients did not experience this toxicity. Next-generation sequencing (NGS) was available for 13 archival tissue. Two patients had pathology-proven RN (one within and one outside of the DLT period). Both tumors had mutations in DDR genes (i.e. ATRX, DICER1). Recurrent tissue was available for one patient after treatment with peposertib showed gain of two ATM mutations.

CONCLUSION
The initial safety data of peposertib plus radiation in newly-diagnosed MGMT unmethylated glioblastoma is favorable. The cases with RN in tumors with DDR mutations, the gain of two ATM mutations in a recurrent tumor and the cases of scalp dermatitis suggest that peposertib is active and possibly potentiates the effect of radiation. Safety and survival data and correlations with genomics will be presented. The study was supported by EMD Serono (CrossRef Funder ID: 10.13039/100004755).
CTNI-46. UPFRONT VERSUS DEFERRED TREATMENT IN LOWER GRADE IDH-MUTANT GLIOMAS: A SINGLE-CENTER RETROSPECTIVE ANALYSIS
Authors: Patel Anuj , Whitfield Benjamin , Ballester Leomar , Puduvalli Vinay , Kamiya-Matsuoka Carlos 
Published: November 2023

Abstract

BACKGROUND
IDH-mutant gliomas are a diverse group of gliomas possessing a mutation in the isocitrate dehydrogenase enzyme. The treatment for both oligodendroglioma (1p/19q co-deleted) and astrocytoma includes resection followed by radiation therapy and chemotherapy. However, there is debate over the optimal timing of adjuvant treatment after surgery. An initial observation approach is sometimes pursued, particularly after gross total resection in young adults. We sought to examine the impact of timing of treatment in order to inform clinical decision-making.

METHODS
We identified 286 biopsied or resected glial tumors treated at MD Anderson Cancer Center from July 2015 to June 2022. Tumors were categorized using available molecular data based on the WHO 2021 diagnostic criteria. Progression-free survival was analyzed using Kaplan-Meier estimates.

RESULTS
Of 286 tumors, 232 had identified IDH-mutation, of which 89 were 1p/19q co-deleted and 143 were non-co-deleted. Of oligodendroglioma patients, 71 received either upfront chemotherapy, radiation or both and 18 received treatment upon progression; of astrocytoma patients, 96 were treated upfront and 47 received treatment at progression. Among oligodendroglioma patients, there were no significant differences in PFS between treatment timing groups (75.6 vs 66.7 months, P = 0.18). There was additionally no difference between oligodendroglioma patients treated initially with PC or PCV regimens vs temozolomide (not reached vs 75.4 months, P = 0.24). Among astrocytoma patients, upfront treatment was associated with longer PFS (93.8 vs 45.2 months, P &lt; 0.01). Patients with low-risk grade 2 gliomas (age &lt;40 and gross total resection) also showed longer PFS with upfront treatment (138.0 vs 45.2 months, P = 0.03).

CONCLUSION
Overall, the results in this molecularly defined cohort suggest a progression-free survival benefit from upfront treatment in IDH-mutant lower grade gliomas, including in low-risk gliomas. The optimal timing and nature of adjuvant treatment for lower grade gliomas remains a matter of debate.
CTNI-56. FEASIBILITY AND EFFICACY OF AI-GUIDED PERSONALIZED PRECISION RADIATION THERAPY IN NEWLY DIAGNOSED GLIOBLASTOMA: A MATCHED-CONTROL STUDY
Authors: Akbari Hamed , Mohan Suyash , Kazerooni Anahita Fathi , Bilello Michel , Sako Chiharu , Garcia Jose , Jiang Cecilia , Liu Fang , Brem Steven , Bakas Spyridon , Rathore Saima , Mamourian Elizabeth , Pepin Abigail , James Paul , Dorsey Jay F , Singh Ashish , Parker Drew , Verma Ragini , Cao Quy , Shinohara Russell T , Bagley Stephen J , Desai Arati , O'Rourke Donald M , Nasrallah MacLean P , Alonso-Basanta Michelle , Teo Boon-Keng Kevin , Kurtz Goldie , Shukla Gaurav , Lustig Robert A , Davatzikos Christos 
Published: November 2023

Abstract

PURPOSE
The aim of this study was to evaluate the feasibility and efficacy of AI-guided personalized precision radiation therapy (PPRT) in improving outcomes for patients with newly diagnosed glioblastoma.

METHODS
In an open-label trial conducted at the University of Pennsylvania (NCT03477513), between August 2018 and April 2021, 17 patients with IDH-wildtype glioblastoma who underwent maximal safe resection were enrolled. They were matched with a cohort of glioblastoma patients based on age, sex, extent of resection (EOR), O6-methylguanine-DNA methyltransferase promoter (MGMTp) methylation status, and IDH status. Propensity Score Matching (PSM) was employed to assess the impact of the intervention on the likelihood of survival, using logistic regression to estimate the propensity score. Four patients were disqualified based on exclusion criteria. The PPRT group received personalized radiation dose escalation guided by AI-based predictive modeling of recurrence, along with concomitant and maintenance temozolomide chemotherapy. The control group received standard-of-care chemoradiotherapy between 2012 and 2020. In this study, we utilized a previously published and evaluated (retrospectively and prospectively) predictive AI model, which accurately estimated neoplastic cell infiltration and predicted future tumor recurrence using preoperative, multi-parametric MRIs.

RESULTS
Median overall survival was 24.4 months in the PPRT-temozolomide group and 17.9 months in the standard-of-care treatment group (hazard ratio, 0.34; 95% CI: 0.15-0.77; p = 0.009). PPRT was well-tolerated, with low-grade adverse events during radiation. Radiation necrosis occurred in 54% of the PPRT-temozolomide group and 36% of the standard-of-care group.

CONCLUSION
AI-guided PPRT in newly diagnosed glioblastoma patients demonstrated feasibility in routine clinical practice and led to a statistically significant improvement in overall survival compared to matched controls receiving standard-of-care treatment. These findings highlight the potential of personalized precision radiation therapy, with focused dose escalation, in enhancing outcomes for glioblastoma patients and emphasize the need for prospective validation in a randomized controlled clinical trial.
CTNI-60. TREATMENT OF RECURRENT GLIOBLASTOMA WITH APG-157 VIA EXPANDED ACCESS: PRELIMINARY RESULTS FROM SIX PATIENTS FROM A SINGLE-CENTER STUDY
Authors: Fonkem Ekokobe , Betts Colton , Bradshaw Eva , Tamini Adam , Anyanda Elizabeth , Mehta Parag 
Published: November 2023

Abstract

INTRODUCTION
Glioblastoma (GBM) is the most common primary central nervous system malignancy. There is poor long-term survival with a median survival of two years and little consensus on second line therapies after progression. APG-157 is a new class of botanical drugs developed under FDA’s Botanical Drugs Guidance. The purpose of this study is to assess the safety and effect of APG-157 on the six-month survival and quality of life (QoL) of patients with recurrent GBM.

METHODS
Approval was obtained from the Baylor Scott and White IRB (# 022-230, Approval number 58100462000) and under group expanded access protocol (IND 162339). Major inclusion criteria include histologically proven GBM and unequivocal tumor progression 12 weeks after completion of standard first-line therapy. APG-157 was administered either as monotherapy or in combination with temozolomide or tumor-treating fields. Adverse events were assessed at each study visit. Patient data were collected from study conception through April 25, 2023.

RESULTS
A total of 6 patients (3 male, 3 females) were treated (median age was 54). A median of 2 treatment cycles were administered. 2 Patients withdrew from the study voluntarily, 2 patients expired while on treatment, and 2 patients continued treatment at the time of data analysis. 47.4% (9/19) of the questionnaire time points were completed, however, we saw low QoL (EORTC-QLQ-C30 and EORTC-QLQ-BN20) with a mean global health status score of 4.5. No patient saw a significant increase in their symptoms and one patient reported a 6-point decrease in their neurological symptoms. One patient who was on monotherapy of APG-157 for two months showed stable disease by MRI evaluation. There were no reported adverse events from the study medication.

CONCLUSION
Future follow-up and a larger sample size are necessary to confirm the impact of APG-157 on six-month survival and QoL.
CTNI-72. PHASE II TRIAL OF PATHOLOGY-BASED THREE-GROUP TREATMENT STRATIFICATION FOR PATIENTS WITH CNS GERM CELL TUMORS: A LONG-TERM FOLLOW-UP STUDY
Authors: Fulvio D'Angelo Hirokazu Takami , Suzuki Tomonari , Takabatake Kazuhiko , Fujimaki Takamitsu , Okamoto Michinari , Yamaguchi Shigeru , Kanamori Masayuki , Matsuda Kenichiro , Sonoda Yukihiko , Natsumeda Manabu , Ichinose Junya , Nakada Mitsutoshi , Muroi Ai , Ishikawa Eiichi , Takahashi Masamichi , Narita Yoshitaka , Higuchi Fumi , Shin Masahiro , Mineharu Yohei , Arakawa Yoshiki , Kagawa Naoki , Kawabata Shinji , Wanibuchi Masahiko , Takayasu Takeshi , Yamasaki Fumiyuki , Fujii Kentaro , Ishida Joji , Date Isao , Miyake Keisuke , Fujioka Hiroshi , Kuga Daisuke , Yamashita Shinji , Takeshima Hideo , Shinojima Naoki , Mukasa Akitake , Tanaka Shota , Asai Akio , Nishikawa Ryo , Matsutani Masao 
Published: November 2023

Abstract

BACKGROUND
Phase II clinical trial funded by Ministry of Health, Labour and Welfare from 1995 to 2003 evaluated efficacy of pathology-based three-group treatment stratification for CNS germ cell tumors (GCTs). We here present long-term follow-up results.

METHODS
Total 228 cases were registered. Germinoma was treated with carboplatin+etoposide (CARE) and extended-local irradiation, local irradiation was added for intermediate-prognosis-group, and poor-prognosis-group was treated with ifosfamide+cisplatin+etoposide (ICE) and whole-brain or craniospinal irradiation.

RESULTS
Mean/median ages at diagnosis were 16.8/16 years and female-to-male ratio was 40-188. Registry included 124 germinomas, 75 intermediate-prognosis-group cases (including 37 germinomas with STGC), 28 poor-prognosis-group cases and 1 mature teratoma. Median 222-months follow-up was conducted, and 56 recurrences and 39 deaths were recorded. 10 and 20-year event-free survival (EFS) for germinoma, intermediate and poor-prognosis-groups were 82/73%, 76/66% and 49/49%, respectively, and overall survival (OS) for each were 97/92%, 87/70% and 61/53%, respectively. Prognosis for germinoma with or without STGC was not statistically different. Basal ganglia germinoma showed significantly shorter RFS but OS was not different from other locations. Median age at death was 24 years, Time from treatment to deaths was significantly shorter for deaths due to original disease (5.7 years) than complications (14.9 years) and other causes (12.7 years) (p=0.005, 0.04, respectively). Overall survival after recurrence was clearly distinct according to the original histological groups; overall survival for germinoma, intermediate prognosis group and poor prognosis group were 94, 88 and 18% at 1 year, 91, 50 and 9% at 2 years and 88, 38 and 9 % at 3 years, respectively.

CONCLUSIONS
Germinoma and intermediate-prognosis-group cases showed long-term survival for approximately 90%, while more intensive treatment would be necessitated for poor-prognosis-group. Long-term survivors often required hormonal supplementation, and increasing frequency of treatment-related complications was observed. There is no end of outpatient follow-up for CNS GCT patients.
DNAR-08. BASE EXCISION REPAIR AS A THERAPEUTIC TARGET FOR DIFFUSE HEMISPHERIC GLIOMA, H3.3G34-MUTANT
Authors: Portante Alessia , Canty Laura , Patel Palak , Pajovic Sanja , Johnson Monique , Kim Byungjin , Negm Logine , Chung Jiil , Dolma Sonam , Dirks Peter , Tabori Uri , Hawkins Cynthia 
Published: November 2023

Abstract
Diffuse hemispheric gliomas with H3.3G34R/V mutations are primarily found in the cerebral hemisphere in adolescents and young adults, with a median age of 16-19 years. H3.3G34R frequently co-occurs with mutations in ATRX and TP53 as well as PDGFRα. We performed mutational signature analysis on a cohort of 28 cases of Diffuse hemispheric glioma, H3G34-mutant (7 WGS and 21 WES). Mutational signatures of defects in mismatch repair (MMR), homologous recombination (HR), and nucleotide excision repair (NER) pathways were found in 86% cases whereas only two (7%) had signatures of impaired base excision repair (BER). Analysis of H3.3G34R interactome data showed loss of association with MMR, HR, and NER pathways, with gains in association with proteins in the BER pathway compared to wildtype Histone H3. We thus hypothesise the Diffuse hemispheric glioma, H3G34-mutant may be dependent on BER over other DNA damage repair pathways. To test if BER could be a therapeutic vulnerability, we knocked down integral members of the BER pathway (UNG, APEX1, MPG, and XRCC1) via shRNA in 4 patient-derived H3.3G34R-mutant cell lines (two primary and two matched recurrent), and found that knockdown of XRCC1 and MPG, led to 99% (p&lt; 0.0001) and 96% (p&lt; 0.0001) cell death, respectively, after 8 days, compared to scrambled control. We next tested Triptolide, a BER inhibitor, and it led to cell death in vitro with IC50s of 1.1 to 1.7 nM. Taken together, these results indicate that inhibition of the BER pathway, specifically of the scaffolding-protein XRCC1, could be used as a novel therapeutic approach for diffuse hemispheric glioma, H3.3G34-mutant.
DDEL-01. UTILIZING SENSOR ARRAYS FOR INTRACRANIAL PRESSURE (ICP) RESPONSE TO CEREBROSPINAL FLUID (CSF) DRUG ADMINISTRATION, AND POTENTIAL IMPLICATIONS FOR PERSONALIZED CARE IN CNS METASTASES PATIENTS
Authors: Vanjani Nisheka , Patel Rajan , Glicksman Marcie , Lee Grace , Kumthekar Priya 
Published: November 2023

Abstract

BACKGROUND
Patients with leptomeningeal carcinomatosis (LC) may have elevated intracranial pressure (ICP) due to LC cancer cells having the potential to obstruct the arachnoid granulations.,Given that LC treatment may involve intrathecal (IT) drug delivery, monitoring ICP may be important for safe IT drug delivery. The EnClear device is a novel CNS drug delivery device with both intracranial and intralumbar CSF access and single-use sensing arrays that measure ICP in these dual locations.

METHODS
This is a non-human primate (NHP) study on three healthy NHP subjects undergoing IT gene therapy via intracerebroventricular (ICV). The sensor arrays measured ICP before, during, and after ICV infusion in both intracranial and lumbar locations. Our goal was to compare individual subject pressure response to drug administration as well as to compare lumbar and cranial pressure waveforms for concordance. Pressure response was quantified as change in pressure (ΔP) following volume (ΔV) administration, known as intracranial elastance (ΔP/ΔV).

RESULTS
Significant correlations were observed between ventricular and lumbar ICP waveforms with an average of 0.88 correlation coefficient. Pressure measurements between subjects demonstrated variable response to identical infusion volumes, with maximum pressures ranging from 20 mmHg to 40 mmHg. Intracranial elastance was calculated for each subject during infusions and resulted in a range of 12 to 36 mmHg/mL, a 3-fold difference in elastance between subjects.

CONCLUSION
In healthy NHPs, changes to cranial volume and pressure response can be measured in the lumbar space with good correlation between the two measurement locations. Despite this consistency between these two locations on the same subject, intersubject variability was seen despite identical drug administration. Pressure waveform sensing systems can be incorporated in the future to enable clinicians to understand individual patient brain compliance and leverage this knowledge for personalized drug delivery, particularly in patients with LC.
DDEL-11. FOCUSED ULTRASOUND-MEDIATED DELIVERY OF ANTI-PROGRAMMED CELL DEATH-LIGAND 1 ANTIBODY TO THE BRAIN OF A PORCINE MODEL
Authors: Fadera Siaka , Chukwu Chinwendu , Stark Andrew H , Yue Yimei , Yuan Jinyun , Chien Chih-Yen , Xu Lu , Albuhssin Mohammad , Chen Hong 
Published: November 2023

Abstract
Focused ultrasound-combined with microbubble-mediated blood-brain barrier opening (FUS-BBBO) has been established as a promising brain drug delivery technology for the treatment of brain tumors. Immune checkpoint inhibitor therapy is a form of cancer immunotherapy that has revolutionized the treatment of cancer and shown remarkable efficacy in a range of cancers. Previous studies reported successful delivery of a checkpoint inhibitor anti-PD-L1 antibody (aPD-L1) by FUS-BBBO in the mouse brain. The objective of this study was to evaluate the feasibility and safety of FUS-BBBO in the delivery of aDP-L1 to the brain of a large animal model. Pigs (4 weeks old, male, n=3) were used as the large animal model. A FUS transducer (frequency of 650 kHz, aperture of 65 mm, and a focal length of 65 mm) was used to sonicate three different brain regions in the presence of systemically injected microbubbles (Definity) for every pig. Near-infrared fluorescent dye-labeled aPD-L1 was injected intravenously to the pig after FUS sonication. Contrast-enhanced MRI was conducted to evaluate the BBB permeability. Pig brains were then harvested and imaged by the Licor Pear imaging system. Successful BBBO was confirmed by in vivo T1-weighted MR imaging. The average MR contrast enhancement volume in the FUS-targeted regions was 4.8× of that in the contralateral non-targeted regions. Ex vivo fluorescence imaging found that FUS sonication enhanced aPD-L1 delivery by 2.1× compared with the non-targeted regions. Histological analysis by hematoxylin and eosin (H&E) staining did not find evidence for tissue damage. These findings suggest that FUS-BBBO can achieve noninvasive, localized, and safe delivery of aPD-L1 to the brain of large animals, providing strong preclinical data to support the clinical translation of this promising technique for brain cancer immunotherapy.
DDEL-12. A CONFORMABLE IMPLANTABLE DEVICE - MICROMESH - FOR THE SUSTAINED DELIVERY OF CHEMOTHERAPEUTIC MOLECULES AND IMMUNE CHECK POINT INHIBITORS AGAINST HIGH-GRADE GLIOMAS
Authors: Palange Anna Lisa , Guerriero Irene , Pesce Cristiano , Mascolo Daniele Di , Decuzzi Paolo 
Published: November 2023

Abstract
High-grade gliomas, like glioblastoma (GBM), continue to have a poor prognosis with therapeutic options limited to maximal safe resection and adjuvant radiochemotherapy. Effective treatment is hampered by the blood-brain barrier, limiting the intratumor permeation of systemically administered agents; and biological heterogeneity of malignant cells, requiring complex therapeutic regimens. A conformable, compartmentalized polymeric implant – microMESH – has been engineered to overcome these obstacles by realizing a localized, sustained release of drugs, small inhibitors, antibodies, and nanomedicines. In the present configuration, microMESH comprises a water-soluble polyvinyl alcohol microlayer, loaded with the immune checkpoint aCD47, intercalated with a microfabricated network of poly lactic-co-glycolic acid, carrying docetaxel (DTXL). Upon deposition over the tumor margins, microMESH adheres and conforms to the local tissue releasing thereof its therapeutic cargo for several weeks, circumventing possible systemic toxicity. Gel permeation chromatography, nuclear magnetic resonance spectroscopy, weight and pH variations were measured to assess the microMESH biodegradation over time. microMESH biocompatibility and cytotoxicity were assessed on cancer cell monolayers and spheroids. The preclinical performance of microMESH was evaluated in two syngeneic mouse models of high-grade gliomas obtained via the intracranial inoculation of murine cancer cells – CT-2A, cold tumor; GL261, hot tumor. Flow cytometry was used to map the immune component in the tumor and assess the expression of immune checkpoints. Bioluminescence imaging was used to monitor tumor proliferation longitudinally. microMESH biodegraded in ~2 months with no documented toxicity. Preliminary experiments with an aCD47/DTXL–microMESH applied over the unresected margins of an orthotopic CT-2A model documented a median overall survival of 33.5 days against 18 days for untreated mice, 22 days for intravenously injected DTXL, 24 days for intraperitoneally administered aCD47 (statistically not significant difference among the control groups). microMESH allowed the sustained delivery of complex combination therapies directly at the tumor bed demonstrating superior efficacy over systemic therapies.