bluuebunny/crossref_metadata_2025_split huggingface dataset:
EXTH-72. TARGETED INHIBITION OF THREE MAJOR PROLIFERATION PATHWAYS IN GLIOBLASTOMA INDUCES SENESCENCE THROUGH A MITOCHONDRIA-DEPENDENT MECHANISM
Authors: Baltira Chrysiida , Mayayo-Peralta Isabel , Guillen-Navarro Miriam , Alkan Ferhat , Thijssen Bram , Pello Kimberley , Fedorushkova Daria , Their Anna , Silva Joana , Jochems Fleur , Bleijerveld Onno , Janssen Hans , Faller William , Bernards Rene , de Gooijer Mark , van Tellingen Olaf 
Published: November 2023

Abstract
Glioblastoma (GBM) is a fatal brain tumor with a great unmet need for better therapies. Research on the genomic landscape of GBM has revealed that three major proliferation pathways — the PI3K-mTOR-AKT, the MAPK, and the CDK4/6-RB pathways — are overactive in the majority of GBM patients. Based on that knowledge we have developed a multi-target combination therapy (MTCT) by employing inhibitors of these three pathways. When these inhibitors are used in combination, lower, clinically more relevant concentrations of each drug are sufficient for target inhibition and proliferation arrest than with single agents. Excitingly, we find that MTCT not only shuts down proliferation but also causes permanent growth inhibition by the induction of senescence and the secretion of a senescence-associated secretory phenotype (SASP). MTCT-senescent cells have increased mitochondrial reactive oxygen species (mtROS). However, they do not acquire nuclear DNA damage but only local mitochondrial DNA damage. Addition of antioxidants that deplete mtROS resulted in senescence rescue both in terms of morphology and proliferation arrest. MTCT-senescent cells display an enhancement in total mitochondrial mass, mitochondrial DNA copy numbers, and the transcription of mitochondrial proteins. Despite this enhancement, the basal respiration rate of these cells is comparable to untreated cells, indicating an impaired maximal respiration capacity in MTCT-senescent cells. Concordantly, these cells display striking disturbances of their mitochondrial network. Intriguingly, depletion of functional mitochondria prevents the induction of mtROS and senescence by MTCT but not by classical senescence inducers such as ionizing radiation or high concentrations of CDK4/6 inhibitors. To conclude, MTCT induces senescence in GBM cells through a unique nuclear DNA damage-independent mechanism for which the mitochondria are essential.
QLTI-02. ADVERSE EVENTS IN GLIOMA SURGERY: RESULTS OF A PROSPECTIVELY COMPILED DATABASE OF A SINGLE-CENTER TERTIARY CARE HOSPITAL
Authors: Trong Philip Dao , Kaes Manuel , Jungk Christine , Unterberg Andreas 
Published: November 2023

Abstract

BACKGROUND
Adverse events in glioma surgery can cause severe problems for patients and can be a significant burden to healthcare systems. Therefore, understanding and avoiding adverse events should be essential in centers performing glioma surgery. Nevertheless, it is still uncommon to assess adverse events in a prospective, standardized manner. In this study we want to share the findings of our prospectively compiled database for adverse events in glioma surgery.

METHODS
Every patient treated at our institution received a peer-reviewed, standardized discharge form focused on adverse events. Any event, that led to readmission, worsening of clinical outcome, new neurological deficits, revision surgery, contributed to death or prolonged hospital stay within 30 days of discharge was recorded and classified according to the treatment-related classification system of Clavien-Dindo (Grade 1 requiring to treatment to Grade 5 resulting in death).

RESULTS
In 2022 a total of n = 194 patients received glioma surgery at our institution. Surgery was performed using a common craniotomy in 145 cases (74.7%), an awake craniotomy in 16 cases (8.2%) and in 33 cases (17.0 %) a stereotactic approach for biopsy was chosen. A total of n = 44 (22.7%) adverse events were recorded among these cases. The most common adverse event was a new neurological deficit after surgery in 20 cases (10.3%) followed by non-surgery related adverse events in 10 cases (5.2%). Wound healing disorders and CSF-leaks were recorded in 8 cases (4.1%) and in 6 cases (3.1%), respectively. Clavien Dindo classification showed low-grade complications (grade 1,2) in 15.9% and high-grade complications (grade 3,4,5) in 6.6%. Revision surgery was necessary in 9 cases (4.6%).

CONCLUSION
Adverse events in glioma surgery are not uncommon. Understanding and classifying these events in a prospective, standardized manner may help to reduce the risk of adverse events in glioma surgery in the future.
QOL-09. QUALITY OF LIFE AFTER SURGERY FOR LOWER GRADE GLIOMAS
Authors: Heffernan Anne , Wu Yilun , Benz Luke , Verhaak Roel , Kwan Bethany , Claus Elizabeth 
Published: November 2023

Abstract

BACKGROUND
Limited data exist on long-term quality of life (QOL) for adults diagnosed with lower grade glioma (LGG).

METHODS
QOL was assessed for 320 adults with LGG (World Health Organization grade 2/3) enrolled in the International Low Grade Glioma Registry using the Medical Outcomes Study 36-Item Short Form (SF-36) health survey. Data on symptoms were also collected. QOL outcomes were examined by treatment group and also compared to those from a population-based case/control study of meningioma (the Meningioma Consortium), in which 1722 meningioma cases diagnosed among residents of Connecticut, Massachusetts, California, Texas, and North Carolina from May 1, 2006 through March 14, 2013 were enrolled and frequency matched to 1622 controls by age, sex and geography.

RESULTS
The LGG sample average age is 45 years at time of interview and 53.1% male. Almost 55% of patients had received radiation and chemotherapy (primarily temozolomide); 32.4% had received neither treatment. Almost 2/3 LGG subjects report difficulty with speaking, memory, or thinking and over 1/3 report personality change or difficulty driving. After controlling for age and other co-morbidities, individuals diagnosed with LGG report levels of physical, emotional, and mental health functioning below those reported in a meningioma as well as a general healthy population.

CONCLUSIONS
Despite being relatively young, persons with LGG report significantly reduced QOL compared to persons with non-malignant brain tumors and to a control population, highlighting the need to better acknowledge and manage these symptoms for this group of patients diagnosed in the prime of life.
QOL-11. ADAPTING CALM PSYCHOTHERAPY FOR CAREGIVERS OF PATIENTS WITH MALIGNANT GLIOMA
Authors: Willis Kelcie , Fox Amber , Reid Morgan , Thumma Lillia , Barrett Sarah , Lo Karen , Loughan Ashlee 
Published: November 2023

Abstract
Caregivers of patients with malignant gliomas (PwMG) report significant emotional distress yet are often omitted from supportive psycho-oncology programs. CALM (Managing Cancer and Living Meaningfully), an evidence-based psychotherapy, has shown preliminarily to reduce depressive and existential distress among PwMG. While caregivers are invited to participate in CALM alongside the patient, the benefit of CALM for caregivers has not yet been evaluated. This NIH ORBIT model phase 1a qualitative study sought to assess caregivers’ interest in CALM and their recommendations to adapt the intervention to their emotional needs. Bereaved caregivers (N = 22, Mage = 47.2, 77% female, 73% White) of PwMG participated in 90-minute focus groups (n = 4-7). Caregivers first received psycho-education on CALM and then participated in a semi-structured group interview. Sessions were audio-recorded, transcribed, and coded by five independent coders using thematic content analysis and NVivo software (kappa = .80-.94). Three major themes were explored: 1) CALM’s relevancy to the neuro-oncology caregiving experience; 2) the suitability of CALM for PwMG caregivers; and 3) suggested adaptations to CALM for PwMG caregivers. First, caregivers felt the four domains of CALM mirrored their experience of caregiving. Secondly, they noted both strengths and weaknesses of the intervention. Lastly, caregivers provided valuable recommendations to improve the timing (e.g., introduce CALM early, continuously), content (e.g., include sessions about bereavement and caregiver burden), and format (e.g., both independent and joint sessions) of the CALM intervention. Examples of each theme will be provided. The results suggest that CALM may be a potentially impactful intervention for the emotional needs of caregivers of PwMG. Nevertheless, adjustments to the timing, content, and format of this intervention are warranted, prior to a future feasibility/acceptability trial. This study not only provides the foundational data required to proceed with future CALM trials, but it also provides valuable considerations for those developing interventions for caregivers of PwMG largely.
QOL-17. SLEEP QUALITY DIMENSIONS IN LOW AND HIGH-GRADE GLIOMA SURVIVORS
Authors: Chen Erica , Wang Chencai , Wall Lucy , Cho Nicholas , Ellingson Benjamin , Cloughesy Timothy , Lai Albert , Chong Robert , Van Dyk Kathleen , Nghiemphu Phioanh 
Published: November 2023

Abstract
In this study, we examined the relationship between sleep disturbance and tumor grades in a group of low-grade (LGG; grade I-II) and high-grade glioma (HGG; grade III-IV) survivors &lt; 1 to 10+ years from initial diagnosis. 42 glioma survivors completed the Pittsburgh Sleep Quality Index (PSQI). We examined frequency of poor sleep quality (defined as PSQI &gt;5) and compared global PSQI between LGG and HGG groups. We obtained high-resolution T1 weighted images from a subset of 24 patients for gray matter volume analyses. The sample was predominantly male (66%) and Caucasian (82%). Of the 42 participants, 31% (n = 13) had LGG and 69% (n = 29) had HGG. 60% (n = 25) of all participants had poor sleep quality, with no differences observed between LGG and HGG. There were no differences between groups in age, education, measures of depression and anxiety, or general health-related quality of life (MOS SF-36). A Mann-Whitney U test indicated that there was no significant difference in global PSQI scores between LGG (Mdn = 4) and HGG groups (Mdn = 6), U = 239, p = .254. Sleep quality was not associated with time since diagnosis for either LGG (r = .108, p = .724) and HGG groups (r=-.058, p = .762). Whole brain vertex-wise comparison revealed smaller gray matter volumes in patients with poor sleep quality versus good sleep quality in the isthmus cingulate, cuneus, and precuneus of the left hemisphere (p &lt; 0.05). Our analyses suggest that sleep quality is important to assess in glioma survivors of any grade and at any time since diagnosis. Poor sleep in glioma survivorship could be associated with structural differences in brain regions sensitive to sleep problems in other populations. Given the high rate of sleep disturbance, further study is warranted to better understand risk and develop targeted interventions.
QOL-20. INCLUDING BRAIN METASTASES PATIENTS IN PSYCHOLOGICAL INTERVENTIONS: A PHASE II SINGLE-ARM INVESTIGATION OF MANAGING CANCER AND LIVING MEANINGFULLY
Authors: Loughan Ashlee , Lanoye Autumn , Davies Alexandria , Willis Kelcie , Braun Sarah , Kleva Chris , Fox Amber , Zarrella Giuliana , Rodin Gary 
Published: November 2023

Abstract

BACKGROUND
Patients with brain cancer demonstrate substantial psychological distress yet are frequently excluded from psychological research. Managing Cancer and Living Meaningfully (CALM), an expressive-supportive psychotherapy designed to address the challenges faced by patients with advanced cancer. CALM is proven to reduce depression and death-related distress; however, patients with brain metastases (bMETs) have not been formally examined for CALM’s appropriateness or effectiveness.

METHODS
In this ongoing Phase II trial, 15 adults with bMETs and heightened distress (PHQ/DADDS) participate in a six-session CALM intervention and complete intervention satisfaction surveys and interviews. Data collection includes established feasibility and acceptability metrics, intervention satisfaction surveys and interviews, and changes in distress patient reported outcomes (pre-to-post CALM).

RESULTS
Of 21 patients screened, 15 enrolled in the study (73% female; 80% White; Mage = 58yrs). All 15 bMET participants completed baseline assessments, with 13 trial initiators, and 2 screen fails. To date, 8 participants have completed treatment. Reasons for withdrawal include disinterest in intervention topics (n = 1) and lost to follow-up (n = 2). Retention is 73%, with 2 participants still in active treatment. No adverse events were determined to be study-related. Perceived benefit was high (4.3/5), and all participants reported they would recommend the program to others. Reductions in depression severity were demonstrated in 6 of 8 completed participants (MPHQ Reduction = 7.6, range = 2-11) and in death anxiety severity for 7 of 8 completed participants (MDADDS-F1 Reduction = 14.7, range = 6-23).

CONCLUSIONS
Preliminary data suggests that CALM is both feasible and acceptable among adult patients with bMETs. Enrollment and retention rates are adequate. Patients report high benefit and recommendation to others. Overall, depression and death-related distress severity scores improved, suggesting CALM may be a promising intervention for neuro-oncology patients as they navigate the challenges of metastatic brain cancer. These findings support advancement to the next stage, a Phase II pilot RCT.
RBIO-02. NOVEL, QUIESCENT SUBPOPULATION EMERGES AFTER LOW-DOSE IRRADIATION OF GLIOMA STEM CELLS
Authors: Lewis Erika , Cascio Costanza Lo , McNamara James , Mehta Shwetal , Plaisier Christopher 
Published: November 2023

Abstract
Glioblastoma (GBM) tumors contain a subset of highly radiation resistant cells referred to as glioma stem cells (GSCs). We used single-cell RNA-seq (scRNA-seq) to characterize the transcriptional states that increase in size following GSC irradiation to further our understanding of the acute responses to radiotherapy. We treated two GBM patient-derived xenograft-derived GSC lines to low-dose irradiation (4 Gy). We then conducted scRNA-seq before irradiation and three days and one-week post-irradiation. As expected, the number of GSCs undergoing division through the cell cycle was drastically reduced relative to control conditions, and a subpopulation of GSCs with DNA damage response markers emerged after irradiation. Interestingly, we observed a novel, distinct subpopulation that was common between GSC lines, expanded after irradiation, and featured marker genes related to cell cycle arrest in response to external stressors. Gene regulatory network analysis identified transcription factors (TFs) likely to regulate these marker genes and potentially the dynamics of this subpopulation. The TFs were also related to cell cycle suppression and the overall expression state of these cells was similar to the quiescent Neural G0 state, indicating that our novel subpopulation may contain quiescent GSCs. In upcoming studies, we plan to perturb these TFs and marker genes to determine the importance of these genes in the GSC response to irradiation. Further exploration of this novel quiescent subpopulation may lead to new druggable targets that sensitize GBM tumors to radiotherapy.
RBIO-05. MITOTIC ENRICHMENT AS AN EFFICIENT RADIOSENSITIZATION STRATEGY FOR INTRACRANIAL TUMORS
Authors: de Gooijer Mark , Colakoglu Hilal , Citirikkaya Ceren , Fedorushkova Daria , El Ouazani Amal , Shah Ronak , Meel Michael , Hulleman Esther , Borst Gerben , van Tellingen Olaf 
Published: November 2023

Abstract
Radiotherapy remains one of the most effective modalities for anticancer treatment and part of standard of care for many primary and metastatic brain tumors. Boosting the efficacy of radiotherapy is therefore a logical avenue to improve patient survival. We have developed a radiosensitization strategy called ‘induction of mitotic enrichment’. It has long been known that the radiosensitivity of a cell depends on the phase of the cell cycle and that mitotic cells are especially vulnerable. Enriching the tumor for mitotic cells by arresting them during division prior to each radiotherapy fraction should therefore render the tumor population more sensitive to irradiation. Ideally, induction of mitotic enrichment should be reversible and non-cytotoxic to prevent healthy tissue toxicity and be compatible with clinically applied fractionated radiotherapy regimens. We have now identified an orally available targeted tubulin polymerization inhibitor that can achieve repeated and reversible mitotic enrichment for up to 10 hours prior to radiotherapy, without causing cytotoxicity in vitro or healthy tissue toxicity in vivo. This tubulin inhibitor (ABT-751) efficiently radiosensitizes a range of preclinical tumor models representing adult and pediatric, primary and metastatic brain tumors. Importantly, ABT-751 also improves survival in mouse models of adult glioblastoma (GBM), but only in a mitotic enrichment setup when given several hours prior to radiotherapy to allow accumulation in mitosis. Of note, induction of mitotic enrichment does not exacerbate healthy tissue toxicity. To conclude, induction of mitotic enrichment by ABT-751 radiosensitizes adult GBM to fractionated radiotherapy. We are currently expanding our preclinical development of mitotic enrichment as a radiosensitization strategy to other targets and cancers and have designed a phase 0/I trial for adult GBM to demonstrate induction of mitotic enrichment and tolerability when combined with radiotherapy. We expect to start enrollment in this trial soon.
RTID-03. A PHASE 1/2 STUDY OF THE WEE1 INHIBITOR DEBIO 0123 IN COMBINATION WITH TEMOZOLOMIDE +- RADIOTHERAPY IN ADULTS WITH RECURRENT OR NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Roth Patrick , Papadopoulos Kyriakos P , Vieito Maria , Yang Jonathan , Majd Nazanin , Sepúlveda Juan , Schaff Lauren , Moreno Victor , Pérez -Larraya Jaime Gállego , Micallef Sandrine , Bellon Anne , Omar Mokhtar , Imedio Esteban Rodrigo , Piggott Luke , Rodriguez-Freixinos Victor , Rodon Jordi 
Published: November 2023

Abstract
BACKGROUND: Debio 0123 is an oral, brain-penetrant, highly selective WEE1 inhibitor. WEE1 inhibition leads to S phase and G2/M cell cycle checkpoint abrogation, permitting mitosis without DNA repair, leading to mitotic catastrophe and subsequent cell death. Preclinically, Debio 0123 has been shown to effectively penetrate the brain and demonstrated improved response to radiotherapy (RT) in vitro and temozolomide (TMZ) in mouse models of GBM, supporting the clinical investigation of Debio 0123 with TMZ +/- RT. Trial design: This Phase 1/2 multi-center study (NCT05765812) is evaluating Debio 0123 in combination with TMZ in patients (pts) with recurrent GBM isocitrate dehydrogenase (IDH)-wildtype (WT) or astrocytoma, IDH-mutant, Grade 3 (per WHO 2021 criteria) after first-line, TMZ-based chemoradiotherapy (CxRT) (Phase 1 Arm A) and Debio 0123 combined with TMZ-based CxRT in pts with newly diagnosed GBM IDH-WT (Phase 1 Arm B). In Arm A, pts will receive escalating doses of Debio 0123 with TMZ in 28-day cycles supported by a Bayesian logistic regression model (BLRM). Arm B is a Debio 0123 dose escalation with concomitant TMZ/RT for up to 6 weeks. The primary objective of both Phase 1 arms is to identify the recommended Phase 2 dose (RP2D). Secondary objectives include safety, pharmacokinetics, and preliminary antitumor activity. Key inclusion criteria are ≤2 prior treatment lines (only 1 systemic line allowed) and Karnofsky Performance Status (KPS) ≥60 (Phase 1 Arm A). In Phase 1 Arm B, pts with KPS ≥70 who are eligible for standard TMZ-based CxRT will be included. Phase 2 will be an externally controlled, open-label study comparing the efficacy (overall survival) of Debio 0123 combined with TMZ at the Phase 1 Arm A RP2D vs. standard of care in pts with recurrent GBM IDH-WT. The control arm will include patient-level data from recently completed clinical trials. Accrual is currently ongoing.
RTID-08. A RANDOMIZED, MULTICENTER, DOUBLE-BLIND, PHASE 2B STUDY OF IGV-001, AN AUTOLOGOUS CELL IMMUNOTHERAPY WITH ANTISENSE OLIGO IMV-001 TARGETING IGF-1R, VS PLACEBO, IN NEWLY DIAGNOSED GLIOBLASTOMA PATIENTS
Authors: Lee Ian , Judy Kevin , Schulder Michael , Hanft Simon , Evans Linton , Wu Julian , Aulakh Sonikpreet , Wong Eric , Agarwal Vijay , Ramakrishna Rohan , Elder J Bradley , Gill Brian , Quiñones-Hinojosa Alfredo , Brennan Cameron , Perez-Olle Raul , Diwanji Madhavi , Pennock Gregory , Scott Charles , Andrews David , Boockvar John 
Published: November 2023

Abstract
Glioblastoma (GBM) is the most common primary brain malignancy in adults. Standard of care (SOC) for suspected GBM begins with maximal safe resection followed by adjuvant radiotherapy and temozolomide, and maintenance temozolomide. Imvax has developed the Goldspire™ platform to create IGV-001, an autologous biologic-device combination product for the treatment of newly diagnosed GBM (ndGBM). IGV-001 consists of autologous GBM tumor cells and an antisense oligonucleotide against IGF-1R mRNA (IMV-001), irradiated and administered via biodiffusion chambers implanted in the abdomen. Together, these components stimulate immunogenic cell death and antigen release. IGV-001 was well tolerated and multiple efficacy signals were observed in a Phase 1b study in patients with ndGBM, including significant improvements in progression-free survival (PFS), radiographic evidence of tumor response, and changes in immune response biomarkers. A Phase 2b randomized, multicenter, double-blind, placebo-controlled study has been initiated to assess the safety and efficacy of IGV-001 in patients with ndGBM (NCT04485949). After surgical resection, patients will be treated with IGV-001 or placebo followed by SOC. 25 US sites have been selected with a target enrollment of 93 patients (2:1 randomization) and the study is open to enrollment. Key inclusion criteria are 18 to 70 years of age, Karnofsky performance status score ≥ 70, diagnosis of GBM based on the treating neurosurgeon's best clinical judgement, confirmed measurable disease pre-operatively, tumor located in the supratentorial compartment, and adequate bone marrow and organ function. Key exclusion criteria include bihemispheric disease, multicentric disease, or treatment with Tumor Treating Fields prior to documented progression. The primary outcome is PFS, defined as the time from randomization to first progression, as determined by blinded central radiology review, or death. Secondary outcomes include overall survival, defined as the time from randomization to death due to any cause, and safety.