bluuebunny/crossref_metadata_2025 huggingface dataset:
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

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

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

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 > 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 > 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.
QOL-12. NEURO-ONCOLOGY INCLUSION IN PSYCHOTHERAPEUTIC INTERVENTION TRIALS: LEARNING WHICH COGNITIVE ADAPTATIONS COULD SUPPORT PATIENT ENGAGEMENT?
Authors: Loughan Ashlee , Lanoye Autumn , Braun Sarah , Fox Amber , Zarrella Giuliana
Published: November 2023

BACKGROUND

Many patients with brain tumors experience double vulnerability—significant emotional distress coupled with cognitive decline—however, these cognitive changes often prohibit their inclusion in psychotherapeutic interventions that might otherwise improve their wellbeing. The primary goal of this analysis was to understand how best to accommodate the neurocognitive needs of patients with brain tumors so that they may effectively participate in future psychotherapeutic interventions. Our secondary goal was to assess potential differences in desired cognitive adaptations between patients with primary compared to metastatic brain tumors.

METHODS

In two recently completed Phase 2 proof-of-concept trials, patients with both primary and metastatic brain tumors (N = 27) participated in a 3-month psychotherapeutic intervention, Managing Cancer and Living Meaningfully (CALM). During exit interviews, participants reported whether evidence-informed accommodations would support their cognitive limitations and enhance engagement in future trials. Additionally, trial interventionists identified which accommodations were used in each session.

RESULTS

Participants recommended several accommodations: appointment reminders (100%), topic refreshers (94%), prior session summaries (88%), visual handouts (82%), time for consolidation (71%), transcription notepads (65%), and questionnaire completion assistance (24%). Interventionists documented using appointment reminders (66%), topic refreshers (53%), prior session summaries (60%), and time for consolidation (60%) in more than half of sessions. Visual handouts (2%), notepads (0%), and questionnaire assistance (17%) were rarely or never used.

CONCLUSIONS: RESULTS

were similar across the two brain tumor populations surveyed: primary and metastatic brain tumors. Accommodations that were recommended by patients and used by interventionists included: (1) appointment reminders to support session attendance, (2) topic refreshers and prior session summaries to support memory, and (3) additional time to assist with slower processing and support comprehension. Implementing supportive cognitive strategies is vital when promoting neuro-oncology inclusion in psychotherapeutic interventions and meeting the needs of this underserved population.
QOL-18. HIGHER VINCRISTINE DOSES CORRELATE WITH LONGER OVERALL SURVIVAL: A POST-HOC ANALYSIS OF PARTICIPANTS RECEIVING PCV ON RTOG 9402
Authors: Donovan Laura , Polly Mei-Yin , Cairncross J Gregory , Lassman Andrew , Iwamoto Fabio , Barani Igor , Souhami Luis , Pitot Henry C , Fisher Barbara , Werner-Wasik Maria , Bahary Jean-Paul , Whitton Anthony , Mishra Mark V , Huang Jiayi , Hartford Alan C , Fink Karen , Laperriere Normand , Won Minhee , Mehta Minesh
Published: November 2023

RTOG 9402 demonstrated procarbazine (P), lomustine (CCNU/C), and vincristine (V), collectively PCV, added to radiation therapy significantly improved survival for patients with newly diagnosed anaplastic oligodendroglial tumors. The improvement was most pronounced in 1p19q codeleted cases, and to a lesser extent, IDH-mutant cases, with no survival benefit in cases with neither biomarker. Analogous results were observed in other phase III trials. However, vincristine (V) can cause substantial toxicity and requires intravenous administration, both negatively affecting quality of life, with debatable contribution to PCV efficacy. As a randomized trial comparing PCV to PC is unlikely to be conducted, we explored correlations between survival and V-dosing in patients randomized to PCV in RTOG 9402. We performed post-hoc analyses of all evaluable participants (n = 143) randomized to PCV on RTOG 9402, supplemented by restricting the analyses to the chemosensitive molecular subsets (IDH-mutant and/or 1p/19q codeleted, n = 118). Total V dose by quartile (Q) was calculated. Survival from six months post-randomization was compared among V dose groups, adjusting for age, extent of resection (EOR), and Karnofsky Performances Status (KPS) in a Cox proportional hazards model. Higher V dose received correlated with longer survival in multivariate analyses (n = 134, median-Q3 vs. < Q1, HR 0.40 (0.22, 0.73), p = 0.003; ≥Q3 vs. < Q1, HR 0.39 (0.22, 0.72), p = 0.002). Excluding chemoresistant cases (IDH wild-type/not codeleted), survival was also significantly longer in evaluable participants receiving the highest doses of vincristine (≥Q3 vs. < Q1 HR 0.42 (0.21,0.81), p = 0.01). In this post-hoc analysis, higher overall V-dose received correlated with longer survival in evaluable patients with anaplastic oligodendroglial tumors receiving PCV chemotherapy in RTOG 9402. Of note, as vincristine dosing was not assigned by randomization, confounding due to differences in patient characteristics among V dose groups cannot be ruled out. Caution should be exercised when considering discarding V from the PCV regimen.
QOL-24. FINANCIAL AID REQUESTS BY BRAIN TUMOR PATIENTS IN ONTARIO THROUGH GOFUNDME
Authors: Devaraja Kaviya , Avery Jonathan , Iyengar Yajur , Zhang Andy , Climans Seth
Published: November 2023

Brain tumors affect individuals globally including Ontario residents. Numerous Ontario brain tumor patients suffer the unequal burden of responsibility to pay for treatments like oral chemotherapy. In addition to chemotherapy, patients and their families have other costs associated with their diagnosis. However, less is known about other direct and indirect financial costs due to their diagnosis. GoFundMe, an online fundraising platform, provides worldwide brain tumor patients the opportunity to raise money for financial assistance with costs associated with their diagnosis The purpose of this study was to analyze publicly-available data from GoFundMe, an online fundraising platform, to explore the financial needs of brain tumor patients across Ontario, unaware and/or unable to get assistance elsewhere. A qualitative descriptive design drawing on thematic analysis was used to analyze GoFundMe requests to support individuals diagnosed with brain cancer in Ontario between 2014 and 2021. A coding framework was created to determine emerging themes using qualitative data analysis software NVivo 10. A final sample of 154 requests described financial strain from the loss of income experienced by the patient and their caregivers to afford cancer treatments. Requests highlighted 1) an overall lack of awareness of how and where access financial aid and affordable psychosocial support; 2) concerns over the long-term financial well-being of bereaving family members; 3) A call for more public awareness of the financial burden and emotional distress experienced by of those impacted by brain cancer. These GoFundMe requests highlight a connection between financial burden and emotional distress and an overall lack of awareness of where/how to seek financial and emotional support. These results will serve as the foundation to advocate for and raise awareness of the financial assistance needed by brain tumor patients and their families.
QOL-25. FOR THE LOVE OF WORK: NOVEL STUDY OF VOCATIONAL COGNITIVE REHABILITATION IN PRIMARY BRAIN TUMOR
Authors: Jamora Christina Weyer , Brie Melissa , Bracci Paige , Smith Ellen , Luks Tracy , Phan Stephanie , Braunstein Steven , Bush Nancy Ann Oberheim , Butowski Nicholas , Clarke Jennifer , Daras Mariza , de Groot John , Chang Susan , Taylor Jennie
Published: November 2023

BACKGROUND

Primary brain cancer survivors live longer, yet experience distress and cognitive impairments that negatively impact their quality of life (QOL), including at work. We present a novel study of vocational tele-cognitive rehabilitation in primary brain cancer survivors.

METHODS

Retrospective review, post-treatment, radiologically stable adult primary brain cancer patients who completed standardized neuropsychological, psychological, vocational, and QOL assessments. Wilcoxon rank sum and Fisher’s exact or Chi-square tests assessed between-group and within-group comparisons. Tests were two-sided and statistically significant for p < 0.05.

RESULTS

79 patients with known baseline work status assessed for between-group comparisons (working versus not). Working (n = 38) and not working (n = 41) subgroups had similar ages, tumor grade/type, and history of radiotherapy. Working had worse executive functioning (p = .05). Not working (n = 41) had worse cognitive function (executive function, attention, verbal learning all p < 0.05) and more engagement in survivorship services (p < 0.04). Of the 79 work-status known patients, 38 underwent vocational tele-cognitive rehabilitation (median 11 sessions) treatment for within-group comparisons. 82% of the treatment group had improved work status compared to 34% in non-treatment. Baseline work status and age were not related to occupational improvements (all p >0.20). Higher dose high radiotherapy dose inversely related to rehab improvements (p< .05). Higher verbal memory (p = 0.05), processing speed (p = .06), executive functioning (p = 0.02), IDH mutation status (p = .06), and motivation for treatment (p = .04) was associated with improvement. Those with depressive symptoms who engaged in clinically indicated psychotherapeutic services significantly improved their work status (p = .01).

CONCLUSION

Occupational functioning improved after cognitive rehabilitation. Cognitive impairments, IDH mutation status, higher dose radiotherapy, and treatment motivation are important. Not working at baseline, despite more cognitive impairments, improved similar to their working counterparts. Those with depression benefitted from psychotherapeutic support. Vocational tele-cognitive rehabilitation shows promise for improving the work-based abilities of primary brain tumor patients and warrants further investigation.
RBIO-10. NEUROMODULATORY EFFECT AND DOSE RESPONSE OF FUNCTIONAL RADIOSURGERY ON CORTICAL NEURONS
Authors: Gholampourkashi Sara , Thivierge Jean-Phillipe , Nair Vimoj
Published: November 2023

PURPOSE

The effects of functional radiosurgery on neuronal circuits remain poorly understood. Neurons of the prefrontal cortex communicate via precisely-timed action potentials that control cognition. Here, we examined the dose response of ablative radiation dose on the patterns of communication of neural circuits in prefrontal acute slices. Materials and

METHODS

Escalating doses from 20 Gy to 100 Gy of ablative radiation were applied to rodent cortical neurons using the robotic Radiosurgery device (CyberKnife(R) G4). Neuronal communication within irradiated prefrontal slices were compared to control slices (sham radiation); and assessed by plating slices on a multielectrode array that captured high-resolution (18 kHz) extracellular activity across 4,096 channels simultaneously. Comparisons also with recordings of slices treated with a pro-epileptiform solution and finally, correlated with staining for cell death.

RESULTS

Compared to control slices (mean rate of 0.06 Hz), the post-radiosurgery slices yielded a 40-fold increase in discharge rates (mean rate of 2.87 Hz for 20 Gy, 2.44 Hz for 50 Gy, and 1.95 Hz for 100 Gy radiation). Pearson cross-correlations were computed across all pairs of channels, yielding a matrix of 4,096-by-4,096 interactions. Radiated slices exhibited decreased correlations relative to control slices. A total of 7,446 neuronal interactions were above a threshold correlation of 0.5 in control slices, compared to none following a 20 Gy dose, 50 interactions following a 50 Gy dose and 28 interactions following a 100 Gy dose. Slices treated with pro-epileptiform solution slices yielded large seizure-like events characterized by increased discharge rates and increased pairwise correlations.

CONCLUSION

Post-radiosurgery slices yielded a unique signature of neuronal activity with increased rates; but with a pronounced decrease in correlations; suggesting diminished communication across neurons to create a neuro-modulatory effect on target tissue; or result in cognitive toxicity on organ-at-risk respectively.
RTID-07. A RANDOMIZED WINDOW OF OPPORTUNITY TRIAL WITH DOSE ESCALATION TO EVALUATE FLUOXETINE AND TEMOZOLOMIDE IN GLIOMA
Authors: Singh Kirit , Railton Chelsea , Hotchkiss Kelly , Herndon James , Peters Katherine , Friedman Henry , Desjardins Annick , Ashley David , Johnson Margaret O , Patel Anoop , Friedman Allan , Lim Michael , Fecci Peter , Piccioni David , McGranahan Tresa , Nagpal Seema , Sulman Erik , Mischel Paul , Khasraw Mustafa
Published: November 2023

The blood brain barrier limits the efficacy of many drugs in brain tumors. Fluoxetine (Prozac) is FDA-approved and brain penetrant. Preclinical studies show synergy between fluoxetine and temozolomide (TMZ), resulting in lysosomal stress and enhanced DNA damage in human-derived glioma in vitro and in vivo. We present our randomized surgical window of opportunity trial (NCT05634707) in patients with recurrent IDH wild type glioma. The primary objective is to evaluate if fluoxetine induces tumoral lysosomal stress while exploratory objectives will determine if combination therapy enhances tumor DNA damage. We will randomize 30 patients, ≥ 24yo, with recurrent glioma and who are eligible for re-treatment with TMZ (MGMT methylated, progression >6 months post TMZ). Following informed consent, patients will be randomized 1:2 to control or experimental arms. Control patients will receive 50 mg/m2 TMZ for 7 days pre-resection. The experimental arm will receive 20 mg/day fluoxetine for 5 days before escalating to 40 mg/day. If < 3/10 participants receiving 40mg/day experience dose-limiting toxicity (DLT), subsequent experimental arm patients will escalate to 60 mg/day. All experimental arm participants will receive 50 mg/m2 TMZ for 7 days after starting fluoxetine, starting 21 days pre-resection. The regimen of 50 mg/m2 TMZ for 7 days is based on a similar pre-surgical trial combining TMZ with experimental therapy (NCT05188508). This reduced dose was chosen to limit potential synergistic toxicities like thrombocytopenia or neutropenia. Following resection, patients will continue TMZ, initially at reduced dose for the first post-op cycle, before reverting to standard doses of 150-200mg/m2 (up to 12 cycles or progression). All patients (control and experimental) will be offered fluoxetine post-operatively. The primary study outcome will be quantification of tumoral lysosomal stress via Lysosomal-associated membrane protein 1 (LAMP1) expression while DNA damage will be assessed via γH2A histone family member X (γH2AX) using immunohistochemistry.
SURG-12. MANAGEMENT OF ATLANTOAXIAL INSTABILITY IN THE SETTING OF CLIVAL CHORDOMA WITH EXTENSION TO THE CRANIOCERVICAL JUNCTION: A COMPREHENSIVE REVIEW OF CLINICAL MANAGEMENT
Authors: Brown Nolan , Musmar Basel , Nguyen Oanh , Kuo Cathleen , Gendreau Julian
Published: November 2023

INTRODUCTION

Clival chordomas that involve the craniovertebral junction (CVJ) are particularly challenging to remove due to risk for postoperative atlantoaxial instability. Preoperative instability can also be present due to mass effect from the clival lesion. Surgery involves a delicate balance of acknowledging existing preoperative instability, when present, and aiming for gross total resection (GTR) while determining the optimal time to fuse occiput to axial spine. This requires extensive knowledge of operative anatomy, neuro-oncology, and spinal biomechanics. Method Adhering to PRISMA guidelines, we examined all currently available neurosurgical literature pertaining to skull base chordomas with extension to the craniocervical junction.

RESULTS

Thirty studies featuring 435 patients (age range: 2-78 years) were identified, including 14 retrospective cohort studies, 6 case reports, and 3 case seriesdescribing surgical management with OCF. The remaining 7 studies (4 retrospective cohort studies and 3 case reports) reported surgical management without OCF. Our findings indicate that cervical instability due to the fracture or loss of the odontoid process in the pediatric population is an indication for OCF. With respect to timing, it appears that OCF can be conducted prior to or following tumor resection if there is clinical suspicion that a patient will eventually develop atlantoaxial instability (odontoid process removal is an indication for OCF).

CONCLUSION

OCF is indicated for patients when concern for craniocervical instability exists. Although it can be performed following surgical chordoma resection, as long as such instrumentation does not interfere with achieving surgical goals of GTR and/or maximal safe resection, results suggest that optimal outcomes may be obtained when OCF precedes tumor resection. In addition to the degree of instability present, brian stem compression, extent of resection, and amount of instrumentation to be performed are factors that should be discussed between a skull base surgeon-spine surgeon multidisciplinary team.
SURG-14. THE ARRAY OF TREATMENTS AVAILABLE FOR HYPOTHALAMIC HAMARTOMA IN THE SETTING OF INTRACTABLE SEIZURE: CURRENT STATE OF THE EVIDENCE FOR ENDOSCOPIC DISCONNECTION (AND RESECTION), LITT, AND RADIOTHERAPY
Authors: Brown Nolan , Singh Rohin , Koester Stefan , Nguyen Oanh , Musmar Basel , Gendreau Julian
Published: November 2023

Numerous minimally invasive approaches to hypothalamic hamartomas (HHs) have been developed though their efficacy in treating seizures has not been closely analyzed. A systematic review was performed using three databases per PRISMA in order to identify all studies comparing seizure outcomes for HHs treated via endoscopic disconnection (ED), resection (ER), ablation, and radiosurgery. Of the initial 235 studies, 67 studies which reported individual patient data were included for analysis encompassing a total of 229 patients (75/219 females). ED: A total of 82 (33 females, 40%) patients were treated via endoscopic disconnection. Mean follow-up was 18 months and 39 patients (48%) were Engel Class (EC) I, 23 patients (28%) were EC II, 15 patients (18%) were EC III, and 4 patients (4.9%) were EC IV. ER: A total of 31 (8 females, 26%) patients were treated via endoscopic resection. Mean follow-up was 18 months and 14 patients (45%) were Engel Class (EC) I, 8 patients (26%) were EC II, 0 patients (0%) were EC III, and 9 patients (29%) were EC IV. Ablation: A total of 83 (24 females, 32%) patients were treated via either LiTT or thermal ablation. Mean follow-up was 16 months and 57 patients (69%) were Engel Class (EC) I, 12 patients (14%) were EC II, 4 patients (4.8%) were EC III, and 10 patients (12%) were EC IV. Radiotherapy: A total of 33 (10, 32%) patients were treated via radiotherapy. Mean follow-up was 32 months and 18 patients (55%) were Engel Class (EC) I, 9 patients (27%) were EC II, 3 patients (9.1%) were EC III, and 3 patients (9.1%) were EC IV. Our findings suggest that patients treated with ablation had the highest percentage of seizure freedom, followed by radiotherapy, endoscopic disconnection, and endoscopic resection. Further studies are needed to determine the long-term efficacy and safety.
TMET-09. SEX DIFFERENCES IN SERINE-DERIVED GLYCINE BIOSYNTHESIS DRIVE RESPONSES TO COMBINED NUTRIENT DEPRIVATION AND PHARMACOLOGICAL INHIBITION IN GBM
Authors: Lu Jianyun , Marquez Camryn , Sponagel Jasmin , Chinnaiyan Prakash , Rubin Joshua B , Ippolito Joseph
Published: November 2023

Glioblastoma (GBM) is the most common and deadly primary brain malignancy. Male GBM patients occur at higher incidence and display more aggressive disease than females. Ambiguity of molecular mechanisms driving sexually dimorphic outcomes in GBM limits the implementation of clinically effective treatments. Therefore, our group seeks to determine and target the metabolic bases of sex-biased GBM proliferation and progression. We have identified glucose utilization as a unique determinant of male but not female GBM patient outcomes. Utilizing a mouse model for mesenchymal GBM (Nf1-/-DNp53), we demonstrated a male-specific decrease in proliferation in response to glucose-deprived media and glycolytic inhibition. Following labeling with [13C] glucose, males had significantly higher de novo serine biosynthesis, measured by enrichment of serine and glycine. This was confirmed with significant upregulation of several serine biosynthetic pathway enzymes in male cells. These mouse model data were validated by metabolomics and enzyme data from human GBM and lung cancer, including pan-cancer gene expression data, underscoring the broad translational importance of these findings. We then sought to determine if sex-biased responses to serine and glycine deprivation were similar to those observed following glucose deprivation. Utilizing serine and glycine-deprived media conditions, we identified a male-specific decrease in proliferation following pharmacological inhibition of the serine biosynthetic pathway. More precisely, in the absence of exogenous glycine, we discovered that pharmacological inhibition of de novo synthesis of glycine from serine drove male-specific decreases in proliferation. Additionally, we discovered that under serine and glycine-deprived conditions, inhibition of de novo synthesis of glycine from serine sensitized female transformed astrocytes to antifolates. These data highlight that de novo glycine synthesis drives sex differences in GBM cell proliferation. As well, our work suggests that dietary restriction of serine and glycine, in combination with pharmacological inhibition of de novo glycine biosynthesis, represents a novel GBM treatment paradigm.
TMET-16. ELUCIDATING MECHANISMS OF ENHANCED OXIDATIVE PHOSPHORYLATION IN MYC-AMPLIFIED MEDULLOBLASTOMA
Authors: Burwag Fares , Delaidelli Alberto , Yao Betty , Negri Gian Luca , Huang Yue Zhou , Huang Albert , Vislovukh Andrii , Langman Sonya , Hughes Christopher , Leprivier Gabriel , Sorensen Poul
Published: November 2023

Medulloblastoma (MBL) is the most commonly diagnosed pediatric brain tumour and the leading cause of childhood cancer deaths. MYC overexpression often accompanies poor prognosis in MBL patients, as MYC-driven transformation is known to promote mitochondrial oxidative phosphorylation (OXPHOS). However, it also induces a high metabolic demand that impairs cell survival under acute nutrient deprivation. We previously reported that eukaryotic Elongation Factor Kinase 2 (eEF2K), the master regulator of mRNA translation elongation, is overexpressed in MYC-driven MBL. Preliminary data suggests a relationship between eEF2K-mediated selective translation of mRNAs needed for efficient OXPHOS, and for the progression of MYC-driven MBL. Multiplexed enhanced Protein Dynamic Mass Spectrometry was carried out in eEF2K knockdown MYC-overexpressing D425 MB cells to identify mRNAs selectively translated upon eEF2K activation. 9 of 10 detected components of the OXPHOS pathway were selectively translated in eEF2K-active MBL cells. Genetic eEF2K knockout led to the disassembly of electron transport chain (ETC) complexes I-V and reduced complex activity, as observed via Blue Native PAGE and colorimetric assays. Furthermore, siRNA knockdown of Cytochrome c oxidase assembly factor 7 (COA7), a mitochondrial OXPHOS assembly factor differentially expressed in eEF2K active or inactive D425 cells, produces the same pattern of supercomplex (SC) loss as the inactivation of eEF2K in wild-type D425 cells. The assembly of ETC SC across D425 eEF2K active and inactive cells was further studied using blue native gel-based mass spectrometry to further characterize patterns in SC loss. In summary, control of translation elongation by eEF2K is critical for mitochondrial ETC complex assembly and efficient OXPHOS in MYC-overexpressing MBL, likely representing an adaptive response against acute metabolic stress. Future therapeutic studies will aim to combine eEF2K inhibition with caloric restriction mimetics.
TMET-20. TARGETING LINKS BETWEEN METHIONINE METABOLISM AND DNA REPAIR TO IMPROVE GBM THERAPY
Authors: Korimerla Navyateja , Wilder-Romans Kari , Xu Jie , Haq Isra , Kalev Peter , Qi Nathan , Evans Charles , Kachman Maureen , Zhou Weihua , Scott Andrew J , Kothari Ayesha , Lin Angelica , O'Brien Alexandra , Palavalasa Sravya , Peterson Erik , Hyer Marc L , Marjon Katya , Lyssiotis Costas , Sleger Taryn , Wahl Daniel
Published: November 2023

Glioblastoma (GBM) is uniformly lethal due to intrinsic resistance to standard of care radiation (RT) and chemotherapy. Recent studies have identified altered cellular metabolism as a key mediator of GBM RT resistance. Methionine uptake is drastically elevated in GBMs compared to normal cells but whether this impacts treatment resistance is uncertain, as is the metabolic fates of methionine once it enters GBM cells. Here, we find that RT acutely increases the levels of methionine-related metabolites in a variety of RT-resistant GBM models. Stable isotope tracing studies further revealed that RT acutely activates methionine to S-adenosyl methionine (SAM) conversion through an active signaling event through DNA damage response. We developed in vivo 13C5 methionine stable isotope tracing techniques to confirm these findings in orthotopic models of GBM. Pharmacological and dietary strategies to block methionine to SAM conversion slowed the DNA damage repair and increased cell death following RT. These effects are selective to GBMs lacking the methionine salvage enzyme methylthioadenosine phosphorylase (MTAP). Pharmacologic and dietary strategies to inhibit SAM synthesis hindered tumor growth in flank and orthotopic in vivo GBM models when combined with RT. In short, these results highlight a new signaling link between DNA damage and SAM synthesis and define the metabolic fates of methionine in GBM in vivo. Inhibiting the RT-induced SAM synthesis slows the DNA damage repair and augments RT efficacy in GBM. This therapeutic strategy provides scope for combining MAT2A inhibitors with RT in GBMs with impaired methionine salvage and spares the adjacent normal brain.
TMIC-01. PERICYTES ORCHESTRATE A TUMOR-SUPPRESSIVE MICROENVIRONMENT BY IMPINGING ON THE CROSSTALK BETWEEN MACROPHAGES AND TUMOR-INITIATING CELLS IN GLIOBLASTOMA MULTIFORME
Authors: Braun Sebastian , Oudenaarden Clara , Bolivar Paulina , Sjölund Jonas , Cordero Eugenia , Rosberg Rebecca , Johansson Elinn , Pietras Alexander , Pietras Kristian
Published: November 2023

Glioblastoma multiforme (GBM) is characterized by fast progression, infiltrative growth pattern and a high rate of relapse. A defining feature of GBM is the existence of spatially and functionally distinct cellular niches, i.e. a hypoxic niche, a leading-edge niche, and a peri-vascular niche, in which malignant cells engage in paracrine crosstalk with cell types comprising the tumor microenvironment, including immune cells, astrocytes, and vascular cells. Here, by analysis of single-cell transcriptomic data of human GBM and transgenic mouse models of GBM, we unexpectedly identified pericytes intimately associated with the endothelium as the most active paracrine signaling hub within the tumor parenchyma. Exclusive signaling axes emanating from pericytes were received by endothelial cells, malignant cells, astrocytes, and immune cells. Depletion of pericytes through genetic engineering in several different transgenic and orthotopic mouse models of GBM demonstrated accelerated tumor progression, a disrupted blood-brain-barrier, and premature death of pericyte-poor mice. Mechanistic studies revealed that pericyte deficiency altered the cellular composition of GBM, remodeled the endothelium, and impacted on the immune cell landscape. Specifically, endothelial cells deprived of pericyte association upregulated Colony Stimulating Factor (CSF)-1, which in turn attracted peri-vascular tumor-associated macrophages polarized towards an immune-suppressive phenotype. In the absence of pericytes, the recruited macrophages expressed Hepatocyte Growth Factor (HGF), which reinforced activation of its receptor tyrosine kinase c-Met on a subset of GBM cells harboring an extreme mesenchymal-like state. Indeed, orthotopic implantation of isolated c-Met-expressing GBM cells corroborated their superior tumor-initiating capability and invasive phenotype, compared to cells negative for c-Met. Taken together, we infer that the pericyte represents a critical modulator of GBM development by orchestrating a tumor-suppressive microenvironment; our findings thus highlight the importance of pericyte preservation in the face of current and future GBM therapies.
TMIC-07. MUTANT IDH-MEDIATED SUPPRESSION OF THE TH17 LINEAGE IN GLIOMA; BIOLOGIC IMPACT AND THERAPEUTIC POTENTIAL
Authors: Reynolds Nathan , Soedel Ashleigh , Miller Emily , Ashley David , Waitkus Matthew , He Yiping , Pirozzi Christopher
Published: November 2023

Great excitement has surrounded the identification of tumor-specific hotspot mutations in IDH1 as they are the first therapeutic targets of low grade gliomas that have been identified in the last several decades. With a low number of viable therapeutic targets, mutations in IDH1 represent new hope in treating these tumors that are invariably recurrent and confer a dismal prognosis in their aggressive forms. Additionally, mutations in IDH1 are tumor-specific suggesting their effective targeting can reduce the collateral damage to the normal brain imparted by standard therapies. Furthermore, mutations in IDH1 lead to the overproduction of D-2-hydroxyglutarate (D-2HG), which mediates many of mutant IDH1’s effects. To gain an understanding of mutant IDH-mediated tumorigenesis, we generated genetically faithful mouse models that harbor the pathognomonic signature including the IDH1-R132H mutation and p53 deletion. This model generates tumors that overproduce D-2HG, are histologically diffuse, and confer a prolonged survival compared to their wildtype counterparts. Additionally, these models display the proneural subtype and are enriched for an oligodendrocyte precursor cell gene expression signature, both of which are typified by IDH mutations in human glioma. Exploring the impact of the IDH mutation on the tumor microenvironment, we identified several diminished immune cell subsets among the mutant IDH murine tumors, including NK cells, monocytes, and M2 macrophages. Further analysis showed a reduced Th17 gene expression profile that was corroborated through in vitro studies. The biological impact of Th17 cells appears to be cancer-context dependent with only a few studies being performed in gliomas. With the potential for Th17-mediated anti-tumor activity, as observed in cases of melanoma, the prospect for elucidating a new therapeutic avenue is exciting. As such, the biological significance of D-2HG-mediated Th17 suppression, the underlying mechanism, as well as the therapeutic potential of Th17 restoration are actively being investigated.
TMIC-19. TARGETING TUMOR-MYELOID CELL SYMBIOSIS IN GLIOBLASTOMA
Authors: Chen Peiwen
Published: November 2023

Heterotypic interactions across diverse cell types of the tumor microenvironment can enable tumor progression and offer points for potential therapeutic intervention. Employing glioblastoma (GBM), a lethal form of brain tumor in adults, as a model system, we sought to (i) understand the nature of specific oncogenic signals in glioma cells that affects myeloid cell biology; (ii) identify myeloid cell factors which may support glioma growth and survival, (iii) develop novel therapeutic strategies targeting the tumor-myeloid cell symbiosis; and (iv) investigate whether blockade of this symbiosis can overcome the primary resistance of immunotherapy. Specifically, the novel oncogenic signals (e.g., CLOCK and TFPI2) and myeloid cell components of microglia and myeloid-derived suppressor cells will be discussed and highlighted. The findings from our studies demonstrate that the newly identified context-dependent tumor-myeloid cell symbiotic interactions not only promote tumor progression but also induce immune checkpoint inhibitor (ICI) therapy resistance in GBM. Thus, our studies provide novel therapeutic targets and offer a great potential to overcome immunotherapy resistance in GBM.
TMIC-36. SPATIAL ARCHITECTURE OF HIGH-GRADE GLIOMA REVEALS TUMOR HETEROGENEITY WITHIN DISTINCT DOMAINS
Authors: Moffet Joel , Fatunla Oluwaseun , Whittle James , Jordan Jones , Roberts-Thomson Samuel , Pavenko Anna , Scoville David , Zhang Liang , Liang Yan , Morokoff Andrew , Freytag Saskia , Best Sarah
Published: November 2023

High-grade gliomas are aggressive primary brain cancers with poor response to standard regimens, driven by immense heterogeneity. In isocitrate dehydrogenase (IDH) wild-type high-grade glioma (glioblastoma, GBM), increased intra-tumoral heterogeneity is associated with more aggressive disease. Recently, spatial technologies have emerged to dissect this complex heterogeneity within the tumor ecosystem by preserving cellular organization in situ. Here, we construct a high-resolution molecular landscape of GBM and IDH-mutant high-grade glioma patient samples to investigate the cellular subtypes and spatial communities that compose high-grade glioma using digital spatial profiling and spatial molecular imaging. This uncovered striking diversity of the tumor and immune microenvironment, that is embodied by the heterogeneity of the inferred copy-number alterations in the tumor. Reconstructing the tumor architecture revealed two distinct niches, one composed of tumor cell states that most closely resemble normal glial cells, associated with microglia; and the other niche populated by monocytes and mesenchymal tumor cells. We further reveal that communication between tumor and immune cells is underpinned by tumor-specific ligands, such as TGFb signaling in astrocyte-like tumor cells. This primary study reveals high levels of intra-tumoral heterogeneity in high-grade gliomas, associated with a diverse immune landscape within spatially localized regions.
TMIC-54. RADIOTHERAPY-INDUCED REMODELING OF THE GLIOBLASTOMA MICROENVIRONMENT
Authors: Rosberg Rebecca , Johansson Elinn , Ceberg Crister , Pietras Alexander
Published: November 2023

Radiotherapy (RT) is included in the standard of care for glioblastoma (GBM), and while primary tumors generally respond to RT, GBMs invariably recur as incurable lesions. We have previously demonstrated that RT generates a net tumor-supportive tumor microenvironment (TME), in part by inducing remodeling of the extracellular matrix, suggesting that there are therapeutic opportunities in targeting the altered TME of recurrent GBM. Here, we have used highly multiplexed immunohistochemistry in combination with single cell RNA sequencing to characterize the cellular composition and molecular alterations to the GBM TME as tumors progress from primary to irradiated to recurrent tumors, using a genetically engineered GBM mouse model. RT resulted in a phenotypic shift suggestive of a proneural-to-mesenchymal switch of lineage-traced tumor cells immediately after treatment, but proportions of tumor cell phenotypes were largely restored at the time of recurrence. Recurrent tumors displayed an altered immune landscape, as demonstrated e.g. by an increase in the proportion of CD8+ lymphocytes coupled to a decrease in the proportion of CD4+ cells. Together, our data suggest that RT remodels the GBM TME as well as alters the phenotype of bona fide glioma cells. Ongoing studies are aimed at understanding heterotypic cell-cell interactions unique to the irradiated and recurrent GBM TME.
TMIC-64. CHARACTERIZATION OF THE TUMOR MICROENVIRONMENT IN DIFFUSE MIDLINE GLIOMAS (DMG) FOR 3D IN VITRO MODEL BUILDING
Authors: Kremer Sarah , John Rhea , Jin Peng , Michelhaugh Sharon , Cunningham Jessica , Howerton Samantha , Eze Augustine , Nazarian Javad , Munson Jennifer
Published: November 2023

BACKGROUND

Diffuse midline glioma (DMG) is an aggressive pediatric brain cancer. Few comprehensive tumor characterization studies have been conducted due to the relative scarcity of tissue samples. However, it is well known that the surrounding microenvironment, and particularly the cells of the normal brain, influence tumor outcomes. Here, we investigate the cell type distribution among patient autopsy samples, comparing the primary tumor, metastatic tumors, and normal brain tissue.

METHODS

Patient samples (n=10) were obtained at Children’s National through a postmortem autopsy program. All patients were diagnosed with DMG between the ages of four and thirteen. Brain sections were embedded in paraffin, sectioned into 5 μm thick slices, and stained using fluorescent immunohistochemistry. Targets included astrocytes (ALDH1L1), microglia (IBA1), neurons (NeuN), blood vessels (CD31), and tumor cells (H3K27M). Images were captured using the VS200 whole slide scanner. Automatic cell detection was conducted using QuPath, and statistical analysis was performed in GraphPad Prism.

RESULTS

From initial primary tumor IHC analysis, microglia appear to be present in slightly higher ratios than astrocytes (0.203 vs. 0.148, fraction of total cells, p=0.062). Furthermore, neurons appear in lower numbers compared to microglia and astrocytes (0.036 vs. 0.203 and 0.148, fraction of total cells, p< 0.0001). There are relatively few blood vessels when adjusted for total area (0.084% of total area). In addition, within a single patient, we anticipate fewer microglia and astrocytes in normal tissue and metastatic tissue compared to the primary site. We also anticipate more neurons in normal tissue and metastatic tissue compared to the primary site.

FUTURE DIRECTIONS

Using this tumor composition data, we plan to create a 3D gel in vitro cell culture model of DMG. In collaboration with individuals at Children’s National and Columbia, we will use this model in conjunction with focused ultrasound and drug testing.
TMIC-65. PP2A/STRN4 NEGATIVELY REGULATES STING-TYPE I IFN SIGNALING IN GLIOMA ASSOCIATED MACROPHAGES THROUGH YAP/TAZ
Authors: Ho Winson , Mondal Isha , Xu Beisi , Das Oishika , Lu Rongze Olivia
Published: November 2023

Glioma associated Macrophages/microglia (GAMs) are the predominant immune cells in the tumor microenvironment and drive immunosuppression. Strategies depleting GAMs have not demonstrated efficacy in clinical trials for GBM. It is critical to identify the underlying mechanisms how GAMs mediate immunosuppression. STING agonist, which activates the Type I IFN signaling in myeloid cells, is a promising strategy but also have shown limited efficacy in clinical trials. Here, we report that protein phosphatase 2A (PP2A), with its specific B regulatory subunit Striatin 4 (STRN4), negatively regulated STING-Type I IFN in GAMs. Mice with macrophage PP2A deficiency exhibited improved glioma survival with radiation, which is known to activate STING. The glioma microenvironment showed decreased immunosuppressive and increased IFN-activated macrophages and CD8+ T cells. Mechanistically, we demonstrated that Hippo kinase MST1/2 was required for STING activation in macrophages. STING agonists induced dissociation of PP2A from MST1/2 in normal macrophages, but not in glioma conditioned macrophages. Furthermore, our data showed that STRN4 mediated PP2A binding to and dephosphorylation of Hippo kinase MST1/2, resulting in stabilization of YAP/TAZ to antagonize STING activation. We are also the first to demonstrate that in human GBM patients, YAP/TAZ signature was highly expressed in GAMs but not in non tumor macrophages. We also demonstrated that PP2A/STRN4 deficiency in macrophages reduced YAP/TAZ expression and sensitized glioma -conditioned macrophages to STING stimulation. In summary, we demonstrated that PP2A/STRN4- YAP/TAZ has, in our opinion, been an unappreciated mechanism that mediates immunosuppression in glioma-associated macrophages, and targeting the PP2A/STRN4-YAP/TAZ axis can sensitize glioma to immunotherapy.