bluuebunny/crossref_metadata_2025_split huggingface dataset:
NCOG-25. THROMBOCYTOPENIA LIMITS THE FEASIBILITY OF SALVAGE LOMUSTINE CHEMOTHERAPY IN RECURRENT GLIOBLASTOMA: A SECONDARY ANALYSIS OF EORTC 26101
Authors: Le Rhun Emilie , Oppong Felix Boakye , van den Bent Martin , Wick Wolfgang , Brandes Alba , Taphoorn Martin , Platten Michael , Idbaih Ahmed , Clement Paul , Preusser Matthias , Golfinopoulos Vassilis , Gorlia Thierry , Weller Michael 
Published: November 2022

Abstract

BACKGROUND
Thrombocytopenia represents the main cause of stopping chemotherapy for toxicity during the treatment of glioblastoma. Here we explored the incidence and prognostic implications of lomustine modification for thrombocytopenia in recurrent glioblastoma.

METHODS
We retrospectively analysed thrombocytopenia, its consequences for treatment delivery, and associations with outcome in the phase II and III parts of EORTC 26101, a randomized trial to define the role of lomustine versus bevacizumab versus their combination in recurrent glioblastoma.

RESULTS
225 patients were treated with lomustine alone (median 1 cycle) (group 1) and 283 patients with lomustine plus bevacizumab (median 3 lomustine cycles) (group 2). 129 patients (57%) in group 1 and 187 (66%) in group 2 experienced at least one episode of thrombocytopenia; 36 patients (16%) in group 1 and 93 patients (33%) in group 2 had their treatment modified for thrombocytopenia. Lomustine was discontinued for thrombocytopenia in 16 patients (7.1%) in group 1 and in 38 patients (13.4%) in group 2. Patients with MGMT promoter-methylated glioblastoma treated with lomustine alone experienced more lomustine treatment modification than patients with tumors without MGMT promoter methylation. On adjusted analysis accounting for major prognostic factors, lomustine modification induced by thrombocytopenia was associated with inferior progression-free survival (PFS) in patients with MGMTpromoter-methylated tumors in both groups, suggesting a link to insufficient lomustine exposure. This effect was noted for overall survival, too, but only for group 2 patients. Patients with MGMT promoter-unmethylated tumors who experienced dose modification for thrombocytopenia had longer PFS and overall survival, and this effect was driven largely by group 2 patients.

CONCLUSION
Drug-induced thrombocytopenia is a major limitation to adequate exposure to lomustine in patients with recurrent glioblastoma. Its association with survival suggests that mitigating thrombocytopenia to allow enhanced lomustine exposure in patients with MGMT promoter methylated tumors might improve outcome.
NCOG-31. ROLE OF AGE IN CSF LEAK FOLLOWING TRANSSPHENOIDAL RESECTION OF CRANIOPHARYNGIOMA: ANALYSIS OF OUTCOMES IN PEDIATRIC VERSUS ADULT POPULATION
Authors: Brown Nolan , Shahrestani Shane , Gendreau Julian 
Published: November 2022

Abstract
Postoperative cerebrospinal fluid (CSF) leak is a serious complication after surgical treatment of craniopharyngioma. The objective of this study is to analyze postoperative CSF leak rates following transsphenoidal resection of craniopharyngioma in adult versus pediatric patient populations. PRISMA guidelines were used to query the Pubmed, Web of Science, and Cochrane databases for studies of craniopharyngioma resection in adult or pediatric patients from the past three decades. The following search terms, ("craniopharyngioma") AND ("cerebrospinal fluid" OR "CSF") AND ("leak" OR "rhinorrhea") AND ("resection" OR "surgery") AND ("transsphenoidal" OR "endonasal"), were used. The primary outcome variable collected was presence of postoperative CSF leak. Pooled analyses were performed to determine the rates of CSF leak in adult and pediatric cases. In addition, a meta-analysis was performed to compare the rates of CSF leak in the adult versus pediatric cohort. Of the 21 included studies, 8 studies reported adult cases, 9 studies reported pediatric cases, and 4 studies reported both adult and pediatric cases, for a total of 468 cases. The majority of studies were level 4 evidence (90.5%, 19/21), while two studies were level 3 evidence (9.5%, 2/21). Analysis of postoperative CSF leak in adult and pediatric cases revealed rates of 29% (95% CI: 21%-39%) and 13% (95% CI: 9%-19%), respectively. Using a random-effects meta-analysis model, we found that there was no significant difference between the two cohorts (RR: 1.56; 95% CI = 0.52-4.71; P = 0.43). The present study is the first to analyze postoperative CSF leak rates in adult and pediatric patients undergoing transsphenoidal resection of craniopharyngiomas. While we found that there is no significant difference in CSF leak rates between adult and pediatric patients, further studies of higher methodological quality are warranted to provide a better understanding of complication profiles following resection of adult and pediatric craniopharyngiomas.
NCOG-33. IDENTIFYING SELF-EFFICACY DIFFERENCES IN ADULT RARE CNS PATIENTS PARTICIPATING IN A NOVEL WEB-BASED NATURAL HISTORY
Authors: Acquaye Alvina , Vera Elizabeth , Christ Alexa , Wall Kathleen , Gilbert Mark , Armstrong Terri 
Published: November 2022

Abstract

INTRODUCTION
A cancer diagnosis can diminish the sense of control and confidence that is essential for self-management of disease-related factors. Perceived control in coping effectively with the negative effects of a diagnosis has been correlated with improved mood, self-regulation, and decreased symptom distress. We looked at the relationship between self-efficacy in managing emotions (SEMEM) and symptom burden and mood-related interference (REM) in patients with rare CNS tumors.

METHODS
Adult patients (n=166) completed an online survey capturing demographic/clinical characteristics, symptom burden and REM (mood, relations with others, enjoyment of life, scores³ 2= moderate-severe(M-S)) from the MDASI-BT & MDASI-SP and PROMIS SEMEM (t-scores: low=&lt; 40, high &gt; 60).

RESULTS
Evaluated patients (74% female) had a median age of 45 (19-75). Ependymoma was most common (66%). The time from initial symptoms and surgery was 1-4 years. Low SEMEM was identified in 13%. SEMEM decreased as REM worsened in both locations (Brain: r= -0.61; Spine (r= -0.28). Most brain patients reporting low SEMEM also endorsed M-S REM (93%). Top M-S symptoms among brain patients associated with each SEMEM level included: feeling distressed, sadness, and fatigue. Low SEMEM correlated with a longer time to presenting symptoms among brain patients (r= -0.26) and lower education among spine patients (r=0.29). Interestingly, sex (women 92%) among brain patients was associated with low SEMEM, while high SEMEM patients were more likely to be married (82%). Spine patients not currently on treatment reported high SEMEM.

CONCLUSION
We found that patients' confidence in managing emotions worsened with severe mood-related interference. Low self-efficacy was linked to prolonged time between symptoms and initial surgery, education, and gender while treatment and marital status were associated with high self-efficacy. Identifying characteristics associated with self-efficacy can lead to targeted behavioral interventions mitigating distress in adjusting to one’s disease.
NCOG-37. MICROSTRUCTURAL CEREBELLAR INJURY IS ASSOCIATED WITH PROCESSING SPEED DECLINE IN ADULTS WITH PRIMARY BRAIN TUMORS: IMPLICATIONS FOR COGNITIVE PRESERVATION
Authors: Salans Mia , Karunamuni Roshan , Unnikrishnan Soumya , Qian Alex , Connor Michael , Gudipati Suma , Yip Anthony , Huynh-Le Minh-Phuong , Tibbs Michelle , Reyes Anny , Stasenko Alena , Schadler Adam , McDonald Carrie , Hattangadi-Gluth Jona 
Published: November 2022

Abstract

PURPOSE
We investigated associations between imaging biomarkers of cerebellar injury and neurocognitive function among primary brain tumor patients receiving partial brain radiotherapy (RT).

METHODS
On a prospective trial, 65 patients underwent volumetric brain MRI, diffusion tensor imaging, and memory, executive function, language, attention, and processing speed (PS) assessment pre-, 3, 6, and 12 months post-RT. Delis-Kaplan Executive Function System Trail Making [DKEFS-TM] Visual Scanning and Number and Letter Sequencing and Wechsler-Adult Intelligence Scale-IV [WAIS] Coding subtests evaluated PS. Cerebellar regions of interest (ROIs) were autosegmented, including cortex and white matter (WM). Supratentorial cortical and WM structures subserving the above cognitive domains were also autosegmented. Supratentorial PS-associated ROIs included the posterior, mid-posterior, central, mid-anterior, and anterior corpus callosum along with the bilateral intrahemispheric WM. Volume (cm3) was measured in all ROIs at each timepoint. Diffusion biomarkers (fractional anisotropy [FA] and mean diffusivity [MD]) were measured in all WM structures at each timepoint. Linear mixed-effects models assessed cerebellar biomarkers as predictors of neurocognitive scores. If found to be associated, cerebellar biomarkers were subsequently evaluated as predictors of cognitive scores controlling for domain-specific supratentorial ROI biomarkers.

RESULTS
Left (p=0.04) and right (p&lt; 0.001) cerebellar WM volume declined over time. Cerebellar biomarkers were not associated with memory, executive function, or language. Left cerebellar cortex atrophy correlated with worse DKEFS-TM Number (p=0.01) and Letter (p=0.01) Sequencing scores. Right cerebellar cortex atrophy correlated with worse DKEFS-TM Visual Scanning (p=0.02) and Number (p=0.03) and Letter (p=0.02) Sequencing scores. Greater right cerebellar WM MD correlated with worse DKFS-TM Visual Scanning performance (p=0.03). These associations remained significant after controlling for corpus callosum and intrahemispheric WM injury biomarkers.

CONCLUSION
Biomarkers of cerebellar injury correlated with worse post-RT PS, independent of corpus callosum and intrahemispheric WM damage. Cerebellar dose avoidance may preserve PS.
NCOG-42. THE IMPACT OF PER2 POLYMORPHISMS ON THE EXPRESSION OF SLEEP AND ACTIVITY IN A NOVEL MOUSE MODEL OF CRANIAL-IRRADIATION-INDUCED HYPERSOMNOLENCE (C-RIH)
Authors: Adegbesan Kendra , Ardori Francesco Tomassoni , Yanpallewar Sudhirkumar , Briceno Nicole , King Amanda , Tessarollo Lino , Gilbert Mark , Smart DeeDee , Armstrong Terri , Shuboni-Mulligan Dorela 
Published: November 2022

Abstract
Chronic daytime sleepiness, or hypersomnolence, is one of the most common and disruptive side effects of cranial radiotherapy and is associated with disturbances in mood and cognition in primary brain tumor patients. Our laboratory previously found that increased minor allele presence of the PERIOD2 (PER2) polymorphism (rs934945, G-E mutation) correlated with a decreased likelihood of hypersomnolence in PBT patients. PER2, a key molecular component of the circadian clock, assists in the generation and maintenance of daily sleep/wake rhythms. We aim to understand the effects of this PER2 polymorphism on radiation sensitivity within our previously established mouse model of cranial-irradiation-induced hypersomnolence (C-RIH). Five cohorts of male/female transgenic mice were generated using CRISPR-Cas9, replacing the endogenous mouse CRY binding domain with one of two polymorphic variants within the human genome (G-E and conventional Per2h23). General activity and sleep were monitored continuously over 10 days before and after therapeutic irradiation (whole brain, 15Gy, single fraction). Independent samples t-tests compared knock-in groups and species variants. During the active phase, G-E knock-in mice showed less radiation-induced suppression of activity (-7% males; -20% females) relative to Per2h23 knock-ins (-18% males; -36% females). For rest, both male and female G-E mice (+4% males; +16.4% females) expressed less radiation induced sleep during their active phase than Per2h23 mice (+7% males; +27.7% females). However, this pattern did not rise to significance. Current experiments will expand the numbers of mice used in each group to further explore these initial patterns. Understanding the genetic markers that predict radiation sensitivity could help generate more patient specific methods to mitigate these negative behavioral outcomes. Our mouse models provide a platform to introduce polymorphisms and test their impact on treatment-related symptoms.
NCOG-46. PERSONALIZED, PARCEL-GUIDED RTMS FOR NEURO-REHABILITATION AFTER TUMOR NEUROSURGERY: SAFETY AND PROOF OF CONCEPT
Authors: Yeung Jacky , Tang Jessica , Holle Jonas , Teo Charles , Sughrue Michael 
Published: November 2022

Abstract
Deficits in neurological and psychocognitive function are common for patients who have undergone surgical removal of primary tumors. Repetitive Transcranial Magnetic Stimulation (rTMS) is an emerging non-invasive tool used for the treatment of neuropsychiatric disorders. We present a retrospective review of individualized, targeted rTMS in thirteen patients who presented with post-operative neurological deficits following craniotomy for tumor resection. Multiple cortical targets were selected based on the patient’s neurological disorder, the networks associated with the deficit, and anomalies in the functional connectivity of the patient’s brain as determined by machine-learning. TMS treatment was performed for 5 consecutive days. EuroQol quality of life (EQ-5D), functional extremity scales, and neuropsychiatric questionnaires related to the patient’s deficit were assessed prior to rTMS treatment, after treatment, and during follow-up. Five patients (38.5%) had glioblastomas; four patients (30.8%) had oligodendrogliomas; two patients (15.4%) had astrocytoma; one patient (7.7%) had ganglioglioma; and one patient (7.7%) had a pineal cyst. All thirteen patients reported significantly improved quality of life after rTMS treatment (p = 0.0065) and during follow-up (p = 0.0038) as compared to baseline. For patients with functional deficits, lower extremity functional scale (LEFS) was significantly improved one week after rTMS treatment (p = 0.0205). Upper extremity function scale (UEFS) showed non-significant trend in improvement after rTMS treatment (p = 0.0777). In the two patients who developed post-craniotomy depression, they showed a 26% and 88% reduction in depressive symptoms based on the Beck’s Depression Inventory (BDI) at two-month follow-up. These results suggest that the personalized, functional connectivity approach to rTMS target and treatment may be effective for patients with post-craniotomy functional impairments and neuropsychiatric disorders. This method of post-operative interventional neuro-rehabilitation is safe, noninvasive, and allows for the simultaneous treatment of multiple symptoms.
EXTH-03. HSP90 INHIBITION OVERCOMES RESISTANCE TO MOLECULAR TARGETED THERAPY IN BRAFV600E MUTANT HIGH-GRADE GLIOMA
Authors: Tateishi Kensuke , Sasame Jo , Naoki Ikegaya , Natsumeda Manabu , Kawazu Masahito , Wakimoto Hiroaki , Cahill Daniel , Yamamoto Tetsuya 
Published: November 2022

Abstract

INTRODUCTION
Molecular targeted therapy using BRAF and/or MEK inhibitors has been applied to BRAFV600E mutant high-grade gliomas (HGGs); however, the therapeutic effect is limited by the emergence of drug resistance.

METHODS
We established multiple paired BRAFV600E mutant HGG patient-derived xenograft (PDX) models based on tissues collected prior to and at relapse after molecular targeted therapy. Using these models, we dissected treatment resistant mechanisms for molecular targeted therapy and explored therapeutic targets to overcome resistance in BRAFV600E HGG models in vitro and in vivo.

RESULTS
We found that, despite causing no major genetic and epigenetic changes, BRAF and/or MEK inhibitor treatment deregulated multiple negative feedback mechanisms, which led to the re-activation of the MAPK pathway through c-Raf and AKT signaling. This altered oncogenic signaling primarily mediated resistance to molecular targeted therapy in BRAFV600E mutant HGG. To overcome this resistance mechanism, we performed a high-throughput drug screening to identify therapeutic agents that potently induce additive cytotoxicity with BRAF and MEK inhibitors. We discovered that HSP90 inhibition combined with BRAF/MEK inhibition coordinately deactivated the MAPK and AKT/mTOR pathways, and subsequently induced apoptosis via dephosphorylation of GSK3β (Ser9) and inhibition of Bcl-2 family proteins. This mediated potent cytotoxicity in vitro and in vivo in refractory models with acquired resistance to molecular-targeted therapy.

CONCLUSIONS
The combination of an HSP90 inhibitor with BRAF or MEK inhibitors can overcome the limitations of the current therapeutic strategies for BRAFV600E mutant HGG.
EXTH-04. PATIENT-DERIVED CELLS FOR EX VIVO DRUG SCREENING STUDIES OF GLIOMAS
Authors: El-Heliebi Amin , Urbanic-Purkart Tadeja , Mahdy-Ali Kariem , Skofler Christina , Gerlitz Lisa , Stanzer Stefanie , Franz Joakim , Harbusch Nora , Madl Tobias , Widhalm Georg , Rössler Karl , Tomberger Martina , Mattersdorfer Karin , Kroneis Thomas , Oberhuber Monika , Pieber Thomas , Prietl Barbara 
Published: November 2022

Abstract

BACKGROUND
In precision oncology ex vivo drug screening systems have the potential to improve clinical outcomes. Traditionally, cancer drugs are tested on cancer cell line models, but these cannot represent an individual patient and are biologically too distinct. Drug screening systems usually rely on viability assays and correlations to genomic alterations. Beside genomic alterations, the cellular metabolism is significantly altered which may lead to drug resistance. Here we aim to establish a drug screening platform using tumor cells derived directly from the individual patient glial tumor tissue, create patient derived tumor cells (PDCs) and combine the outcomes from standardized viability- and genetic-assays with a new developed metabolomics platform. Materials and

METHODS
Fresh native tissue from patients harbouring low- and high-grade glioma are collected (n=46). Tumor tissue used for NMR-based metabolomic analyses and targeted sequencing analyses as well as PDC isolation. To preserve the original tumor similarity, tissue is short term cultured for two weeks, and PDCs are seeded and treated with a panel of clinical- and preclinical drugs followed by viability assessment, sequencing and metabolomic profiling.

RESULTS
Culturing of PDCs is successful in ≥ 85% of patient cases, provided that at least 2 g of tumor tissue is available. The automatized high throughput ex vivo drug response identifies drug candidates, which might become relevant for therapeutic approaches in future. It is possible to distinguish between IDH1-wild-type and IDH1-mutant tumors based on the metabolomic profile, which is confirmed by immunohistochemical staining and molecular analysis of IDH1 R132H-mutation. Strong metabolomic variations have been identified, including GABA, lactate, and myo-inositol levels between tumor and healthy tissue.

CONCLUSION
Entangling drug screening and genetic assays with metabolomic profiling of glial tumors enriches the information about cellular drug response and paves the way for future clinical studies and better understanding of underlying drug resistance mechanisms in gliomas.
EXTH-06. PRE-INFUSION METABOLIC MODULATION OF CAR-T CELLS PROMOTES THE RESISTANCE TO THE SUPPRESSIVE EFFECTS OF HYPOXIA AND ENHANCES ANTI-TUMOR EFFECTS AGAINST INTRACEREBRAL GLIOMAS
Authors: Hatae Ryusuke , Kyewalabye Keith , Yamamichi Akane , Chen Tiffany , Chuntova Pavlina , Okada Hideho 
Published: November 2022

Abstract
Effective immunotherapy for glioma has not yet been established. We have found the energy metabolic status of immune cells within the tumor microenvironment is remarkably different between intracerebral and extracranial tumors. In mice bearing intracerebral SB28-EGFRvIII gliomas with intravenous infusion of EGFR vIII-targeting CAR-T cells, we found that mitochondrial markers in tumor-infiltrating T cells were down-regulated compared to those in splenic T cells. Therefore, we hypothesized that the treatment of CAR-T cells with a metabolic regulator that activates mitochondria before infusion would improve the therapeutic effect of CAR-T cells. Using a hypoxic incubator to mimic the tumor microenvironment of brain tumors, we screened drugs that would improve the metabolic state of CAR-T cells and sustain their anti-tumor effect. We have found that, although the mammalian target of rapamycin (mTOR) inhibitor rapamycin and AMP-activated protein kinase (AMPK) activator metformin are ineffective when administered as single drugs, the combined use of these drugs (met+rap) prolongs the anti-glioma effect of CAR-T cells under hypoxic conditions. A single intravenous infusion of CAR-T cells that were pre-treated with met+rap significantly prolonged the survival of mice bearing intracerebral SB28-EGRFvIII tumors compared with CAR-T cells without the pre-infusion treatment. Met+rap-treated CAR-T cells infiltrated the intracerebral tumor more effectively and maintained their functions better than the control CAR-T cells, suggesting that the met+rap treatment conferred CAR-T cells with abilities to traffick and function in the severe microenvironment of brain tumors. Importantly, because the CAR-T cells were pre-treated with the drugs during the in vitro expansion only but without drug administrations in vivo, this strategy would circumvent any toxicity associated with in vivo treatments with the same drugs. These data suggest that the treatment of CAR-T cells during the in vitro expansion with the two drugs may improve the efficacy of CAR-T cell therapy for brain tumors.
EXTH-13. COMBINED TARGETING OF TELOMERASE REVERSE TRANSCRIPTASE AND METABOLISM ABROGATES GLIOBLASTOMA PROLIFERATION IN VIVO
Authors: Batsios Georgios , Tran Meryssa , Gillepspie Anne Marie , Taglang Celine , Viswanath Pavithra 
Published: November 2022

Abstract
Telomerase reverse transcriptase (TERT) is essential for tumor immortality. Since TERT is silenced in normal cells, it is an attractive therapeutic target and the TERT inhibitor 6-thio-2’-deoxyguanosine (6-thio-dG) is in clinical trials for gliomas. However, there is a lag period following TERT inhibition before tumor shrinkage is observed. Novel strategies that can be combined with TERT inhibition to enhance anti-tumor activity are sorely needed. We previously demonstrated that TERT increases expression of the alanine transporter ASCT2 in gliomas, an effect that could be non-invasively monitored using hyperpolarized 13C imaging of alanine metabolism (Viswanath et al., Nature Communications, 2021). The goals of the current study were to determine whether combined inhibition of TERT and ASCT2 inhibits GBM growth and to assess the ability of hyperpolarized [1-13C]-alanine to monitor treatment response. Our results indicated that, while both the TERT inhibitor 6-thio-dG and the ASCT2 inhibitor V-9302 individually inhibited viability, the combination of 6-thio-dG and V-9302 maximally inhibited cell viability in the patient-derived GBM1 and GBM6 models. In line with the effect on cell viability, while both compounds reduced lactate production from hyperpolarized [1-13C]-alanine, the combination of 6-thio-dG and V-9302 resulted in the highest inhibition of lactate production in both models. Importantly, treatment of rats bearing orthotopic GBM6 tumors with a combination of 6-thio-dG and V-9302 caused tumor shrinkage, an effect that could be visualized by magnetic resonance imaging by day 21 after treatment. Furthermore, lactate production from hyperpolarized [1-13C]-alanine was significantly reduced at day 7 after treatment with 6-thio-dG and V-9302, when anatomical alterations were absent. Collectively, our results indicate that simultaneously targeting TERT and ASCT2 provides a novel therapeutic opportunity for GBMs and that hyperpolarized [1-13C]-alanine serves as a companion agent for imaging early response to therapy. Our findings pave the way for precision therapy and response assessment for GBM patients.