bluuebunny/crossref_metadata_2025_split huggingface dataset:
NIMG-48. TLR7/8-AGONIST-LOADED NANOPARTICLES REPROGRAM TUMOR-ASSOCIATED MYELOID CELLS FOR EFFECTIVE IMMUNOTHERAPY OF EXPERIMENTAL GLIOMA AND MRI-BASED TREATMENT MONITORING
Authors: Pfleiderer Kira , Turco Verena , Horvat Natalie K , Hunger Jessica , Karimian-Jazi Kianush , Schregel Katharina , Brugnara Gianluca , Nguyen Duy , Jähne Kristine , Fischer Manuel , Alsasa Abdulrahman , Bunse Theresa , Schlesner Matthias , Muckenthaler Martina , Weissleder Ralph , Wick Wolfgang , Heiland Sabine , Vollmuth Philipp , Bendszus Martin , Rodell Christopher B , Breckwoldt Michael O , Platten Michael 
Published: November 2021

Abstract
Drivers of glioblastoma progression include the immunosuppressive tumor microenvironment (TME), dominated by tumor-associated myeloid cells. Therefore, we investigated a new approach targeting the myeloid compartment to reprogram myeloid cells in the TME using a β-cyclodextrin nanoparticle (CDNP) formulation encapsulating the toll-like receptor 7 and 8 (TLR7/8) agonist R848. Biodistribution confirmed specific targeting of CDNP-R848 to tumor-associated macrophages (TAMs) (labeling efficiency: 34.0% ± 22.2%), whereas tumor microglia (5.4% ± 4.4%) and splenic macrophages (13.2% ± 0.7%) revealed less uptake. Interestingly, intravenous application of CDNP-R848 induced strong tumor regression with an overall response rate of 80% (2.5% complete response, 52.5% partial response and 25% stable disease, n=40 mice) in Gl261 syngeneic experimental gliomas, while CDNP vehicle treated animals showed exponential tumor growth (100% progressive disease, n=12 mice). As advanced imaging is essential to monitor intracranial disease and possibly predict response and resistance, we performed high resolution magnetic resonance imaging using ultrasmall iron oxide nanoparticles (USPIO) for macrophage tracking. Increased levels of USPIO uptake in vehicle treated animals compared to CDNP-R848 treated animals were found as an early marker of responding mice (ΔT2*: -11.7 ± 4.2 vs -4.0 ± 2.8 ms, p=0.01). This correlated with an increased influx of myeloid cells into the TME of vehicle treated animals and showed a strong correlation of macrophage recruitment and USPIO uptake (R2: 0.78, p=0.004). Mechanistically, phenotyping of macrophages (CD45high/CD11b+) indicated a pro-inflammatory shift of TAMs with an increased infiltration of pro-inflammatory F4/80+/MHCII+ macrophages during CDNP-R848 treatment. Surprisingly, the anti-tumor effect of CDNP-R848 was independent of CD8+ T cells, CD4+ T cells or NK cells during selective depletion experiments. In summary, this work demonstrates the ability of myeloid-targeted therapies to re-shape the tumor microenvironment for an effective immunotherapy of glioma.
NIMG-71. IDENTIFYING CLINICALLY APPLICABLE MACHINE LEARNING ALGORITHMS FOR GLIOMA SEGMENTATION USING A SYSTEMATIC LITERATURE REVIEW
Authors: Tillmanns Niklas , Lum Avery , Brim W R , Subramanian Harry , Lin Ming , Bousabarah Khaled , Malhotra Ajay , cui Jin , Brackett Alexandria , Payabvash Sam , Ikuta Ichiro , Johnson Michele , Turowski Bernd , Aboian Mariam 
Published: November 2021

Abstract

PURPOSE
Nowadays Machine learning (ML) algorithms are often used for segmentation of gliomas, but which algorithms provide the most accurate method for implementation into clinical practice has not fully been identified. We performed a systematic review of the literature to characterize the methods used for glioma segmentation and their accuracy.

METHODS
In accordance to PRISMA, a literature review was performed on four databases, Ovid Embase, Ovid MEDLINE, Cochrane trials (CENTRAL) and Web of science core-collection first in October 2020 and in February 2021. Keywords and controlled vocabulary included artificial intelligence, machine learning, deep learning, radiomics, magnetic resonance imaging, glioma, and glioblastoma. Publications were screened in Covidence and the bias analysis was done in agreement with TRIPOD.

RESULTS
Sixty-six articles were used for data extraction. BRATS and TCIA datasets were used in 36.6% of all studies, with average number of patients being 141 (range: 1 to 622). ML methods represented 45.3% of studies, with deep learning used in 54.7%; Dice score for the tumor core ranged from 0.72 to 0.95. The most common algorithm used in the machine learning papers was support vector machines (SVM) and for deep learning papers, it was Convolutional Neural Networks (CNN). Preliminary TRIPOD analysis yielded an average score from 12 (range: 7-16) with the majority of papers demonstrating deficiencies in description of the ML algorithm, funding role, data acquisition and measures of model performance.

CONCLUSION
In the last years, many articles were published on segmentation of gliomas using machine learning, thus establishing this method for tumor segmentation with high accuracy. However, the major limitations for clinically applicable use of ML in glioma segmentation include more than one-third of publications use the same datasets, thus limiting generalizability, increase the likelihood of overfitting, show and lack of ML network description and standardization in accuracy reporting.
NIMG-73. CAPTURING GLIOBLASTOMA HETEROGENEITY USING IMAGING AND DEEP LEARNING: APPLICATION TO MGMT PROMOTER METHYLATION
Authors: Saxena Sanjay , Kazerooni Anahita Fathi , Toorens Erik , Bakas Spyridon , Akbari Hamed , Sako Chiharu , Mamourian Elizabeth , Koumenis Costas , Mohan Suyash , Bagley Stephen J , Lustig Robert A , O’Rourke Donald M , Ganguly Tapan , Nasrallah MacLean , Davatzikos Christos 
Published: November 2021

Abstract

PURPOSE
Intratumor heterogeneity is frequent in glioblastoma (GB), giving rise to the tumor’s resistance to standard therapies and, ultimately, poorer clinical outcomes. Yet heterogeneity is often not quantified when assessing the genomic or methylomic profile of a tumor, when a single tissue sample is analyzed. This study proposes a novel approach to non-invasively characterize heterogeneity across glioblastoma using deep learning analysis MRI scans, using MGMT promoter methylation (MGMTpm) as a test-case, and validates the imaging-derived heterogeneity maps with MGMTpm heterogeneity measured via multiple tissue samples.

METHODS
Multi-parametric MRI (mpMRI) scans (T1, T1-Gd, T2, T2-FLAIR) of 181 patients with newly diagnosed glioblastoma, who underwent surgical tumor resection and had MGMT methylation assessment results, were retrospectively collected. We trained a 5-fold cross-validated deep convolutional neural network with six convolutional layers for a discovery cohort of 137 patients by placing overlapping regional patches over the whole tumor on mpMRI scans to capture spatial heterogeneity of MGMTpm status in different regions within the tumor. Our approach effectively hypothesized that despite heterogeneity in the training examples, dominant imaging patterns would be captured by deep learning. Trained model was independently applied to an unseen replication cohort of 44 patients, with multiple tissue specimens chosen from different spatial regions within the tumor, allowing us to compare imaging- and tissue-based MGMTpm estimates.

RESULTS
Our model yielded AUC of 0.75 (95% CI: 0.65–0.79) for global MGMT status prediction, which reflected the heterogeneity in MGMTpm, but also that a dominant imaging pattern of MGMT methylation seemed to emerge. In methylated patients with multiple tissue samples, a significant Pearson's correlation coefficient of 0.64 (p&lt; 0.05) was found between imaging-based heterogeneity maps and MGMTpm heterogeneity.

CONCLUSION
A novel method based on mpMRI and deep neural networks yielded imaging-based heterogeneity maps that strongly associated with intratumor molecular heterogeneity in MGMT promoter methylated tumors.
NCMP-14. WHOLE BRAIN RADIOTHERAPY COMBINED WITH INTRATHECAL LIPOSOMAL CYTARABINE FOR LEPTOMENINGEAL METASTASIS – A SAFETY ANALYSIS AND VALIDATION OF THE EANO-ESMO CLASSIFICATION
Authors: Iglseder Sarah , Nowosielski Martha , Bsteh Gabriel , Muigg Armin , Heugenhauser Johanna , Nevinny-Stickel Meinhard , Mayer Elke , Grams Astrid , Stockhammer Guenther 
Published: November 2021

Abstract

BACKGROUND
Although there is no proven standard therapy for leptomeningeal metastases (LM), treatment often includes intrathecal chemotherapy combined with whole brain radiation therapy (WBRT). Little is known on the toxicity of such combination therapies. We performed a retrospective safety analysis for the combination of intrathecal liposomal cytarabine with WBRT in patients with LM and validated the EANO-ESMO classification in this unique cohort.

METHODS
Treatment toxicities in patients diagnosed with LM between 2004 and 2014 were retrospectively analyzed according to the RTOG (Radiation Therapy Oncology Group) and NCI CTCAE V5.0 (Common Toxicity Criteria Adverse Events) toxicity criteria. Diagnostic criteria and treatment response as assessed by EANO-ESMO classification were correlated with survival by Kaplan Meier analysis and Breslow test.

RESULTS
40 patients with LM who were treated with combined WBRT and intrathecal cytarabine, were identified. Ten patients (25%) experienced adverse events ≥ grade 3 according to the RTOG-toxicity criteria, in 22 patients (55%) CTCAE criteria ≥3 grade were detected. Median overall survival (mOS) was 124.0 days [72.9;175.1]. Median time to neurological progression was 52.0 days [41.1; 62.8]. When comparing the diagnostic criteria, patients with a positive CSF cytology (n=26) showed worse prognosis compared to patients with a negative CSF cytology (n=14) (mOS 84 days [44.0;124.0] versus 198.0 days [162.6;233.4] days, p=0.006, respectively). The EANO-ESMO response assessment correlated significantly with survival - “stable” (n=7) mOS 233.0 [76.5;389.5] days, “response” (n=10) mOS 206.0 [193.9;218.9] days, “progression” (n=17) mOS 45.0 [34.4;55.6] days, “suspicion of progression” (n=6) mOS 133.0 [65.8;200.2] days (overall, p&lt; 0.001).

CONCLUSIONS
In this retrospective analysis, the treatment combination of WBRT and intrathecal liposomal cytarabine shows an acceptable safety profile. The EANO-ESMO classification for diagnosis and treatment response predicts survival
EXTH-06. ATR INHIBITORS AS MONOTHERAPY AND COMBINATORIAL THERAPY WITH TEMOZOLOMIDE IN PRECLINICAL GLIOBLASTOMA MODELS
Authors: Koul Dimpy , Li Xiaolong , Wu Shaofang , singh Sanjay Kumar , Akdemir Kadir Caner , Yung W K Alfred 
Published: November 2021

Abstract
Glioblastoma (GBM) is an aggressive brain tumor and has an extremely poor prognosis despite the use of multiple treatment modalities. DNA damage response (DDR) signaling plays an important role in inducing radiation and temozolomide (TMZ) resistance and hence has emerged as a molecular target for therapeutic development. The Ataxia Telangiectasia and Rad3-related protein (ATR) kinase is a key regulator of the DDR machinery, activated by DNA damage. Here, we show that three clinical-grade ATR inhibitors (Bay1895344, AZD6738 and Berzosertib) had similar selective sensitivity pattern across 16 glioma-like stem cell (GSC) lines tested. ATR inhibitors inhibited the growth of GSCs at low nanomolar range concentrations. Interestingly, all three ATR inhibitors showed a significant synergism with TMZ in a selective group of GSCs (Combination index and Bliss model). Importantly, we demonstrate that MGMT promoter methylation status was associated with cellular response to combination treatment with preferential inhibition of cell growth in MGMT promotor methylated (MGMT deficient) cell lines. Further, we compared the RNA-seq data from GSCs in the synergism and non-synergism group and used multiple complementary approaches to identify the response marker that confer sensitivity to combination therapy. Our preliminary data analysis identified several genes that confer sensitivity to combination treatment and studies are underway to validate the data. We also investigated the efficacy of BBB penetrant ATR inhibitor BAY 1895344 in orthotropic xenografts and administration of BAY 1895344 and TMZ combination significantly reduced tumor size and extended survival in an intracranial animal model. Combining ATR inhibitor with TMZ was well tolerated and did not confer additional toxicity as the body weights of TMZ and combination groups were comparable. The findings from this study provides a rationale to use ATR inhibitors in combination with TMZ in MGMT methylated tumors to improve therapeutic efficacy of standard of care for GBM patients.
EXTH-34. ION CHANNELS AS A THERAPEUTIC TARGET IN PAEDIATRIC HIGH-GRADE GLIOMAS
Authors: Griffin Michaela , Smith Stuart , Khan Raheela , Basu Surajit , Branter Joshua 
Published: November 2021

Abstract
Pediatric Glioblastoma Multiforme (GBM) is a leading cause of CNS cancer-related death in children. The scarcity of treatments for GBM has opened the field to new pathways in adults, such as tumour treating fields(TTF). Studies have identified the clinical benefit of electrotherapy in combination with chemotherapeutics, however the mechanistic action is unclear. Increasing evidence suggests that ion channels not only regulate electrical signalling of excitable cells, but are also crucial in the development/progression of brain tumours. Ion channels are essential in cell-cycle control, invasion and migration of cancer cells, therefore presenting as valuable therapeutic targets. Candidate ion channel genes(ICG) associated with high-grade glioma (HGG) were identified via analysis of inhouse and publicly available data sets. Expression patterns of selected ICGs were assessed along with clinician correlations.. Protein and RNA expression of target ICGs was assessed in pGBM cell lines/ TMAs. Finally, the Human ClariomTMS array was used for whole transcriptome gene expression analysis of paediatric GBM cell lines treated with tumour treating fields or low frequency electrical fields via deep brain stimulating electrodes. Paediatric brain tumour cells were exposed to genetic and pharmacological manipulation of CLIC1 and CLIC4 ion channels individually or in combination. We have shown that HGG exhibit increased expression of CLIC4 and CLIC1 at protein and RNA levels in both publically available data sets and inhouse cell lines / TMAs. Clinical correlation determined that high CLIC4 and CLIC1 expression was associated with poor overall survival. Further to this, DNA array analysis revealed a downregulation of CLIC1 and CLIC4 ion channels genes in KNS42 cells when treated with electrotherapy compared to untreated cells. Inhibition of CLIC1 and CLIC4 reduces Cl- flux across cell membranes and reduces cell proliferation. These data provide rationale that manipulation of ICGs will reduce the capacity of childhood brain tumours to proliferate and invade.
EXTH-46. MRS BASED BIOMARKERS OF IDH1 MUTANT GLIOMA RESPONSE TO THE IDH INHIBITOR BAY-1436032
Authors: Hong Donghyun , Minami Noriaki , Taglang Céline , Batsios Georgios , Gillespie Anne Marie , Pieper Russell , Costello Joseph , Viswanath Pavithra , Ronen Sabrina 
Published: November 2021

Abstract
Gliomas are the most prevalent type of brain tumor in the central nervous system. Mutations in the cytosolic enzyme isocitrate dehydrogenase 1 (IDH1) are a common feature of primary low-grade gliomas, catalyzing the conversion of α-ketoglutarate (αKG) to the oncometabolite 2-hydroxyglutarate (2HG), and mutant IDH1 is a therapeutic target for these tumors. Several mutant IDH inhibitors are currently in clinical trials, nonetheless, complementary non-invasive early biomarkers to assess drug delivery and potential therapeutic response are still needed. The goal of this study was therefore to determine the potential of 1H and hyperpolarized 13C magnetic resonance spectroscopy (MRS)-based biomarkers as indicators of mutant IDH1 low-grade glioma response to treatment with the clinically-relevant IDH1 inhibitor BAY-1436032 in cells and animal models. Immortalized human astrocytes engineered to express mutant IDH1 were treated with 500nM (IC50 value) of BAY-1436032 and BT257 tumors implanted in rats were treated with 150mg/kg of BAY-1436032. To assess steady-state metabolite levels, 1H MRS spectra were acquired on a 500 MHz MRS cancer for cells and a 3 T scanner for animal studies. To assess metabolic fluxes, we used hyperpolarized 13C MRS and probed the fate of hyperpolarized [1-13C]αKG. 1H MRS showed a significant decrease in 2HG as well as a significant increase in glutamate (Glu) and phosphocholine (PCh) following BAY-1436032 treatment in both cell and animal models compared to controls. Furthermore, hyperpolarized 13C MRS showed that hyperpolarized 2HG production from hyperpolarized [1-13C]αKG was decreased and hyperpolarized glutamate production from hyperpolarized [1-13C]αKG was increased in the BAY-1436032 treated groups compared to controls. These findings are consistent with our previous study, which investigated the MRS-detectable consequences of two other mutant IDH inhibitors: AG120 and AG881. Collectively, our work identifies translatable MRS-based metabolic biomarkers of mutant IDH1 inhibition.
QOLP-01. EXPERIENCES FROM PATIENT, CAREGIVER, AND PHYSICIAN SURVEYS ON DIAGNOSIS AND TREATMENT OF BRAIN METASTASES
Authors: Kim Albert , Wang Gi-Ming , Waite Kristin , Elder Scott , Fine Avery , Ahluwalia Manmeet , Brat Daniel , Mehta Minesh , Page Robin , Dunbar Erin , Calderone Heather , Robins Debra , DeVitto Ralph , Willmarth Nicole , Barnholtz-Sloan Jill , Brastianos Priscilla 
Published: November 2021

Abstract
The development of brain metastases (BM) is one of the most feared complications of cancer due to the substantial neuro-cognitive morbidity and grim prognosis. In the past decade, targeted therapies and checkpoint inhibitors have demonstrated remarkable intracranial response rates for tumors of multiple histologies. As overall survival for these patients improves, there is a growing need to identify issues surrounding patient survivorship and to standardize physician practice patterns for these patients. To date, there has not been an adequate study to specifically explore these questions of survivorship and practice standardization for patients with advanced cancer and BM. Here, we present results from a cross-sectional survey in which we analyze responses from 237 patients, 209 caregivers, and 239 physicians to identify areas of improvement in the clinical care of BM. In comparing physician and patient/caregiver responses, we found a disparity in the perceived discussion of topics pertaining to important aspects of BM clinical care. We identified variability in practice patterns for this patient population between private practice and academic physicians. Many physicians continue to have patients with BM excluded from clinical trials. Finally, we obtained patient/physician recommendations on high-yield areas for federal funding to improve patient quality of life. Therefore, by identifying potential areas of unmet need, we anticipate this wealth of actionable information will translate into tangible benefits for both patients and caregivers. Future studies are needed to validate our findings.
QOLP-11. WORKING MEMORY TRAINING FOR ADULTS WITH GLIOMA
Authors: Braun Sarah , aslanzadeh Farah , Lanoye Autumn , Loughan Ashlee 
Published: November 2021

Abstract

BACKGROUND
CogMed Working Memory Training (CWMT) is a computer-based program shown to improve working memory (WM) among those with cognitive impairment. No study to date has investigated its feasibility, acceptability, and satisfaction in adult patients with glioma, despite the well-documented incidence of WM impairment in this population.

METHODS
Twenty patients with glioma and objective and/or perceived WM deficits enrolled in the study: 52% high-grade, 57% female, Mage=47 (range=21-72 years). Adverse events were monitored to determine safety. Feasibility and acceptability were assessed based on established metrics. Satisfaction was explored by exit-interviews. Neurocognitive tests and measures of psychological distress were administered pre-/post-CWMT to assess preliminary efficacy.

RESULTS
Of 20 enrolled patients, 16 completed the study protocol (80% retention rate). Reasons for withdrawal included time burden (n=2); tumor-related fatigue (n=1) or lost to follow-up (n=1). No adverse events were determined to be study-related. Adherence was 69%. The perceived degree of benefit was only moderate. Pre- to post-CWMT assessments showed medium to large effects on near-transfer tasks (h p 2 =.35, p=.01 and h p 2 =.25, p=.04) and far-transfer tasks (h p 2 =.20, p=.07 and h p 2 =.16, p=.12) but small to no effects on perceived WM (h p 2 =.01, p=.79) and psychological distress (h p 2 =.01-.06, p=.35-.79).

CONCLUSION
CWMT was found to be safe and acceptable in adult patients with glioma. Enrollment, retention rates, and treatment adherence were all adequate, yet only moderate perceived benefit was reported. Given that objective measures of WM improved but psychological distress did not, it may be worth considering a less burdensome CWMT protocol, perhaps investigating a less time intensive intervention with respect to both frequency and length of training sessions.
QOLP-17. YOGA THERAPY AS A SUPPORTIVE CARE STRATEGY FOR FAMILY CAREGIVERS OF HIGH GRADE GLIOMA PATIENTS: RESULTS OF 3-ARM PILOT RANDOMIZED CONTROLLED TRIAL
Authors: Milbury Kathrin , Li Jing , Weathers Shiao-Pei , Silva Rosangela , Snyder Stella , Li Yisheng , Lorenzo Cohen 
Published: November 2021

Abstract

BACKGROUND
This pilot RCT compared the feasibility and preliminary efficacy of a dyadic versus individual yoga intervention as a supportive care strategy for family caregivers of high grade glioma patients.

METHODS
Caregivers completed self-reported assessments of QOL (SF-36) and caregiver burden (CRA) and were then randomized to a patient-caregiver dyadic yoga (DY), caregiver yoga (CY) or usual are (UC) arm while patients were undergoing standard radiotherapy. Both yoga programs were delivered over 15 sessions either in-person or via videoconference (Zoom). All groups were re-assessed at the end of treatment and then again 3-months later.

RESULTS
We consented 76 dyads (59%) and randomized 23 to the DY, 22 to the CY, and 22 to the UC arm. Attendance in the DY was higher than in the CY group (means, DY=12.23, CY=9.00, P=.06, d=.57). Caregivers reported significantly more overall subjective benefit in the CY compared to the DY arm (means, CY=1.39, DY=1.81, P&lt; .05, d=1.45). Caregivers slightly favored the in-person delivery (means, in person: 1.48; zoom: 1.82, P=.10; d=.77). A clinically significant, medium effect size was found for improved QOL in favor of the CY over the DY group (means, CY=49.45, DY=44.45; F=3.58, P=.07; d=.67). Caregivers in the CY group reported less caregiving-related health declines compared to the DY group (means, CY=2.18; DY=2.48; F=4.23, P&lt; .05; d=.42). Caregivers in the CY group reported less caregiving-related financial burden than the UC group (means: CY=2.79; UC=3.21; F=3.32, P=.08; d=.35).

CONCLUSION
Despite lower attendance, caregivers in the CY arm reported greater subjective overall benefit, experienced better mental QOL and less caregiver burden compared with those in the DY and UC comparison arms. It appears that individual rather than dyadic delivery may be a superior supportive care approach for this vulnerable caregiver population. An adequately powered, larger trial of this intervention strategy is warranted.