bluuebunny/crossref_metadata_2025_split huggingface dataset:
NIMG-43. IMAGING FINDINGS FOLLOWING REGORAFENIB IN PATIENTS WITH MALIGNANT GLIOMA: FET PET ADDS VALUABLE INFORMATION TO ANATOMICAL MRI
Authors: Werner Jan-Michael , Tscherpel Caroline , Stoffels Gabriele , Lohmann Philipp , Fink Gereon R , Langen Karl-Josef , Galldiks Norbert 
Published: December 2020

Abstract

BACKGROUND
Recent phase 2 data showed that the small molecule regorafenib with antiangiogenic properties has promising effectivity in glioblastoma patients at first progression. Following antiangiogenic therapy with bevacizumab, amino acid PET provides valuable additional diagnostic information regarding bevacizumab-related effects on MRI (e.g., pseudoresponse). In contrast, only a little is known about regorafenib. Thus, we evaluated prospectively the value of O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET for the assessment of regorafenib-related treatment effects.

METHODS
Twenty-two patients with progressive malignant glioma (median number of relapses, 2; range, 1-4) were included. Up to now, 10 of 22 patients were eligible for data evaluation and underwent regorafenib therapy (median number of cycles, 2; range, 1-5 cycles). FET PET and MRI were performed at baseline and after the second cycle. After the second cycle, MRI was performed every 8 weeks. In case of a suspicious MRI after the second cycle, a FET PET scan was added. MRI changes were evaluated according to the RANO criteria. Maximum tumor-to-brain ratios (TBRmax) were calculated. Pseudoresponse was considered if (i) the follow-up MRI showed an improvement (i.e., at least “partial response” according to RANO criteria) despite subsequent clinical progression, and (ii) an increase of TBRmax&gt;25% occurred. Pseudoresponse was confirmed if (i) the subsequent MRI follow-up showed progression, and/or (ii) the clinical status worsened, or the patient died.

RESULTS
In 4 of 10 patients, FET PET provided clinically relevant additional information. In two patients, pseudoresponse could be confirmed. Furthermore, in one patient with stable disease according to MRI, increasing TBRmax (+138%) enabled earlier diagnosis of tumor progression (time benefit, 5 weeks). In another patient without signs of MRI response after 2 cycles, decreasing TBRmax (-23%) indicated metabolic response and was associated with a significant clinical improvement.

CONCLUSIONS
FET PET seems to add valuable diagnostic information for regorafenib therapy monitoring.
NIMG-45. DEEP LEARNING-BASED PERITUMORAL MICROSTRUCTURE MAPPING IN GLIOBLASTOMAS USING FREE WATER VOLUME FRACTION
Authors: Samani Zahra Riahi , Parker Drew , Alappatt Jacob Antony , Brem Steven , Verma Ragini 
Published: December 2020

Abstract

PURPOSE
Characterization of the peritumoral microenvironment is a widely researched, but as yet unsolved problem. Determining the tissue microstructure differences between tumor types, arising from differences in infiltration, edema, and disease driven changes in cellularity is important to be able to guide treatment options. Diffusion tensor imaging with characterization of extracellular free water provides unique information of the tissue microstructure. The goal of this work is to leverage this information by applying deep learning on free water maps and create a microstructure map of the peritumoral area, to aid in targeted resection, radiotherapy and treatment management in the form of a crucial supplemental radiomic feature, replacing all other diffusion derived measures.

METHOD
We leveraged the widely different peritumoral microenvironments of GBMs and Metastatic tumors to create the microstructure maps. Tumor and peritumoral regions were automatically delineated in 143 patients with brain tumors (89 glioblastomas and 54 metastasis, ages 19-87 years, 77 females), and free water maps were computed in the peritumoral regions using their DTI data. We trained a Convolutional Neural Network (CNN) on 32x32 mm patches in the peritumoral area from GBMs and Mets, labeled as non-enhancing tumor (low free-water) and edema (high free-water), respectively. An independent test set was used and the CNN associated a voxel-wise probability to their peritumoral region to produce microstructure maps of GBMs and Mets which were then statistically compared.

RESULT
For comparison, a t-test was used showing significant group difference in the microstructure map between Mets and GBMs (p&lt; 0.05).

CONCLUSION
The voxel-wise microstructure map is able to capture the cellularity differences in the peritumoral region, based on DTI-based characterization of the tissue microstructure. CLINICAL

IMPORTANCE
The microstructure map provides a novel insight into the peritumoral microenvironment using a measure that can be derived from clinically feasible DTI data, replacing pre-existing DTI measures.
NIMG-47. METABOLIC CHARACTERIZATION OF IDH MUTANT LOWER GRADE GLIOMA USING SPECTROSCOPIC IMAGING OPTIMIZED FOR 2-HYDROXYGLUTARATE DETECTION
Authors: LaFontaine Marisa , Autry Adam , Philips Elizabeth , Jalbert Llewellyn , Villanueva-Meyer Javier , Chang Susan , Li Yan 
Published: December 2020

Abstract

INTRODUCTION
Mutations in isocitrate dehydrogenase (IDH1/2) genes are both diagnostic and prognostic biomarkers for lower grade gliomas, which can be noninvasively evaluated via MRS detection of 2-hydroxyglutarate (2HG). A high percentage of lower grade gliomas harbor IDH mutations that have a major impact on tumor biology.

METHODS
Forty IDH-mutant lower grade glioma patients were recruited and scanned using 2HG-optimized 97ms PRESS spectroscopy prior to surgical resection, whereupon image-guided tissue samples were acquired and analyzed via histopathology. Spectra were processed and quantified using LCModel. Wilcoxon ranksum tests were used to compare the difference in metabolic parameters between patient subgroups. Cox proportional hazard models were used to evaluate the influence of metabolic parameters on progression free survival (PFS). Pearson and Kendall Tau rank correlations were used for metabolites and histopathology parameters.

RESULTS
Levels of 2HG were quantifiable in 37/40 (92.5%) IDH+ patients, yielding a detection rate of 92.5%. A significant difference in myoinositol/total choline was found between astrocytoma and oligodendroglioma in the newly diagnosed grade II population (N=10/13, p=0.042) and also in the overall population (N=25/15, p=0.022). 2HG/creatine was the only significant prognostic indicator on PFS in newly diagnosed patients (p=0.036, HR=4.435; N=33), who had a median PFS of 1472 days [95%CI 994 1950 days] (15 censored). Significantly decreased glutamate/creatine and increased (2HG+GABA)/creatine (p&lt; 0.0001) were found in the T2 lesion compared to those in the normal appearing white matter. At the location where the biopsy samples were taken, there was a significant relationship between 2HG/creatine and glycine/creatine (0.93±0.01; mean±SD Tau; p=0.0005) as well as 2HG/creatine and glutathione/creatine (0.96±0.02; mean±SD Tau; p=0.001) but no significance between the metabolites and pathology parameters were found.

CONCLUSIONS
The non-invasive detection of 2HG can provide clinically relevant information for patient management and our study demonstrated both the feasibility of 2HG detection and its relationship with PFS.
NIMG-52. CHARACTERIZATION OF COGNITIVE FUNCTION IN SURVIVORS OF DIFFUSE GLIOMAS USING MORPHOMETRIC CORRELATION NETWORKS (MCN)
Authors: Wang Chencai , Van Dyk Kathleen , Cho Nicholas , Raymond Catalina , Choi Justin , Salamon Noriko , Pope Whitney , Lai Albert , Cloughesy Timothy , Nghiemphu Phioanh , Ellingson Benjamin 
Published: December 2020

Abstract
Advanced multimodality treatments have led to improved survival and quality of life for patients with diffuse gliomas, and widespread functional reorganization has been reported to be associated with improved cognitive function. However, investigation of morphological alterations in patients with diffuse gliomas has been problematic, largely due to the tumor resection cavities. This pilot study has overcome these challenges and aims to characterize the relationship between structural plasticity and cognitive function in survivors of diffuse gliomas. High-resolution T1 weighted images were collected from 24 patients with diffuse gliomas (mean age 44.5 ± 11.5) who had completed their treatment within the previous ten years. Interregional correlations of cortical thickness were computed to establish morphometric correlation networks (MCN) for twelve cognitively impaired and twelve non-impaired glioma patients, as well as correlated with self-reported cognitive impairment. Our findings demonstrated that both cognitively impaired (σ=1.5979) and non-impaired (σ=1.3683) glioma patients have a small world architecture in disrupted morphological networks. Although the left fusiform (p=0.0409), left inferior (p=0.0209), and temporal (p=0.0173) gyri were observed to be thicker in non-impaired patients, the robustness of their morphological network was weak and easily vulnerable to pathological attacks and neurological deterioration. Furthermore, regions such as the superior temporal gyrus (p=0.0126) and rostral middle frontal gyrus (p=0.0148) were not only identified as predominant nodes in the MCN of patients but were also found to have greater gray matter thickness, which is associated with better FACT-cognitive function. Together, these results support our hypothesis that a widespread morphological network is altered in survivors of diffuse gliomas. Predominant regions obtained by topological analysis may lead to reliable imaging biomarkers that help evaluate patients’ cognition and ability to function.
NIMG-53. GLUTAMATE/GABA RATIO ON MRS IS ELEVATED IN PATIENTS WITH LOWER GRADE GLIOMAS AND SEIZURES
Authors: Rudà Roberta , Pascuzzo Riccardo , Mo Francesca , Pellerino Alessia , Barker Peter B , Bizzi Alberto , Soffietti Riccardo 
Published: December 2020

Abstract

BACKGROUND
There is lack of information on the role of excitatory and inhibitory neurotransmitters in the development of seizures in patients with lower grade gliomas. Increase of glutamate and downregulation of GABA have been suggested in preclinical models and human surgical samples to be associated with brain tumor-related epilepsy.

MATERIAL AND METHODS
We prospectively investigated with the use of magnetic resonance spectroscopy (MRS) the differences in the ratio of metabolites (glutamate/GABA, glutamate/creatine and GABA/creatine) in the peritumoral areas between patients with or without seizures in a series of lower grade gliomas. Tumors were classified according to WHO Classification of 2016 as follows:11 grade II IDH mutated and 1p/19q codeleted; 3 grade III IDH mutated and 1p/19q codeleted; 6 grade II IDH mutated and 1p/19q intact; 1 grade III IDH mutated and 1p/19q intact; 1 grade II IDH wild-type. Patients received surgery alone or followed by temozolomide chemotherapy according to the presence of risk factors.

RESULTS
At baseline evaluation, maximum glutamate/GABA values were significantly higher (p=0.023) in the peritumoral area of patients with seizures (1.008 ± 0.368) with respect to those without seizures (0.691 ± 0.170). No other metabolites ratio showed significant differences between the two groups. Similar results were obtained when analyzing the metabolites ratio in the examinations during the follow-up. In the cohort of patients with seizures (n.14) variations of metabolite ratios were not associated with tumor location, 1p/19q codeletion, use of AEDs, concomitant chemotherapy or seizure characteristics (type, duration, frequency).

CONCLUSIONS
The study is ongoing with the aim of analyzing further the correlations between ratio of metabolites and status of the tumor (stable vs progressive).
NIMG-58. THE EFFECT OF CELL CONFLUENCE ON THE DISTRIBUTION OF TUMOR TREATING FIELDS
Authors: Marciano Tal , Levi Shay , Bomzon Zeev 
Published: December 2020

Abstract

BACKGROUND
Tumor Treating Fields (TTFields) are known to exert anti-mitotic effects on cells. Numerical simulations investigating the electric field distribution within isolated cells have been reported. These studies have shown that during metaphase a uniform electric field forms within the rounded cells. This field is thought to disrupt spindle formation through alignment of the tubulin dimers with the field. Simulations also show that during cytokinesis, a non-uniform electric field forms at the furrow, leading to strong dielectrophoretic forces that further disrupt cell division. Cells in the tumor are densely packed. We used numerical simulations to investigate how the clustering of cells influences TTFields distribution.

METHODS
COMSOL was used to numerically simulate delivery of TTFields to clusters of round cells placed in a hexagonal arrangement. The influence of the distance between the cells on field distribution was investigated. The effect of pores in the cell membrane on field distribution was also investigated.

RESULTS
Placing round cells in clusters resulted in regions of highly non-uniform fields within the cells. Strong gradients in the electric field were also observed around pores placed in the membrane. Non-uniformity and gradients in the field could result in strong dielectrophoretic forces capable of disrupting key cellular structures such as the cytoskeleton and mitotic spindle, as well as cell membrane integrity.

CONCLUSIONS
The placement of cells in close proximity to one another creates gradients in the electric field, which could be associated with very strong dielectrophoretic forces that enhance the effects of TTFields on cells. Strong dielectrophoretic forces were also observed around the membrane pores. Previous studies have reported that TTFields increases membrane permeability [Chang et al Cell Death Discovery. 2018]. The strong dielectrophoretic forces in the membrane may provide a physical mechanism by which TTFields enhance membrane permeability.
NIMG-65. STUDY OF LOCAL PERTURBATION IN COMPUTATIONAL MODELLING ON TUMOR TREATING FIELDS (TTFIELDS) THERAPY
Authors: Zeevi Oshrit , Bomzon Zeev , Marciano Tal 
Published: December 2020

Abstract

INTRODUCTION
Tumor Treating Fields (TTFields) are an approved therapy for glioblastoma (GBM). A recent study combining post-hoc analysis of clinical trial data and extensive computational modelling demonstrated that TTFields dose at the tumor has a direct impact on patient survival (Ballo MT, et al. Int J Radiat Oncol Biol Phys, 2019). Hence, there is rationale for developing TTFields treatment planning tools that rely on numerical simulations and patient-specific computational models. To assist in the development of such tools is it important to understand how inaccuracies in the computational models influence the estimation of the TTFields dose delivered to the tumor bed. Here we analyze the effect of local perturbations in patient-specific head models on TTFields dose at the tumor bed.

METHODS
Finite element models of human heads with tumor were created. To create defects in the models, conductive spheres with varying conductivities and radii were placed into the model’s brains at different distances from the tumor. Virtual transducer arrays were placed on the models, and delivery of TTFields numerically simulated. The error in the electric field induced by the defects as a function of defect conductivity, radius, and distance to tumor was investigated.

RESULTS
Simulations showed that when a defect of radius R is placed at a distance, d &gt;7R, the error is below 1% regardless of the defect conductivity. Further the defects induced errors in the electric field that were below 1% when σrR/d &lt; 0.16, where σrR/d &lt; 0.16, where σr = (σsphere – σsurrounding)/(σsphere + σsurrounding).σsurroundings is the average conductivity around the sphere and σsphere is the conductivity of the sphere.

CONCLUSIONS
This study demonstrates the limited impact of local perturbations in the model on the calculated field distribution. These results could be used as guidelines on required model accuracy for TTFields treatment planning.
PATH-04. THE BLOOD-BRAIN BARRIER IN DIFFUSE MIDLINE GLIOMA AND ITS IMPLICATIONS FOR DRUG DELIVERY
Authors: Haumann Rianne , El-Khouly Fatma , Breur Marjolein , van Zanten Sophie Veldhuijzen , Kaspers Gertjan , Hendrikse Harry , Hulleman Esther , van Vuurden Dannis , Bugiani Marianna 
Published: December 2020

Abstract

INTRODUCTION
Chemotherapy has been unsuccessful for pediatric diffuse midline glioma (DMG) most likely due to an intact blood-brain barrier (BBB). However, the BBB has not been characterized in DMG and therefore its implications for drug delivery are unknown. In this study we characterized the BBB in DMG patients and compared this to healthy controls.

METHODS
End-stage DMG pontine samples (n=5) were obtained from the VUmc diffuse intrinsic pontine glioma (DIPG) autopsy study and age-matched healthy pontine samples (n=22) were obtained from the NIH NeuroBioBank. Tissues were stained for BBB markers claudin-5, zonula occludens-1, laminin, and PDGFRβ. Claudin-5 stains were used to determine vascular density and diameter.

RESULTS
In DMG, expression of claudin-5 was reduced and dislocated to the abluminal side of endothelial cells. In addition, the expression of zonula occludens-1 was reduced. The basement membrane protein laminin expression was reduced at the glia limitans in both pre-existent vessels and neovascular proliferation. PDGFRβ expression was not observed in DMG but was present in healthy pons. Furthermore, the number of blood vessels in DMG was significantly (P&lt; 0.01) reduced (13.9 ± 11.8/mm2) compared to healthy pons (26.3 ± 14.2/mm2). Markedly, the number of small blood vessels (&lt; 10µm) was significantly lower (P&lt; 0.01) while larger blood vessels (&gt; 10µm) were not significantly different (P= 0.223). The mean vascular diameter was larger for DMG 9.3 ± 9.9µm compared to 7.7 ± 9.0µm for healthy pons (P= 0.016).

CONCLUSION
Both the BBB and the vasculature are altered at end-stage DMG. The reduced vascular density might have implications for several drug delivery methods such as focused ultrasound and convection enhanced delivery that are being explored for the treatment of DMG. The functional effects of the structurally altered BBB remain unknown and further research is needed to evaluate the BBB integrity at end-stage DMG
PATH-05. A RETROSPECTIVE STUDY OF TREATMENT STRATEGIES AND OUTCOMES IN WHO GRADE II AND III ISOCITRATE DEHYDROGENASE (IDH) WILD-TYPE ASTROCYTOMA
Authors: Aaroe Ashley , Dono Antonio , Youssef Michael , Alfaro-Munoz Kristin , Weathers Shiao-Pei , O’Brien Barbara , Majd Nazanin , Harrison Rebecca , Loghin Monica , Soomro Zaid , Williford Garret , Fuller Gregory , Yung W K Alfred , Yeboa Debra , Esquenazi Yoshua , Ballester Leomar Y , de Groot John , Kamiya-Matsuoka Carlos 
Published: December 2020

Abstract

BACKGROUND
WHO grade II and III IDH wild-type astrocytomas behave more aggressively than their IDH mutated counterparts. A subpopulation shares molecular features with the novel entity proposed in cIMPACT-NOW Update 3 “Diffuse astrocytic glioma, IDH wild-type, with molecular features of glioblastoma (GBM), WHO IV”.

METHODS
We performed a retrospective analysis of clinical and molecular features, management and survival of 134 adult patients treated for grade II and III IDH wild-type astrocytoma between 06/2012 and 12/2018 at MD Anderson Cancer Center (MDACC - 112) and UT Health Science Center at Houston (UTHSC - 22). All patients had IDH1 sequenced, all but 2 had IDH2 sequenced, and 73 had further next generation sequencing.

RESULTS
Median age at diagnosis was 53 (interquartile range 18-83). 82 patients (61%) were male. 31 patients were histologically diagnosed with grade II astrocytoma, 102 with grade III astrocytoma, and one with diffuse glioma (insufficient tissue to render histologic grade or perform sequencing). EGFR alterations were found in 31 patients and TERT promoter mutations in 22. 84 (63%) received concurrent chemoradiation and adjuvant temozolomide (grade II, n=9; grade III, n=74; NOS, n=1). PFS overall was 12.0 months (grade II = 17.9; grade III = 10.7). OS in patients treated with concurrent chemoradiation and adjuvant temozolomide was 17.1 months versus 17.7 in patients treated with sequential radiation and temozolomide (p = NS), and 10.6 in patients treated with RT alone or surveillance (p&lt; 0.016). The highest 2-year OS was seen in grade II patients treated with concurrent chemoradiation and adjuvant temozolomide (60%).

CONCLUSIONS
WHO grade II and III IDHwt astrocytoma survival is similar to historical GBM cohorts. The proportion meeting molecular criteria for GBM is yet undefined. Groups who received chemotherapy may perform better than those who do not. Further analysis of MGMT methylation and other molecular factors is ongoing.
PATH-07. SIGNIFICANCE OF H3K4me3 IN PEDIATRIC HIGH-GRADE GLIOMAS
Authors: Lewis Rebecca , Wadhwani Nitin , Mania-Farnell Barbara , Tomita Tadanori , James Charles , Xi Guifa 
Published: December 2020

Abstract
Pediatric high-grade gliomas (pHGGs) account for ~20% of childhood brain tumors, are incurable in nearly all instances, and have an average patient survival of less than 15 months. Histone posttranslational modifications (PTMs) are deregulated in pHGGs. There are many gaps in our knowledge regarding the mechanisms by which “normal” PTM is subverted during pHGG development. Preliminary results from our lab show pHGGs are enriched in H3K4me3 and that the extent of this specific PTM is predictive of patient survival length. H3K4me3 levels are controlled by methyltransferase and demethylase activity. Gene expression analysis indicates SETD1A and WDR82, enzymatic subunits of human SETD1A containing methyltransferase complex (referred to as hSETD1A-COMPASS), are responsible for H3K4 methylation. SETD1A and WDR82 are significantly elevated in pHGGs, relative to pediatric low-grade gliomas (pLGGs), and both show a direct association with glioma malignancy. Interestingly, these associations do not exist in adult gliomas. The results suggest that hSETD1A-COMPASS specifically impacts pHGG development and is a potential therapeutic target for these tumors.