bluuebunny/crossref_metadata_2025 huggingface dataset:
PATH-43. DIAGNOSIS OF GLIOMAS USING CIRCULATING GLIAL CELLS
Authors: Patil Darshana , Akolkar Dadasaheb , Schuster Stefan , Govardhan H B , Datta Vineet , Bhatia Jatinder , Patil Revati , Puranik Sneha , Apurwa Sachin , Srinivasan Ajay , Fulmali Pooja , Datar Rajan
Published: November 2019

Invasive procedures for diagnosis of CNS malignancies carry inherent risks of high morbidity and mortality. Although circulating biomarkers such as cell free DNA (cfDNA) and microvesicle (MV) borne nucleic acids have been proposed as potential diagnostic aids, their stand-alone utility has inherent limitations. However, Circulating Glial Cells (CGCs) combined with cfDNA could offer a viable alternative to invasive biopsies for diagnosis of CNS malignancies; yet the technological challenge in the detection of CGCs in glioma patients presents a formidable challenge. In this study, we evaluated the feasibility of harvesting CGCs from suspected cases of Glioma. From a cohort of 23 suspected cases of CNS malignancies, we used 15ml of peripheral blood and used the CellWizard™ process and related protocol for isolation of CGCs. CellWizard™ is an epigenetically active media with paradoxical chemo-toxicity that selectively induces lethality in normal cells which have a functionally responsive cell death (apoptosis) mechanism, while simultaneously conferring survival privilege on apoptosis resistant cells typically released from a malignant tumor. This paradoxical cytotoxicity of the medium leads to selective elimination of most leukocytes thus facilitating a label free negative enrichment of CGCs, which can be harvested and further characterized. Patients included 11 Glioblastoma, 3 Anaplastic astrocytoma, 2 Medulloblastoma, 5 Oligodendroglioma, 1 Gliosarcoma and 1 meningioma patient. Characterization of CGCs was performed using GFAP, S100 and CD45 markers. CGCs were detected in 16 out of 23 (69.6 %) patients and could be stained positively for both GFAP and S100 and negatively for CD45. Detection of viable CGCs in cases of CNS malignancies can be used for characterization of markers related to the diagnosis.
PATH-45. DIFFERENT TYPES OF HYPERMUTATOR PHENOTYPE OF GLIOBLASTOMA ACCORDING TO MUTATION PATTERNS OF MISMATCH REPAIR GENES
Authors: Saito Kuniaki , Shimizu Saki , Nozaki Eriko , Kobayashi Keiichi , Sasaki Nobuyoshi , Yamagishi Yuki , Shiokawa Yoshiaki , Nagane Motoo
Published: November 2019

BACKGROUND

Although precision medicine has been widely applied to routine care, only few molecular targeted drugs have been developed for glioma. Immune checkpoint inhibitors hold a potential promise to improve outcome of malignant glioma especially with the hypermutator phenotype. Mismatch repair deficiency could induce hypermutation during temozolomide (TMZ) treatment, but the mechanism of mutation acquisition is not well understood.

METHODS

We present the results of target sequencing of 57 longitudinal specimens from 27 individuals with glioblastoma (GBM). We used Ion AmpliSeq Cancer Hotspot Panel v2 (CHP) and/or Ion AmpliSeq Comprehensive Cancer Panel (CCP) for target sequencing.

RESULTS

Acquired mutations with G:C >A:T transition at non-CpG sites were found in 70% of recurrent MGMT methylated samples, whereas only 8% in MGMT unmethylated cases (p< 0.001). Two cases of hypermutator phenotype were identified in MGMT methylated, IDH wild type recurrent GBMs after TMZ chemotherapy. One case gained mutations in mismatch repair genes of MLH1, MSH2, MSH6, and PMS1. Most of the acquired mutations were G:C >A:T mutations typical to TMZ-induced hypermutation. The recurrent tumor was highly aggressive with overall survival after recurrence of 3.7 months. The other case gained mutations in mismatch repair genes of MLH1 and PMS1 only. Most of the acquired mutations were insertion mutations. The prognosis after recurrence was much longer.

CONCLUSIONS

We identified two types of hypermutator phenotype according to mutation pattern of mismatch repair genes. It has been suggested that MSH2-MSH6 complex deficient tumor cannot repair TMZ-induced mismatch mutation, thereby causing hypermutation. Conversely, MLH1-PMS1 complex deficient tumor with intact MSH2-MSH6 complex can repair mismatch mutation but is susceptible to insertion mutation. Taken together, MSH6 mutation plays a key role in TMZ-induced hypermutation, while MLH1 and PMS1 mutations might cause insertion-based hypermutation. Larger and prospective studies are warranted to clarify the mechanism, outcome, and effectiveness of checkpoint inhibitors.
PATH-48. THE DNA METHYLATION LANDSCAPE OF CORE AND PERIPHERAL DIFFUSE GLIOMA REGIONS SHOWS LITTLE SPATIAL SUBTYPE HETEROGENEITY AFTER CONSIDERING TUMOR PURITY
Authors: Verburg Niels , Barthel Floris , Anderson Kevin , Koopman Thomas , Yaqub Maqsood , Hoekstra Otto , Lammertsma Adriaan , Barkhof Frederik , Pouwels Petra , C Reijneveld Jaap , Heijmans Jan , Rozemuller Annemieke , Costello Joseph , Taylor Michael , Vandertop William , Boellaard Ronald , Johnson Kevin C , Wesseling Pieter , de Witt Hamer Philip , Verhaak Roel
Published: November 2019

While diffuse gliomas are notorious for their histopathological, genetic and transcriptional spatial heterogeneity, little is known about their epigenetic spatial heterogeneity. The result of spatial (epi)genetic analysis is strongly influenced by the proportion of cancer cells in a sample, so called tumor purity. However, a gold standard for assessment of tumor purity is lacking. We set out to analyze tumor purity using different measurement modalities and explore tumor purity-corrected DNA methylation spatial heterogeneity in glioma. DNA methylation(-derived), quantitative histological and radiological measurements of tumor purity, as well as DNA methylation profiles, were analyzed in 133 image-guided multi-sector stereotactic biopsy samples of 16 patients with newly diagnosed glioma. These biopsies were acquired in regions with and without abnormalities on MRI. Data was validated in two independent populations of respectively 102 multi-region samples in 24 glioma patients and 64 single-region samples from patients without glioma. DNA methylation profiles from The Cancer Genome Atlas and the patients without glioma was used to predict DNA methylation and transcriptional subtype. Consensus measurement of tumor purity estimates (CPE) ranged from 0 to 91% and was most correlated with the DNA methylation measurement of tumor purity. Neuropathological qualitative assessment of tumor presence generally corresponded well with CPE, but occasionally samples reported as ‘histologically normal’ demonstrated tumor purities up to 53%. After filtering specimens with tumor purity less than 50%, DNA methylation subtype showed little spatial heterogeneity, this in contrast to transcriptional subtype. Samples from core and peripheral regions showed similar DNA methylation profiles. Non-purity related intratumoral heterogeneity for promotor methylation of epigenetically regulated genes was minimal, but higher in IDH-wildtype than in IDH-mutant gliomas. In conclusion, after considering DNA methylation-based measurement of tumor purity DNA methylation in diffuse gliomas shows little spatial heterogeneity; incorporating such tumor purity information can further increase the reliability of methylation-profiling-based tumor classification.
PATH-53. IMMUNOLOGICAL PROFILING OF MUTATIONAL AND TRANSCRIPTIONAL SUBGROUPS IN PEDIATRIC AND ADULT HIGH-GRADE GLIOMAS
Authors: Bockmary Michael , Klauschen Frederick , Maire Cecile , Rutkowski Stefan , Westphal Manfred , Lamszus Katrin , Schüller Ulrich , Mohme Malte
Published: November 2019

Immunological treatment strategies, including checkpoint inhibition, are currently under investigation for high-grade gliomas, but their success is limited. Hence, it is crucial to determine immunological pathways that can be targeted and to identify subgroups of patients likely to benefit from immunotherapies. Previous studies are still limited by comparably small sample sizes and there is only few data about specific immunological mechanisms in pediatric high-grade glioma. We gathered published gene expression data from 1135 adult and pediatric high-grade gliomas and applied a machine learning technique to determine their mutational (K27, G34, IDHmut, IDHwt) and transcriptional subtype. Subsequently, immune cell infiltration and functional immune pathway signatures were evaluated in correlation to histological diagnosis, age, transcriptional and mutational subtype. T-SNE analysis and unsupervised hierarchical clustering was applied to detect subgroup-specific immune microenvironments across all high-grade glioma subtypes. Four distinct microenvironmental phenotypes of immune cell infiltration were identified, which can be stratified into vascular, monocytic/stromal, monocytic/T-cell and APC/NK/T-cell dominant immune clusters. Immune cell infiltration correlated strongly with transcriptional and mutational subtypes but was independent of age and histological diagnosis (p< 0.01). H3F3A mutated tumors had significantly fewer tumor infiltrating lymphocytes and macrophages. By including functional pathways and correlating the expression of immunostimulatory and inhibitory receptor/ligand interactions, we were able to define the immunological microenvironment and to identify possible immunological subtypes associated with poor prognosis as well as subtypes that might be especially amenable to checkpoint inhibition. In addition, comparisons of overall survival with the immunological microenvironment and specifically with immune checkpoint molecules revealed diverse correlations within the transcriptional and mutational subgroups. In conclusion, we shat that mutational and transcriptional subgroups of pediatric and adult high-grade gliomas are characterized by distinct immunological tumor microenvironments. Our analysis demonstrates the immunological heterogeneity within this entity and emphasizes an immune specific stratification of subgroups for upcoming immunotherapy trials.
PATH-57. MRI-LOCALIZED BIOPSIES REVEAL HISTOPATHOLOGIC HETEROGENEITY IN POST-TREATMENT RECURRENT HIGH-GRADE GLIOMA
Authors: Boyett Deborah , Grinband Jack , Canoll Kai , Englander Zachary , Save Akshay , Zanazzi George , Pereira Brianna , Lignelli Angela , Lassman Andrew , McKhann Guy , Bruce Jeff , Canoll Peter D
Published: November 2019

Evaluation of recurrence in post-treatment glioma is challenging because contrast-enhancing (CE) lesions are a mixture of tumor and treatment effect. This study characterizes intratumoral heterogeneity using quantitative digital pathology to correlate intraoperative MRI-localized biopsies with histopathology in the post-treatment setting. Findings will inform multiparametric radiographic models of intratumoral heterogeneity. A retrospective review was performed on adult patients with MRI-localized biopsies obtained during resection for post-treatment recurrent high-grade glioma. 68 patients and 170 MRI-localized samples were analyzed (median 2 samples/patient). Immunohistochemistry (IHC) for markers of glioma cells (SOX2), macrophages (CD68), and proliferating cells (KI67) was used to characterize biopsies. Slides were digitized and quantified using an automated cell-counting algorithm. Histopathological criteria based on IHC data was developed to classify biopsies. IHC quantification was compared across histological groups using ANOVA and paired t-tests. Most patients (52/68) yielded multiple biopsies. 75% (39/52) demonstrated heterogeneity in histological classification of all specimens obtained from their lesion. 47/170 (28%) biopsies were predominantly treatment effect, and most were CE (31/47 or 66%). Only 75/170 (44%) biopsies contained recurrent glioma, and 21/75 (28%) were NE. SOX2 labeling index was higher in biopsies containing recurrent tumor (p=5.13E-25). CD68 labeling index was higher in biopsies with predominant treatment effect (p=1.35E-12). IHC data from MRI-localized biopsies informed a multiple linear regression model which demonstrated significant predictive value for determining the distribution of recurrent tumor in the post-treatment setting. Contrast enhancement is not a reliable predictor of tumor in recurrent high-grade glioma. Most patients demonstrated marked intratumoral heterogeneity, highlighting the difficulty of accurate tumor sampling post-treatment glioma. Our histopathological classification significantly distinguished recurrent tumor from treatment effect and informed a multiparametric radiomic model which can guide surgical sampling and assess response to therapy.
PATH-62. QUANTITATIVE ANALYSIS OF SEX-ASSOCIATED MGMT METHYLATION IN NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Barnett Addison , Saeed Bamashmos Anas , Li Hong , Bosler David , Lathia Justin , Yeaney Gabrielle , Ali Assad , Sagar Soumya , Mohammadi Alireza , Stevens Glen , Angelov Lilyana , Peereboom David , Barnett Gene , Ahluwalia Manmeet
Published: November 2019

INTRO/OBJECTIVE

Glioblastoma (GBM) and MGMT have been reported to have sexual dimorphism. In multiple studies, including our own population-based cohort analysis, females had higher rates of MGMT methylation and improved methylation-associated progression-free and overall survival outcomes compared to males. MGMT methylation is assessed as a mean of five cysteine-phosphate-guanine (CpG1-5) islands (CpG methylation is highly inversely correlated with MGMT RNA expression). The primary objective of this study was to investigate differences in mean and individual CpG methylation by sex.

METHODS

155 patients who underwent first surgical intervention for newly diagnosed GBM at a single tertiary care institution between 2016 and 2018 were reviewed. Of these, 135 patients had available CpG methylation data determined by a clinically validated test using bisulfate conversion followed by PCR and pyrosequencing. MGMT was defined as methylated if the mean of CpG1-5 ≥ 12. The mean of CpG1-5 and each CpG parameter were compared by sex using the Wilcoxon signed-rank test.

RESULTS

Overall (mean age 62, 34% female, 42% MGMT methylated), the median (IQR) of mean degree of methylation was 4.0% (2–33) and median CpG1-5 ranged from 3.0 to 4.5%. More females (53.3%) were MGMT methylated than males (37.1%). Females had significantly higher rates of mean methylation compared to males (14.0 vs 3.0%, p=0.046). Females also had higher rates of methylation at each CpG island compared to males CpG1(7.0 vs 3.0%, p=0.15), CpG2(8.0 vs 4.0%, p=0.10), CpG3(9.0 vs 4.0%, p=0.23), CpG4(7.0 vs 3.0%, p=0.047), and CpG5(6.0 vs 4.0%, p=0.097).

CONCLUSION

Females had higher rates of mean methylation and methylation of each CpG island compared to males, although only mean and CpG4 methylation values were statistically significant given the limited sample size. Further investigation with a larger cohort is ongoing to elucidate this dimorphism and establish whether sex-specific methylation cut-offs need to be implemented into clinical practice.
PATH-66. THE GENOMIC LANDSCAPE OF SPINAL CORD EPENDYMOMA
Authors: Ramani Biswarathan , Villanueva-Meyer Javier , Glastonbury Christine , Meram Ece , Walsh Kyle , Taylor Jennie , van Ziffle Jessica , Onodera Courtney , Grenert James , Bollen Andrew , Perry Arie , Tihan Tarik , Solomon David , Pekmezci Melike
Published: November 2019

INTRODUCTION

Ependymomas are seen throughout the neural axis but spinal cord is most common in adults. A subset arises in the setting of neurofibromatosis 2, whereas most are sporadic, potentially with somatic NF2 inactivation. The genetic drivers in NF2 wildtype tumors are unknown, as is the spectrum of cooperating genetic alterations.

METHODS

We performed targeted next-generation sequencing (NGS) to assess mutations, rearrangements, and chromosomal copy number alterations in 46 adult spinal cord ependymomas.

RESULTS

The 24 females and 22 males ranged from 20–73 (median 46) years of age. Tumors were in the cervical (n=24), thoracic (n=12), and lumbar (n=10) spinal cord. Nine tumors (20%) harbored truncating NF2 mutations with loss of the remaining wildtype allele, with frequent monosomy 13q. Thirteen NF2-wildtype tumors (28%) showed monosomy 22q with frequent monosomy 13q and trisomy 7, 9, and 12. Seventeen tumors (37%) carried a near-tetraploid genome, likely due to genomic reduplication with frequent preservation of diploidy in chromosomes 13q (77%), 14q (88%), 21q (53%) and 22q (65%). Remaining cases did not show a recurrent pattern, but one harbored focal high-level MYCN amplification. Three of the six recurrences were seen in the last subgroup; however, there was no significant difference for progression-free survival between four subgroups. None of the NF2-mutant tumors were in lumbar spinal cord, but there was no difference for tumor location or patient age between four subgroups.

DISCUSSION

Biallelic NF2 mutational inactivation characterizes only a subset of spinal cord ependymomas, and MYCN amplification is likely a genetic driver in a small subset of NF2 wildtype cases. The high frequency of chromosome 22q loss even in NF2-wildtype tumors raises the possibility of cryptic alterations in the NF2 gene not detected by our panel, or perhaps implicates the presence of another as yet unidentified tumor suppressor gene on chromosome 22q.
NCOG-06. PILOT STUDY OF NEUROCOGNITIVE DECLINE IN MALIGNANT GLIOMA PATIENTS TREATED WITH CHEMORADIATION AND ADJUVANT CHEMOTHERAPY
Authors: Emery Ivette , Lucas Frances , Vreeland Sarah , Cushing Deborah , Tripp Dana , Miller Thomas , Lary Christine , Lu-Emerson Christine
Published: November 2019

The majority of glioma patients experience declines in neurocognitive function (NCF), presumably due to tumor and treatment effects. We sought to understand the natural history of this decline in grade III and grade IV patients. A condensed battery of cognitive tests (HTLV, COWAT, GPT, TMT, and BTA) was administered at three time points: prior (T0) and after (T1) chemoradiation, and during adjuvant chemotherapy (T2). 31 patients were enrolled of which 25, 9 grade III and 16 grade IV, were analyzed. Although our N was too small for statistically significant results, we observed potentially meaningful clinical trends. Changes in HTLV, TMT, and COWAT scores among grade III patients displayed a pattern different from that of grade IV, with a steep decline seen after chemoradiation (T0-T1) followed by improvement several months later (T1-T2), despite ongoing chemotherapy. Grade IV patients, in contrast, showed minimal decline in scores (little change in score between T0-T1 and between T1-T2), perhaps highlighting that NCF is more impacted by disease rather than treatment. We tried to identify a subset of patients who seemed more susceptible to NCF decline. Examination of key clinical features showed that less than gross total resection and less than 4 year degree education level trended to associate with steeper NCF decline (only 40% of those experiencing steep declines in multiple domains had more than 4 yr degree, versus 60% of those with moderate or no decline). This pilot study highlights that assessing neurocognitive function routinely in clinical practice is feasible in a rural academic hospital. Based on patterns of changes in NCF, it appears that grade III and grade IV gliomas are distinct tumor subtypes with respect to NCF decline. Level of education may be a useful biomarker to identify those patients most at risk for neurocognitive decline after treatment.
NCOG-07. COGNITIVE SEQUELAE OF RADIOTHERAPY IN LOW-GRADE GLIOMA PATIENTS 26 YEARS AFTER INITIAL DIAGNOSIS: FINAL REPORT
Authors: WM den Otter Patricia , MC Lorenz Linda , C Reijneveld Jaap , C de Witt Hamer Philip , Taphoorn Martin , CM Kouwenhoven Mathilde , Snijders Tom , T Lie Süan , Douw Linda , Klein Martin
Published: November 2019

BACKGROUND

Our previous study among 195 low-grade glioma (LGG) patients six years after initial diagnosis, showed that high radiation doses (>2 Gy) were associated with neurocognitive disability. Follow-up at 12 years in 64 LGG patients showed patients without radiotherapy to have stable neurocognitive and radiological status while attentional functioning deteriorated between 6 and 12 years in irradiated patients. The present assessment at a mean of 26 years after initial diagnosis and treatment, investigates the neurocognitive sequelae of radiotherapy in long-term survivors.

METHODS

Patients who were alive since the 12 year follow-up were invited for assessment of the same neurocognitive domains as tested at 6 and 12 years: attention, executive functioning, verbal memory, working memory, psychomotor functioning, and information processing speed. Using a mixed model, standardized scores of neurocognitive performance were compared between treatment (radiotherapy versus no radiotherapy) and over time. FINDINGS: 32 patients, of whom 13 (41%) had received radiotherapy, completed the assessment at a mean of 26 years (range 20–35 years) after initial diagnosis. Patients who had radiotherapy had more attentional deficits at the present assessment, than those who did not (–1·0 [SD 1·6] vs 0·33 [0·65], p=0·01; mean difference 1·3, 95% CI 0·3–2·3). Furthermore, patients who had radiotherapy had reduced attentional functioning over time (p=0·03), regardless of antiepileptic drug use. Three (23%) patients who had radiotherapy developed neurocognitive disabilities deficits in at least four of the 20 neuropsychological test parameters compared with five (26%) patients who did not have radiotherapy. INTERPRETATION: Extreme long-term, and probably surviving LGG patients who had radiotherapy show relatively stable and adequate neurocognitive functioning when compared to patients who did not have radiotherapy. Apart from attentional functioning, no progression of neurocognitive deficits at 26 years after initial diagnosis were found.
NCOG-08. COGNITIVE DEFICITS AS A PREDICTOR OF THE COURSE OF TREATMENT IN DIFFUSE GLIOMA
Authors: IJpelaar Suzanne , Van Kessel Emma , Van Zandvoort Martine , De Vos Filip , Verhoeff Joost , Robe Pierre , Snijders Tom
Published: November 2019

INTRODUCTION

Over half of patients with a diffuse glioma suffer from cognitive deficits in one or more domains. Cognitive functioning, especially for the domains executive functioning (EF) and memory, is an independent prognostic factor for overall survival. A possible explanation for this prognostic effect is that patients with cognitive deficits receive less intensive treatment, or do not tolerate treatment as well as other patients.

METHODS

Retrospective cohort study of patients with a diffuse glioma (WHO grade 2–4) who underwent an awake craniotomy, with pre-operative neuropsychological testing, followed by adjuvant radio- and/or chemotherapy. Outcome measures were (a) choice of adjuvant treatment, compared to appropriate treatment according to contemporary guidelines; (b) intensity and compliance: number of received treatment cycles, and adherence to prescribed medication; and (c) complications. Cognitive deficits (in one or more domains, Z-score < -2), as well as deficits in the domains EF and memory, were correlated to the outcome measures.

RESULTS

We included 187 consecutive patients. Cognitive deficits in one or more domains, EF or memory were neither associated to the choice of treatment (adherence to guidelines), nor to intensity or compliance of treatment. Having a cognitive deficit was associated with an increased risk of complications (P < .001), including severe complications (CTCAE grade 3–5, p < .05). A deficit in EF was also associated with more complications (p < .005). This risk of complications was increased for the categories of infectious, cerebral, gastro-intestinal and hematological complications.

CONCLUSION

Of all patients with a diffuse glioma, patients with cognitive deficits have an increased risk of complications of postoperative antineoplastic therapy. Choice of, intensity of, and compliance to treatment did not differ from cognitively intact patients. The increased risk of complications may form an explanation for the poor prognosis of glioma patients with cognitive deficits.
NIMG-06. OUR THERAPEUTIC STRATEGIES FOR GLIOBLASTOMA: INTRAOPERATIVE SUPPORT SYSTEMS [INTRAOPERATIVE MRI, PET, 5-AMINOLEVULINIC ACID (5-ALA)] AND NEOADJUVANT CHEMOTHERAPY
Authors: Miyake Keisuke , Ogawa Daisuke , Okada Masaki , Hatakeyama Tetsuhiro , Tamiya Takashi
Published: November 2019

OBJECTIVE

Neuronavigation systems with magnetic resonance imaging (MRI) and positron emission tomography (PET) imaging (methionine [MET], fluorothymidine [FLT], and fluoromisonidazole [FMISO]) are routinely used in glioblastoma surgery. Residual tumor identified using intraoperative MRI (IoMRI) or 5-aminolevulinic acid (5-ALA) fluorescence is removed. Neoadjuvant bevacizumab therapy is offered to patients with low Karnovsky performance status (KPS) or with tumors in eloquent regions. We evaluated the usefulness of neoadjuvant bevacizumab therapy.

METHODS

Twelve patients with glioblastoma with low KPS or tumors in eloquent regions on multiple PET and IoMRI evaluations were enrolled between January 2016 and April 2019. Six had received neoadjuvant bevacizumab before surgery; six had not. Postsurgical 5-ALA fluorescence (strong, vague, and none) tumor extraction rate, residual volume on MRI and PET imaging, and prognosis in the patients with and without bevacizumab were compared.

RESULTS

In patients with bevacizumab adjuvant therapy, the KPS scores immediately prior to surgery were 90 in 3 cases, 80 in 2, and 70 in 1. The scores in patients without bevacizumab were 50 in 2 and 40 in 4. The 5-ALA fluorescence in patients with bevacizumab was vague in one and none in five. Vague fluorescence was noted in all six patients without bevacizumab. Tumor extraction rates in patients with vs. those without bevacizumab were 97.6% vs. 91.5% by T1-Gd, 95.4% vs. 99.9% by MET, 96.2% vs. 90.2% by FLT, and 97% vs. 92% by FMISO. Corresponding residual volumes (ml) were (0.6 vs. 1.7) for T1-Gd, 1.2 vs. 2.9 for MET, 1.0 vs. 2.1 for FLT, and 0.5 vs. 1.1 for. FLT. Median progression free survival (PFS) was 10.1 vs. 4.9 months; median overall survival (OS) was 15.7 vs. 13.3 months.

CONCLUSIONS

Neoadjuvant bevacizumab therapy improved KPS at the time of surgery, increased extraction rate, reduced residual tumor volume, and improved PFS and OS prognosis.
NIMG-11. VISUALIZATION OF JUDGMENT BASIS OF CNN TO GRADING GLIOMA
Authors: Takahashi Satoshi , Tanaka Shota , Takahashi Masamichi , Yamazawa Erika , Hana Taijun , Kitagawa Yosuke , Takayanagi Shunsaku , Takahashi Wataru , Nakamoto Takahiro , Haga Akihirio , Hamamoto Ryuji , Saito Nobuhito
Published: November 2019

BACKGROUND

convolutional neural network (CNN) model using MRI imaging are likely to be effective for grading glioma. However, interpretation of the judgment basis of CNN is difficult. The purpose of this study is twofold. One is to create a high accuracy machine learning model that grading of glioma (Glioma grade II, between III and IV). The other is to visualize the judgment basis of the model.

METHODS

We targeted cases that were imaged at our Hospital during the period from August 2014 to January 2018. Five types of MRI are used. The five types are two types of DWI (b1000DWI and b2000DWI, respectively, with a value of 1000 and 2000), apparent diffusion coefficient (ADC), fractional anisotropy (FA), and mean kurtosis (MK). The images were input to CNN wtihout ROI. Seven types of CNN were prepared, and 100 epochs of learning were performed.

RESULTS

55 cases were included. There were 14 grade II, 12 grade III, and 29 grade IV). Of these, 44 cases up to July 2017 in chronological order were used as a dataset for learning, and 11 cases from August 2017 to January 2018 were taken as independent test dataset. The best results were obtained using MK as input, with a percentage of correct cases of test data of 0.82. Subsequently, we applied Grad-CAM to the model. Grad-CAM is visualized technique that shows where CNN focused on. The model focused on the tumor part of the image. In addition, in the cases of glioma and meningioma coexisting, grading was performed focusing on the glioma area not on meningioma area.

CONCLUSION

When grading glioma, it was considered that CNN decide glioma’s grade focusing on tumor part of the image, as well as humans.
NIMG-13. GLYCINE IS A METABOLIC BIOMARKER OF MALIGNANCY IN GLIOMAS: IN VIVO MAGNETIC RESONANCE SPECTROSCOPY STUDY
Authors: Choi Changho , Tiwari Vivek , Daoud Elena , Hatanpaa Kimmo , Zhang Song , Raisanen Jack , Lewis Cheryl , Levy Michael , Maher Elizabeth , Pan Edward , Patel Toral , Mickey Bruce
Published: November 2019

Malignant tumors reprogram cellular metabolism, resulting in altered concentration of some metabolites. We measured glycine (GLY) and 2-hydroxyglutarate (2HG) in 37 adult subjects with gliomas noninvasively using proton magnetic resonance spectroscopy and examined their association with immunochemical analyses of tumor biopsies and overall patient survival. MRS data were acquired using optimized point-resolved spectroscopy (PRESS TE 97ms) at 3T and the millimolar concentrations of metabolites were estimated with reference to water. The GLY concentration was positively correlated with MIB-1 proliferation index (p=1.7×10−7). The GLY estimation was inversely correlated with expression of glycine decarboxylase (GLDC) (p=0.02), without showing significant correlation with expression of serine hydroxymethyltransferase 2 (SHMT2). There was a strong association between elevated GLY and breakdown of blood-brain barrier, as indicated by higher GLY in post-gadolinium enhancing tumors than in non-enhancing tumors (p=10−6). In contrast, 2HG did not show significant correlation with MIB-1 index or post-gadolinium enhancement. In Kaplan-Meier survival analysis, patients with GLY level above 2.5 mM were significantly associated with poor survival (log-rank p value 0.003; median survival 8.8 months), compared to those with GLY level below 2.5 mM. The hazard ratio of the high-GLY tumors with respect to the low-GLY tumors was 6.7. 2HG level lower than a detection threshold (1 mM), which may represent IDH wildtype tumors, was associated with poor survival (p=0.01). In addition, we performed Kaplan-Meier analysis for the GLY-to-2HG ratio. 2HG estimates less than 1 mM were put as unity. Tumors with GLY/2HG > 2 showed strong association with poor survival (p=5.2×10−9; medial survival 5.4 months), with a 12-fold higher hazard rate compared to those with GLY/2HG < 2. Together, our data suggest that GLY-mediated one-carbon metabolism may underlie rapid cell proliferation in malignant gliomas and that elevation of GLY provides a noninvasive imaging biomarker predictive of cell proliferation and patient outcome.
NIMG-17. CLINICOPATHOLOGIC AND ULTRASOUND VARIABLES ASSOCIATED WITH THE UNFAVORABLE PATHOLOGY IN NEUROBLASTOMA
Authors: Sun Peixuan , Tong Yuyang , Du Jun
Published: November 2019

BACKGROUND

The International Neuroblastoma Pathology Classification has a prognostic impact that distinguishes two neuroblastoma categories: favorable histology (FH) and unfavorable histology (UFH). The aim of this study was to identify the clinicopathological and ultrasound variables that were associated with the UFH.

METHODS

With ethic approval, the clinical, pathologic, and ultrasonographic data of the 104 patients with the pathologic diagnosis of neuroblastoma were retrospectively analyzed. Pathologic findings were ascertained by the paraffin pathologic, fluorescent in situ hybridization (FISH), and the immunohistochemical stain analysis. Tumors were assessed for the following ultrasonographic characteristics: size, boundary, shape, internal echo, acoustic pattern, posterior features, calcification, internal blood flow, and pushing peripheral organs. Univariate and multivariate logistic regression analyses were used to assess the clinicopathologic and ultrasound variables that were associated with UFH.

RESULTS

There were 27 neuroblastoma cases (26.0%) of the UFH group. The independent clinicopathologic variables for the UFH were: older than one year (Odds ratio [OR]=32.84, p=0.003), presence of metastases (OR=4.92, p=0.032), and the MYCN amplification ratio >5 (OR=47.06, p=0.003). The independent ultrasound feature of neuroblastoma which associated with UFH was the ill-defined boundary (OR=4.64, p=0.047) and tumor size ≥50mm (OR=15.77, p=0.05).

CONCLUSION

Patients older than one year, with the presence of metastases, and the MYCN amplification ratio >5 on the FISH analysis as well as the ill-defined boundary and tumor size ≥50mm on an ultrasound assessment were associated with the UFH in neuroblastoma. These characteristics of the neuroblastoma should be considered in patient stratification and prognostic evaluation. Key words: Neuroblastoma; Unfavorable histology; Ultrasound
NIMG-19. T1- AND T2-RELAXOMETRY FOR TISSUE CELL DENSITY QUANTIFICATION IN GLIOMA IMAGING: EXPLORATORY STUDY VIA 11C-METHIONINE PET AND VALIDATION VIA STEREOTACTIC TISSUE SAMPLING
Authors: Kinoshita Manabu , Uchikoshi Masato , Tateishi Souichiro , Miyazaki Shohei , Sakai Mio , Ozaki Tomohiko , Asai Katsunori , Fujita Yuya , Matsuhashi Takahiro , Kanemura Yonehiro , Shimosegawa Eku , Hatazawa Jun , Nakatsuka Shinichi , Kishima Haruhiko , Nakanishi Katsuyuki
Published: November 2019

Visualization of non-contrast-enhancing tumor lesions in glioma is one of the most crucial yet challenging issues for patients with this pathology. This study examined the hypothesis that quantitative T1- and T2-relaxometry could reflect glioma tumor load within the brain and could further be used for visualizing non-enhancing heavily tumor-loaded areas. Participants comprised patients with low- or high-grade glioma. Correlation between T1- or T2-relaxation time and 11C-methionine uptake as measured by positron emission tomography (Cohort-1) was investigated followed by comparing T1- or T2-relaxation time with tumor cell density as measured by stereotactic image-guided tissue sampling in a different cohort (Cohort-2). T1-relaxometry was achieved by converting Magnetization Prepared Rapid Gradient Echo (MP2RAGE) images and T2-relaxometry by multi-echo T2-weighted images via Bayesian inference modeling. T1-relaxation time >2000 ms but < 3200 ms or T2-relaxation time >115 ms but < 265 ms were indicative of high 11C-methionine uptake. Stereotactic tissue sampling study confirmed that tissue cell densities obtained from locations with a T1-relaxation time of 2000–3200 ms or a T2-relaxation time of 125–225 ms were significantly higher than those obtained from other locations (p < 0.001 and p = 0.03, respectively). Synthetic tumor load images were successfully reconstructed using T1- and T2-relaxation mapping. T1- and T2-relaxation times both correlated well with tumor cell density in glioma tissues. The ideal ranges for identifying high tumor load tissues were 2000–3200 ms for T1-relaxation time and 115–220 ms for T2-relaxation both measured at 3.0 T.
NIMG-25. LESION-NETWORK ANALYSIS TO IDENTIFY PREFERENTIALLY-ENGAGED NETWORKS IN EPILEPTOGENIC TUMORS
Authors: Mansouri Alireza , Boutet Alexandre , Elias Gavin , Germann Jurgen , Mithani Karim , Ibrahim George , Lozano Andres , Valiante Taufik
Published: November 2019

BACKGROUND

Lesion network mapping (LNM) is a method used to identify potential networks that can be ascribed to particular neurological functions/ deficits. LNM has yet to be implemented for large brain lesions such as tumors. OBJECTIVES: To apply LNM for potential identification of vulnerable epileptogenic networks in tumors causing medically-refractory epilepsy (MRE), compared with non-epileptogenic tumors.

METHODS

MRE and non-epileptogenic lesions were normalized to standard space for group analysis. These were used as a seed in high-resolution normative resting state fMRI, which was then transformed to t-maps and thresholded by t = 5.1; this corrected for multiple comparisons (Bonferroni corrections) across the whole brain at pcor < 0.05. The statistically-significant thresholded maps were binarized and summed connectivity maps were generated for both groups. This allowed computation of voxel-wise odds ratios (VORs) in order to identify voxels that were more likely associated with tumors that either did or did not result in MRE.

RESULTS

Twenty-seven patients were included. Eleven brain metastases with no history of seizures, M/F: 5/6, mean age 68.4+/-8.4 years, and 16 had MRE (10 low-grade glioma, 2 cavernoma, 3 “other”), M/F: 7:9, mean age 33.7 +/-12.2 years. Lesions causing MRE were preferentially located in the cingulate gyrus, calcarine fissure, parahippocampal gyrus and lateral temporal neocortex. The resting-state networks that were >1.5x likely to be connected with MRE lesions were the salience, executive control, and dorsal default mode networks.

CONCLUSION

In this proof of concept study, we have demonstrated that (1) in addition to stroke, tumors may also be amenable to LNM and (2) the underlying normative neural circuitry may in part explain the propensity of particular lesions toward development of MRE. This has ramifications in patient counseling and surgical management planning, as earlier surgery could be applied for lesions thought to be more prone to development of MRE.
NIMG-27. EVALUATING THE POTENTIAL OF 18F-FLUCICLOVINE POSITRON EMISSION TOMOGRAPHY TO DETECT WHOLE BRAIN TUMOR BURDEN: A PRECLINICAL STUDY
Authors: Scarpelli Matthew , Healey Debbie , Luna Melendez Ernesto , Mehta Shwetal , Quarles Chad
Published: November 2019

BACKGROUND

Accurately identifying the boundary of invasive brain tumors is critical for planning effective treatment. Conventional imaging includes T1-weighted contrast-enhanced MRI to identify regions where tumor angiogenesis has broken down the blood-brain barrier. However, conventional MRI has limited sensitivity for identifying invading tumor cells. Amino acid PET with 18F-fluciclovine may offer improved sensitivity. We investigate whether 18F-fluciclovine PET provides a superior measure of tumor burden than MRI.

METHODS

Rats were implanted with patient-derived glioblastoma xenografts that had been transduced to enable fluorescent imaging of the TdTomato protein. When the tumors grew to a sufficient size, the rats were scanned with 18F-fluciclovine PET followed immediately by contrast-enhanced MRI. Rats were sacrificed and whole brains were removed. Western blots were performed to measure amino acid transporter levels. Fluorescent imaging of optically cleared brain slices enabled visualization of the labelled tumor and determination of whole tumor burden. A methodology for registering in vivo PET/MRI slices to ex vivo fluorescent images of optically cleared brain slices (1-mm thickness) has been developed. Tumor volumes are manually segmented on all images.

RESULTS

The ratio of tumor to normal brain uptake (TNB) of 18F-fluciclovine peaked ten minutes post-injection (mean value 7.1) and was followed by a continual decrease in the TNB ratio (mean value 4.6 at fifty minutes post-injection). The mean percentage of MRI segmented tumor volume that was inside the PET segmented tumor volume was 95%. The mean percentage of PET segmented tumor volume that was inside the MRI segmented tumor volume was 40%. Tumors with the highest level of amino acid transporters had the highest 18F-fluciclovine uptake.

CONCLUSIONS

The majority of 18F-fluciclovine PET identified tumor regions were not identified using conventional MRI, indicating the potential of this approach to detect invasive tumor cells and provide a more robust assessment of whole tumor burden.
NIMG-28. VALIDATION OF SINGLE-DOSE DSC-MRI PROTOCOLS FOR ROBUST PERFUSION ASSESSMENT IN BRAIN TUMORS
Authors: Quarles Chad , Bell Laura , Semmineh Natenael , Fuentes Alberto , Prah Melissa , Nespodzany Ashley , Alhilai Lea , Karis John , Rand Scott , Dardis Chris , Braun Kelly , Connelly Jennifer , Zhou Yuxiang , Schmainda Kathleen , Hu Leland , Boxerman Jerry , Stokes Ashley
Published: November 2019

Dynamic susceptibility contrast (DSC) MRI measures of brain tumor cerebral blood volume (CBV) are able to predict grade, overall survival and response to treatment. Wide-spread acceptance of DSC-MRI has been challenged by the need to balance contrast agent dose and CBV accuracy. The goal of this study was to identify and validate single-dose, BTIP compliant, DSC-MRI protocols. Using a validated, patient-based DRO, we evaluated CBV accuracy across a range of acquisition parameters (field strength, TR, TE, flip angle, multi-echo acquisitions, dosing protocols) and post-processing steps. To validate the optimal protocols, we next collected DSC-MRI data following ASFNR’s recommended “double – dose” approach, where a single-dose preload (to minimize T1 effects) is given prior to a second bolus injection (for DSC-MRI data acquisition). The single-dose DSC-MRI data was collected during the preload bolus injection. Consistency of the derived CBV data, visual agreement and data characteristics (e.g. CNR) was statistically evaluated. When using a single-dose and routine single-echo pulse sequence, the DRO analysis found that a low flip angle (LFA = 30o) and 30ms TE provided the highest CBV accuracy (concordance correlation coefficient (CCC) = 0.92) and precision (coefficient of variation (CV) = 8.2%)). For comparison, the maximum accuracy found with the DRO utilizes a double-dose injection protocol and yielded a CCC of 0.98 and CV of 6.8%. Single-dose, multi-echo acquisitions provided higher accuracy than the LFA data and matched that found with the double-dose approach. In patients (data collection ongoing), the agreement between single-dose LFA (n > 40) or multi-echo (n > 40) based CBV values and the reference double-dose approach was very high (CCC > 0.94) and were statistically equivalent. Optimized single-dose DSC-MRI protocols provide highly accurate CBV data, use lower doses of contrast agent, and simplify scan procedures, indicating their potential for robust use in clinical practice and trials.
NIMG-31. BRAIN CONNECTIVITY PATTERNS CHARACTERIZE COGNITIVE IMPAIRMENT IN LONG-TERM SURVIVORS OF LOW-GRADE GLIOMA (LGG) USING RESTING-STATE FUNCTIONAL MRI (rs-fMRI)
Authors: Wang Chencai , Van Dyk Kathleen , Raymond Catalina , Heimberg Brandon F , Choi Justin , Lai Albert , Cloughesy Timothy , Leia Nghiemphu P , Ellingson Benjamin
Published: November 2019

Advanced multimodality treatments that have led to longer survival rates for patients with low-grade gliomas (LGGs) have also resulted in significant changes in cognition and quality of life (QoL). These changes remain poorly understood, largely due to the lack of multifactorial and in-depth studies on cognitive impairment in patients with LGG. Resting-state functional MRI (rs-fMRI) has been widely used as a reliable imaging biomarker to evaluate the treatment outcome by characterizing the cerebral networking alteration associated with a patient’s neurological status. In this preliminary report of an active study, we investigated the cognitive function and cerebral networking connectivity via rs-fMRI in survivors who had completed treatment for LGG within the past 10 years. Survivors were administered a battery of standardized neuropsychological tests. Of the 20 participants enrolled to date (mean age 43 ± 11), 10 participants were categorized as cognitively impaired based on the International Cognition and Cancer Task Force (ICCTF) guidelines, with recommended adjustments considering the number of tests in the battery. Compared to cognitively unimpaired participants, functional connectivity in cognitively impaired patients was lower between memory, visuospatial processing, and primary sensorimotor regions. These preliminary observations suggest there is a potential link between overall cognitive impairment and functional connectivity of various networks as measured using resting-state fMRI.
NIMG-34. MULTI-PARAMETRIC MR-PET IMAGING PREDICTS PHARMACOKINETICS AND CLINICAL RESPONSE TO GDC-0084 IN HUMAN RECURRENT HIGH-GRADE GLIOMA
Authors: Ellingson Benjamin , Yao Jingwen , Raymond Catalina , Nathanson David , Simpson Jeremy , Garner James , Olivero Alan , Mueller Lars , Rodon Jordi , Gerstner Elizabeth , Cloughesy Timothy , Wen Patrick
Published: November 2019

Alterations in the PI3K pathway are found in the majority of malignant gliomas, but lack of efficacy has caused investigators to question the viability of this target, particularly due to lack of brain penetration. GDC-0084 was specifically optimized to penetrate the brain, targeting both PI3K and mTOR. Since these two targets alter tumor vascularity and metabolism, respectively, we hypothesized that multi-parametric MR-PET could be used to quantify the response, estimate pharmacokinetic (PK) parameters, and predict progression-free survival (PFS) in patients with recurrent malignant gliomas. In this first-in-man, multicenter, phase I, dose-escalation study (NCT01547546), we show in 47 patients that the measured maximum concentration (Cmax) of GDC0084 was associated with a decrease in enhancing tumor volume (P=0.0287) and an increase in fractional anisotropy (FA) (P=0.0418). Post-treatment tumor volume, 18F-FDG uptake, Ktrans, and relative cerebral blood volume (rCBV) were all correlated with Cmax. A linear combination of change in 18F-FDG PET uptake, apparent diffusion coefficient (ADC), FA, Ktrans, vp, and rCBV were able to estimate both Cmax (R2=0.4113, P< 0.0001) and drug exposure (AUC) (R2=0.3481, P< 0.0001). Using this composite multi-parametric MR-PET imaging response biomarker to predict PK, patients with an estimated Cmax >0.1 uM and AUC > 1.25 uM*hr demonstrated significantly longer PFS compared with patients with a lower estimated concentration and exposure (P=0.0039 and P=0.0296, respectively). Results from the current study suggest composite biomarkers created from multi-parametric MR-PET imaging targeting metabolic and/or physiologic processes specific to the drug mechanism of action may be useful for subsequent evaluation of treatment efficacy for larger phase II-III studies.
NIMG-37. PREDICTING SEIZURE IN GLIOMA PATIENTS USING A RANDOM FOREST CLASSIFIER TRAINED ON SEX-SPECIFIC AND MIXED COHORTS
Authors: Khurana Aditya , Johnston Sandra , Whitmire Paula , Ranjbar Sara , Sharma Akanksha , Hawkins-Daarud Andrea , Rubin Joshua , Porter Alyx , Canoll Peter D , Egan Kathleen , Hu Leland , Mrugula Maciej , Kumthekar Priya , Swanson Kristin
Published: November 2019

PURPOSE

Brain tumor related epilepsy (BTE) is a major co-morbidity in patients with glioma. It is difficult to determine whether the use of anti-epileptic drugs is necessary. We attempted to build a machine-learning model to predict the probability of seizure presentation (SP) with glioma.

METHODS

We trained a random forest classifier using the following variables: volumetric data of pre-treatment MR images (T1Gd and T2-FLAIR sequences), patient demographics (age; sex), and measurements of tumor proliferation (log(ρ)), invasiveness (log(D)) and their relative ratio (log(ρ/D)). Our cohort consisted of 221 patients total. Using an 80-20 ratio, we used 176 patients (76 SP, 100 nSP) for training and the remaining 45 patients (19 SP, 26 nSP) were used for testing. We also trained on male-only and female-only cohorts to evaluate any sex differences in prediction. For training, 108 males (53 SP, 55 nSP) were used and 28 for testing (14 SP, 14 nSP). We used 72 females (21 SP, 49 nSP) for training and 15 (7 SP, 8 nSP) for testing. We corrected for class imbalance in the female cohort before training. Using 10-fold cross-validation and a separate testing set, we measured performance by ROC curve (AUC), accuracy, sensitivity, and specificity of predictions (average of folds in cross validation).

RESULTS

The female model achieved the highest AUC (0.853) followed by the mixed model (0.726) and the male model (0.651). In the validation set, the accuracy/sensitivity/specificity of the three cohorts were as follows: mixed (0.726/0.696/0.750), female (0.853/0.830/0.875), and male (0.651/0.577/0.722). The performance of the testing set, in terms of accuracy/sensitivity/specificity were: mixed (0.733/0.74/0.73), female (0.8/0.57/1), and male (0.714/0.64/0.79).

CONCLUSION

We found a negative correlation between seizure probability and size and invasiveness of tumors. Our model shows promising performance on testing set data. Further cohort studies and training is warranted.