bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract

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

Abstract

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

Abstract
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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract
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

Abstract

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

Abstract
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.