bluuebunny/crossref_metadata_2025 huggingface dataset:
PATH-40. PROFILING PLEOMORPHIC XANTHROASTROCYTOMA WITH DNA METHYLATION AND EXPLORING THE TUMOR IMMUNE CELL-TYPE COMPOSITION WITH METHYLATION-BASED DECONVOLUTION
Authors: Tang Karen , Kurland David , Vasudevaraja Varshini , Serrano Jonathan , Radmanesh Alireza , Snuderl Matija
Published: November 2019

INTRODUCTION

Pleomorphic xanthoastrocytoma (PXA) is a rare type of brain tumor that commonly affects children and young adults. PXAs are typically characterized by tumor lymphocytic infiltration, but the significance of the tumor immune microenvironment has not yet been well-defined. In this study, we correlated DNA methylation profiling of PXAs with clinical outcome and explored the tumor microenvironment by analyzing inflammatory cell populations.

METHODS

We retrospectively analyzed 30 tumor samples, of which 21 tumor samples from 18 subjects had a diagnosis of PXA both by DNA methylation and by histology. MethylCIBERSORT was used to deconvolute PXA inflammatory cell populations and compare them with inflammatory cell populations in previously published cohorts of IDH wildtype glioblastoma and ganglioglioma samples.

RESULTS

Median age at diagnosis was 16 years (range 7–32). 3-year and 5-year overall survival (OS) was 73% and 71% respectively. CDKN2A/B deletion was noted in 15 out of 18 subjects (83%). 10 out of the 12 subjects (83%) that had testing for BRAFV600E showed the mutation. CDKN2A/B deletion and Trisomy 7 did not show any significant association with overall survival (p = 0.39 and p = 0.69). Decreased survival was observed in subjects with tumors lacking the BRAFV600E mutation (p = 0.03). PXAs were observed to have significantly increased CD8 T-cell epigenetic signatures compared to gangliogliomas (p = 0.0019) and significantly increased CD8 T-cell and CD19 B-cell signatures compared to IDH wildtype glioblastomas (p = 0.0011 and p = 0.0011).

CONCLUSION

This research suggests that PXAs have a distinct methylation profile that correlates with clinical outcome. PXAs show significant upregulation of CD8 T-cell epigenetic signatures compared to gangliogliomas and significant upregulation of CD8 T-cell and CD19 B-cell epigenetic signatures compared to IDH wildtype glioblastomas. This distinct characterization of immune cell-types in PXAs could have an impact on future development of immunotherapy.
PATH-44. MULTIPLE BIOMARKER ALGORITHM BASED ON CXCL13, IL-10, IL-2 RECEPTOR, AND β2-MICROGLOBULIN IN CEREBROSPINAL FLUID TO DIAGNOSE CENTRAL NERVOUS SYSTEM LYMPHOMA
Authors: Sasayama Takashi , Tanaka Kazuhiro , Maeyama Masahiro , Nakamizo Satoshi , Tanaka Hirotomo , Nishihara Masamitsu , Hirose Takanori , Fujita Yuichi , Kohmura Eiji
Published: November 2019

BACKGROUND

Brain biopsy is the gold standard for the diagnosis of primary central nervous system lymphoma (PCNSL). However, the biopsy procedure has a risk of complications, such as hemorrhage and seizure. We have reported that cerebrospinal fluid (CSF) interleukin-10 (IL-10), soluble IL-2 receptor (sIL-2R), and β2-microglobulin (β2-MG) are the useful diagnostic biomarkers for PCNSL. Recently, the C-X-C motif chemokine ligand 13 (CXCL13) has been reported to be another useful biomarker for the PCNSL. The aim of this study was to validate the diagnostic performance of the CSF CXCL13 and diagnostic algorithm based on the combination of these biomarkers.

METHODS

We retrospectively examined the CSF CXCL13 concentration, as well as IL-10, sIL-2R, and β2-MG, in a case-control study (n=230). We used logistic regression analyses to create diagnostic algorithms based on these CSF biomarkers. To examine the utility of the multivariate diagnostic algorithm, we conducted the prospective study and evaluated the accuracy of this algorithm.

RESULTS

In case-control study, we have demonstrated that CSF CXCL13 levels were significantly higher in the patients with PCNSL (area under the curve (AUC)=0.981). A total of 84 patients were enrolled in the prospective study. The multivariate diagnostic algorithm using CSF levels of CXCL13, IL-10, sIL-2R, and β2-MG demonstrated excellent diagnostic performance: positive predictive value was 89% and negative predictive value was 100%. Four markers’ combination (CXCL13 + IL-10 + β2-MG + sIL-2R) had the highest AUC (AUC=0.998). The misdiagnosis cases of the algorithm were only 3 cases; CNS Sjögren’s syndrome, histiocytic sarcoma, and glioblastoma. In addition, CSF CXCL13 levels were prognostic biomarkers in PCNSL patients.

CONCLUSIONS

Our study suggests that the algorithm based on 4 CSF biomarkers had excellent diagnostic performance in CNS lymphoma. However, this algorithm should be further validated in prospective cohort studies with larger numbers of patients.
PATH-67. RECOMBINANT INTERLEUKIN-7 ENHANCES THE ANTI-TUMOR IMMUNITY OF A DENDRITIC CELL VACCINE IN A MURINE MALIGNANT GLIOMA
Authors: Hooy Oh Sol , Ahn Stephen , Sung Park Jae , Kil Hong Yong , Jeon Sin-Soo
Published: November 2019

BACKGROUND

Dendritic cell (DC)-based vaccines have been suggested as one of the promising immunotherapies for treating various cancers, including glioblastoma. We already developed a novel vaccination protocol with peptide-loaded DCs followed by a mixture of synthetic peptides, polyinosine- polycytidylic acid (poly-IC) and anti-CD40 antibodies (Trivax) in a melanoma mouse model. However, in a glioma mouse model, therapeutic efficacy is not as much as enough maybe due to relatively low antigenicity and blood brain barrier.

MATERIAL AND METHODS

IL-7, which is one of the most important cytokines to expand and develop T cells with anti-tumor immunity, was co-administrated intravenously with Trivax in an orthotopic murine malignant glioma.

RESULTS

Co-administration of the Trivax and recombinant IL-7 (Trivax7) increased the number of survivin specific T cells measured using ELISPOT assay and the population of central memory T cells, comparing with administration of Trivax. The tumor size of orthotopic mouse model in Trivax 7 group was smaller than those of Trivax only group. Finally, overall survival in Trivax 7 was longer than those of Trivax only. In addition, there was a prolonged survival of antigen-specific T cells in Trivax7 group than Trivax only group.

CONCLUSION

In summary, our novel combinational immunotherapy may overcome the limitations of current cell-based cancer vaccines and could be applicable for the treatment of glioblastoma patients.
NCOG-04. COGNITIVE FUNCTIONS BEFORE RADIOTHERAPY IN PEDIATRIC PATIENTS WITH BRAIN TUMORS
Authors: Li Juan , Cai Linbo , Lai Mingyao , Hu Qingjun
Published: November 2019

OBJECTIVE

To assess the cognitive functions before radiotherapy in pediatric patients with brain tumors and explore the related influence factors.

METHODS

Before radiotherapy for brain tumors, adaptive behavior scale (adaptive quotient) and Wechsler intelligence scale for children were used to evaluate the cognitive functions in pediatric patients. Herein the assessment items of verbal IQ, performance IQ, total score and the corresponding percentile. The cognitive functions of pediatric patients with different pathological diagnoses, lesion locations, with or without epilepsy, hydrocephalus or hypopituitarism were compared.

RESULTS

A total of 128 pediatric patients were enrolled in this study. The mean verbal IQ score was 83.7±20.8 (range, 36–128), and the corresponding percentile mean value was 27.699±30.3. The mean performance IQ score was 82.83±20.5 (range, 30–126), and the corresponding percentile mean value was 26.6±29.1. The total score of Wechsler intelligence scale was 0–128, with a mean value of 81.4±21.7, and the corresponding percentile was 0–97, with a mean value of 25.5±28.5. Moreover, the adaptive quotient for all enrolled patients was 32–164, with a mean value of 95.1±29.4. The results of multivariate analysis on the clinical factors related to cognitive functions revealed that the mean performance IQ, the corresponding percentile and the mean of the total score of Wechsler intelligence scale in patients with lesions involving basal ganglia region were 76±16, 15.1±19.6 and 75.29±15, respectively, which were lower than 84±20.7, 28±19.1 and 82.4±22 in those with lesion without involving basal ganglia region, with statistical differences (P= 0.031, 0.018, 0.046).

CONCLUSION

The cognitive functions before radiotherapy in pediatric patients with brain tumors are proved to be inferior to those in normal children. The performance IQ and total score of pediatric patients with brain tumors involving basal ganglia region were lower than those of the other patients for the lesions have affected the limb movement.
NCOG-09. TREATMENT DECISION MAKING IN THE SETTING OF ADVANCED CANCER
Authors: Triebel Kristen , Maulhauser Kyler , Fiveash John , Marrotta Dario , Gammon Meredith , Vance David , Nabors Louis
Published: November 2019

OBJECTIVE

To investigate medical decision-making capacity (MDC) in patients with advanced stage cancer.

METHODS

Participants were 113 newly diagnosed adults with brain metastases and 41 adults with metastatic cancer without brain metastases who were recruited from an academic medical center and 40 demographically-matched healthy controls recruited from the community. We evaluated MDC using the Capacity to Consent to Treatment Instrument (CCTI) Vignette B and its four clinically relevant consent standards (expressing a treatment choice, appreciation, reasoning, and understanding). Capacity impairment ratings (no impairment, mild/moderate impairment, and severe impairment) on the consent standards were also assigned to each participant using cutoff scores derived statistically from the performance of the control group.

RESULTS

Both of the metastatic cancer groups (with and without brain metastasis) performed significantly below controls on consent standards of understanding and reasoning. The brain metastasis group performed below the non-metastatic cancer group on understanding. Capacity compromise was defined as performance ≤1.5 standard deviations (SD) below the control group mean. Using this definition, approximately 65% of the participants with brain metastases and 51% of participants with metastatic cancer without brain metastases were impaired on at least one MDC standard.

CONCLUSION

Over half of participants with metastatic cancer regardless of whether they have brain disease have reduced capacity to make treatment decisions. The finding of impaired MDC in patients without brain metastases is surprising and suggests this group likely exhibits cognitive deficits that impact their ability to understand and reason about different treatment options. This finding suggests that clinicians need to carefully consider the patient’s ability to engage in treatment decision making when they are discussing treatment options for metastatic cancer. These results also indicate a need for the development and investigation of interventions to support MDC in this patient population.
NCOG-11. NEUROPSYCHOLOGICAL OUTCOMES FOLLOWING AWAKE CRANIOTOMY FOR LOW GRADE GLIOMA
Authors: O’Hara Daniel , Miller Amy , Goodden John , Graham Christopher , Kitchingman Hayley , Mathew Ryan , Richards Oliver , Chumas Paul
Published: November 2019

BACKGROUND

Awake craniotomy is an established treatment for tumours in eloquent brain regions. It aims to achieve maximal resection without significant neurological and functional morbidity. There is an emerging evidence base about the neuropsychological outcomes following awake craniotomy for low grade gliomas (LGGs) with inconsistent findings potentially reflective of methodological confounders such as the inclusion of mixed tumour types and the use of varied neurocognitive measures and timescales for repeat testing. We describe detailed neuropsychological outcomes for a cohort of patients following awake craniotomy for LGGs.

METHOD

Data were collected from patients undergoing first-time awake resection of presumed LGGs at Leeds Teaching Hospitals, UK between 2010 and 2018. Patients were included if they consented to and completed the full battery of pre- and postoperative neuropsychological testing. Neuropsychometric testing involved assessment of general intellectual functioning, language, memory, executive functioning, perception, processing speed and mood. Data were analysed using paired-samples t-test or Wilcoxon signed-rank test with Bonferroni correction for multiple statistical comparisons.

RESULTS

Twenty-two patients undergoing awake craniotomy for presumed supratentorial LGG (13 left hemisphere, 9 right hemisphere; mean age 35 years) met the above inclusion criteria. Tumour location was heterogenous (11 insular, 9 frontal, 1 temporal, 1 parietal). Histopathology confirmed WHO Grade II diffuse astrocytoma (n=11), WHO Grade II oligodendroglioma (n=10) and WHO Grade III anaplastic oligodendroglioma (n=1). No statistical differences in neurocognitive test scores were found pre- and post-neurosurgery (mean follow-up was 61 weeks). Other outcomes including extent of resection and reliable change statistics for neurocognitive tests and measures of mood were also analysed.

CONCLUSION

No significant change in neurocognitive functioning was found in patients following recovery from awake craniotomy for LGG. Our findings suggest that awake craniotomy is a safe treatment for LGG and that neuropsychological input is an important part of the treatment pathway for patients with LGG.
NIMG-01. T2WI-FLAIR MISMATCH SIGN IN LOWER GRADE GLIOMA AND DYSEMBRYOPLASTIC NEUROEPITHELIAL TUMOR
Authors: Onishi Shumpei , Yamasaki Fumiyuki , Takano Motoki , Yonezawa Ushio , Taguchi Akira , Sugiyama Kazuhiko , Kurisu Kaoru
Published: November 2019

BACKGROUND

T2-FLAIR mismatch sign was reported as a specific imaging marker for diffuse astrocytoma with IDH-mutant and 1p/19q non-codeletion. However, most of the previous studies for T2-FLAIR mismatch were confirmed only among lower grade glioma (LGG). The purpose of this study is to explore the T2-FLAIR mismatch sing in supratentorial non-enhancing tumor including LGG and dysembryoplastic neuroepithelial tumor (DNET) and to unveil the exception rules of the sign.

METHODS

Forty-four patients of non-enhancing LGG and DNET were included in this study. LGG（diffuse astrocytoma with IDH mutant (IDHmut-Noncodel), oligodendroglioma with IDH-mutant and 1p19q codeletion (IDHmut-Codel), diffuse astrocytoma with IDH wildtype (IDHwt)）and DNET were diagnosed based on WHO 2016 classification. The tumors were evaluated MRI by 2 independent reviewers to assess presence or absence of T2-FLAIR mismatch sign. CT was also performed to evaluate the localized thinning of the skull bone. Inter-reviewer agreement with Cohen’s kappa (κ) was calculated. RESULT: Ten out of 18 cases (55.6%) of IDHmut-Noncodel presented T2-FLAIR mismatch sign. None of the other LGG (IDHmut-Codel and IDHwt) presented T2-FLAIR mismatch. Eight out of 11 cases (72.7%) of DNET also present the T2-FLAIR mismatch. The overlying part of the skull bone thinning was observed in 5 cases of DNET, but none of LGG presented the localized skull bone thinning. The inter-rater agreement for the T2-FLAIR mismatch and the localized thinning of the skull bone were excellent (κ= 1.00).

CONCLUSION

The T2-FLAIR mismatch sign was specific marker for IDHmut-Noncodel among LGG. However, DNET also presented the T2-FLAIR mismatch sign. The localized skull bone thinning could be useful for differentiating between IDHmut-Noncodel and DNET
NIMG-03. PROSPECTIVE PHASE II RANDOMIZED TRIAL COMPARING PROTON THERAPY VS. PHOTON IMRT FOR GBM: SECONDARY ANALYSIS COMPARISON OF PROGRESSION FREE SURVIVAL BETWEEN RANO VS. CLINICAL AND RADIOLOGICAL ASSESSMENT
Authors: Al Feghali Karine , Randall James , Wefel Jeffrey , Guha-Thakurta Nandita , Grosshans David , Dibaj Seyedeh , McAvoy Sarah , Li Jing , McGovern Susan , McAleer Mary , Ghia Amol , Paulino Arnold , Sulman Erik , Penas-Prado Marta , Wang Jihong , DeGroot John , Heimberger Amy , Armstrong Terri , Gilbert Mark , Mahajan Anita , Brown Paul , Chung Caroline
Published: November 2019

PURPOSE

To compare tumor progression based on clinical radiological assessment and on Response Assessment in Neuro-Oncology (RANO) criteria between GBM patients treated with proton radiotherapy (PT) vs. photon intensity modulated radiotherapy (IMRT).

METHODS

Eligible patients were enrolled on the described prospective phase II trial and had MR imaging at baseline and follow-up beyond 12 weeks from treatment completion. ‘Clinical’ progression was based on a radiology report of progression in combination with changes in treatment due to suspected disease progression. A single blinded observer applied RANO criteria to determine the RANO-based tumor progression.

RESULTS

Of 90 enrolled patients, 66 were evaluable, with median follow-up of 19.8 (Range: 3.2–65.1) months; median of 22.6 months for PT (n=25) vs. 18.9 months for IMRT (n=41). Median time to progression (TTP) was 7.9 months based on clinical progression criteria (8.1 months IMRT, 6.3 months PT) and 7.2 months (7.3 months IMRT, 5.7 months PT) by RANO criteria (p=ns for all). Median ‘clinical’ progression-free survival (PFS) was 8.7 (Range: 6.4–11.1) months; 8.9 months IMRT vs. 8.7 months PT (p=0.065). Median RANO PFS was 8.3 (range, 5.8–11.6) months: 8.3 months IMRT vs. 6.9 months PT (p=0.226). There were 14 discrepant cases: 3 had progression based on ‘clinical’ but not RANO criteria, and 11 had progression based on RANO but not ‘clinical’ criteria.

CONCLUSION

Based on this secondary analysis of a randomized trial of PT vs. IMRT for GBM, there was no difference in tumor progression relative to treatment technique used. There was no statistical difference in PFS noted between clinical and RANO-based assessments, but RANO criteria identified progression more often than clinical assessment, and TTP was shortened with the use of RANO criteria alone. Further development of tumor assessment tools that improve consistency and accuracy of determining tumor progression are needed to guide therapeutic trials in GBM.
NIMG-08. 2-HYDROXYGLUTARATE MAGNETIC RESONANCE SPECTROSCOPY IN BRAINSTEM TUMOR PATIENTS IN VIVO
Authors: Choi Changho , Tiwari Vivek , Levy Michael , Maher Elizabeth , Pan Edward , Patel Toral , Mickey Bruce
Published: November 2019

Evaluation of 2-hydroxyglutarate (2HG) by magnetic resonance spectroscopy (MRS) has significant application in assessing the isocitrate dehydrogenase (IDH) mutational status in brain tumor patients noninvasively. This clinical role of 2HG MRS may be demonstrated most clearly in patients with brainstem lesions, where surgical biopsy presents high risk of permanent neurological injury. We conducted 2HG MRS in 20 subjects with a radiographically identified brainstem tumor (13 male and 7 female, age 20 - 73, median age 38). Proton MRS data was acquired from the T2-FLAIR volume using a 2HG-tailored MRS protocol (PRESS TE 97 ms). The millimolar concentration of 2HG was estimated with reference to water. Excluding data with unacceptable quality, data from 16 patients were included in subsequent analysis. The 16 patients were clearly divided into two groups in terms of 2HG level. The tumors in 5 patients showed a clearly discernible 2HG signal (2.25 ppm) while those in 11 patients did not. The 2HG estimation ranged from 2.1 to 6.3 mM in the 5 patients (IDH mutation) and from 0 to 0.7 mM in the 11 patients (most likely IDH wildtype). The mean concentration of 2HG differed significantly between the groups (p=3.3×10−6). One tumor was confirmed to be IDH mutated from autopsy. A representative case for 2HG MRS utility was a patient in whom 2HG was estimated to be 5.3 mM in the first MRS scan and the clinical decision was made to follow with 2HG MRS without surgery and chemoradiation therapy. The patients had 22 follow-up MRS scans for 5.4 years (scan intervals ~3 months), during which the tumor was stable clinically and radiographically. The present study demonstrates the clinical utility of 2HG MRS in brainstem tumors. 2HG MRS provides reliable estimation of 2HG and can be utilized for evaluating the IDH mutation status in brainstem lesion noninvasively.
NIMG-09. NONINVASIVE PERFUSION IMAGING BIOMARKER OF MALIGNANT GENOTYPE IN ISOCITRATE DEHYDROGENASE MUTANT GLIOMAS
Authors: Mureb Monica , Jain Rajan , Poisson Laila , Aguiar Littig Ingrid , Nunes Neto Lucidio , Wu Chih-Chin , Ng Victor , Patel Sohil , Patel Seema , Serrano Jonathan , Kurz Sylvia , Cahill Daniel , Bendszus Martin , von Deimling Andreas , Placantonakis Dimitris , Golfinos John , Kickingereder Philipp , Snuderl Matija , Chi Andrew
Published: November 2019

OBJECTIVE

A small subset of IDHmut astrocytomas behave aggressively, similarly to IDHwt glioblastoma. Genomic correlates of poor prognosis IDHmut astrocytomas include global relative DNA hypomethylation, MYCN amplification copy number variation (CNV) abundance, and CDKN2A/B homozygous deletion. We sought to identify a non-invasive imaging correlate of poor prognosis IDHmut astrocytomas.

METHODS

30 IDHmut astrocytomas (NYU=18, TCGA=12) were included. Relative cerebral blood volume was obtained from 4 regions of interest within the highest perfusion areas. Genomic CNV analysis and CDKN2A/B copy number status was obtained using Illumina Infinium 450k or Illumina EPIC methylation array data. Associations between rCBV, survival, and genomic alterations were evaluated. An additional 22 IDHmut astrocytomas were obtained from another institution for validation.

RESULTS

CNV stable (CNV-S, n=14) astrocytomas demonstrated significantly lower mean rCBV than and CNV unstable (CNV-U, n=16) (P=0.0.0155) ones. IDHmut astrocytomas with CDKN2A/B homozygous deletion (n=7) had higher rCBV (3.9 ± 2.3, mean ± SD) compared to those without this alteration (n=22; 1.8 ± 1.9, mean ± SD; P=0.0489). In the validation set, there was no significant evidence in rCBV between CNV-S and CNV-U tumors (P=0.3976). These results were sensitive to a single outlier in the CNV-S group. Excluding this case with rCBV=7.15, the CNV-S tumors demonstrated significantly lower mean rCBV (P=0.0279). IDHmut astrocytomas with CDKN2A/B homozygous deletion (n=9) tended to have higher rCBV (4.2 ± 1.8, mean ± SD) compared to those without this alteration (n=16; 2.5 ± 1.5, mean ± SD; P=0.0757, t-test). This led to significant discrimination (P=0.0328, Wilcoxon).

CONCLUSION

Our study is the first to identify a non-invasive imaging biomarker for prognostic genomic alterations in IDHmut astrocytomas. Greater CNV abundance and/or CDKN2A/B homozygous deletion have higher rCBV and worse prognosis. Our methods can be applied to standard clinical practice and may enhance informed treatment decisions in the preoperative and immediate postoperative settings.
NIMG-14. THE RELATION BETWEEN T2-FLAIR MISMATCH SIGN AND ADC VALUES REFLECTING PATHOLOGICAL MICROSTRUCTURE IN LOWER-GRADE GLIOMAS
Authors: Fujita Yuichi , Sasayama Takashi , Nagashima Hiroaki , Tanaka Kazuhiro , Hashigutchi Mitsuru , Kohmura Eiji
Published: November 2019

BACKGROUND

Although the recent studies have identified “T2-FLAIR mismatch sign” specific to IDH-mutant and 1p/19q-intact gliomas, it is unclear what the mismatch sign represents. We aimed to investigate the mechanisms and validate the clinical utility.

METHODS

We identified 79 lower-grade gliomas treated at Kobe University Hospital, and classified into three groups: (i) LGGIDH(m),1p19q(-) (n = 18): IDH-mutant and 1p/19q-intact, (ii) LGGIDH(m),1p19q(+) (n=26): IDH-mutant and 1p/19q co-deleted, (iii) LGGIDH(w) (n=35): IDH wild-type. We retrospectively analyzed the relation with apparent diffusion coefficient (ADC) values, metabolites in magnetic resonance spectroscopy and pathological features, and examined the influence of the presence of the mismatch sign on progression-free survival (PFS) and overall survival in LGGIDH(m),1p19q(-).

RESULTS

Compared to the rim presenting hyperintense on T2WI and FLAIR, the core presenting hyperintense on T2WI and reversely hypointense on FLAIR had significantly higher ADC values (p = 0.002). The core/rim ratios of ADC values were significantly higher in the cases with the mismatch sign (p = 0.001), not depending on IDH status, 1p/19q status and WHO grade. There was no significant difference in metabolites changing between the presence and absence of the mismatch sign. The cases with the mismatch sign in LGGIDH(m),1p19q(-) had abundant microcysts as a pathological feature, and longer PFS than those without the mismatch sign (5-yr PFS: 100% vs 37.5%). Multivariate analysis found the mismatch sign to be the only significant predictor for preferable PFS in LGGIDH(m),1p19q(-) (p = 0.044).

CONCLUSION

Our study provided the new evidence that the T2-FLAIR mismatch sign had the significantly different ADC values between the core and the rim, suggesting that the mismatch sign reflected the difference of the tumor cellularity and the microenvironment.
NIMG-40. ROBUST MODALITY-AGNOSTIC SKULL-STRIPPING IN PRESENCE OF DIFFUSE GLIOMA: A MULTI-INSTITUTIONAL STUDY
Authors: Thakur Siddhesh , Doshi Jimit , Min Ha Sung , Shukla Gaurav , Kotrotsou Aikaterini , Talbar Sanjay , Kulkarni Uday , Marcus Daniel , Colen Rivka , Davatzikos Christos , Erus Guray , Bakas Spyridon
Published: November 2019

BACKGROUND

Skull-stripping describes essential pre-processing in neuro-imaging, directly impacting subsequent analyses. Existing skull-stripping algorithms are typically developed and validated only on T1-weighted MRI scans without apparent gliomas, hence may fail when applied on neuro-oncology scans. Furthermore, most algorithms have large computational footprint and lack generalization to different acquisition protocols, limiting their clinical use. We sought to identify a practical, generalizable, robust, and accurate solution to address all these limitations.

METHODS

We identified multi-institutional retrospective cohorts, describing pre-operative multi-parametric MRI modalities (T1,T1Gd,T2,T2-FLAIR) with distinct acquisition protocols (e.g., slice thickness, magnet strength), varying pre-applied image-based defacing techniques, and corresponding manually-delineated ground-truth brain masks. We developed a 3D fully convolutional deep learning architecture (3D-ResUNet). Following modality co-registration to a common anatomical template, the 3D-ResUNet was trained on 314 subjects from the University of Pennsylvania (UPenn), and evaluated on 91, 152, 25, and 29 unseen subjects from UPenn, Thomas Jefferson University (TJU), Washington University (WashU), and MD Anderson (MDACC), respectively. To achieve robustness against scanner/resolution variability and utilize all modalities, we introduced a novel “modality-agnostic” training approach, which allows application of the trained model on any single modality, without requiring a pre-determined modality as input. We calculate the final brain mask for any test subject by applying our trained modality-agnostic 3D-ResUNet model on the modality with the highest resolution.

RESULTS

The average(±stdDev) dice similarity coefficients achieved for our novel modality-agnostic model were equal to 97.81%+0.8, 95.59%+2.0, 91.61%+1.9, and 96.05%+1.4 for the unseen data from UPenn, TJU, WashU, and MDACC, respectively.

CONCLUSIONS

Our novel modality-agnostic skull-stripping approach produces robust near-human performance, generalizes across acquisition protocols, image-based defacing techniques, without requiring pre-determined input modalities or depending on the availability of a specific modality. Such an approach can facilitate tool standardization for harmonized pre-processing of neuro-oncology scans for multi-institutional collaborations, enabling further data sharing and computational analyses.
NIMG-50. DOES THE PRESENCE OF GADOLINIUM AFFECT T2 –WEIGHTED IMAGES OF GLIOMA?: IMPLICATIONS FOR MRI PROTOCOL STANDARDIZATION
Authors: Jackson Pamela , Zhou Yuxiang , Hoxworth Joseph , Swanson Kristin , Hu Leland
Published: November 2019

There have been increasing efforts to standardize MRI scanning protocols for both routine and clinical trial imaging of glioma. The recent BTIP guidelines propose acquisition of T2-weighted images after gadiolinium (Gd) based contrast injection and before post-contrast 3D T1-weighted (T1W) images to control timing of images after contrast administration. While Gd-contrast shortens T1W signal and appears hyperintense on magnetic resonance imaging (MRI), Gd-contrast also shortens T2W signal, which could result in unintended alternations in T2W signal intensities. This has potential implications for model-based approaches for GBM diagnosis and the differential diagnosis of other tumor types (e.g., lymphoma) that rely on T2W signal characteristics. To our knowledge, no neuroimaging studies have formally evaluated the impact of Gd contrast on T2W imaging. We acquired multi-echo T2 sequences (TE=14, 28, 41, 55, 69 ms) both prior to and after the administration of Gd for 5 patients suspected of having a brain tumor. Quantitative T2 maps were created by fitting the signal decay to a signal exponential with the Levenburg-Marqurdt algorithm. Percent difference maps were calculated to compare the quantitative T2 changes between the pre- and post-Gd T2 maps. Additionally, we performed a Wilcoxon Rank-Sum test comparing T2 values within regions of interest (ROIs) representing the tumor and normal appearing white matter (NAWM). Significant differences between the T2 values in the tumor and NAWM ROIs were seen for 4 and 3 of the patients, respectively (all p-values < 0.01). Our initial data suggests that the administration of Gd contrast may affect T2 values in both the tumor and NAWM, which could impact quantitative image-based models and diagnoses in glioma. We are currently replicating these preliminary results in an expanded cohort.
NIMG-55. TO ASSESS THE UTILITY OF ADVANCED QUANTITATIVE DIFFUSION MRI DERIVED FROM MULTI B VALUE ACQUISITIONS IN THE ASSESSMENT OF TREATMENT RESPONSE, USING A SPATIALLY-INDEPENDENT APPROACH
Authors: Islam Shah , Morrison Melanie , Waldman Adam
Published: November 2019

PURPOSE

To assess the utility of advanced diffusion MRI derived from multi b value acquisitions in the assessment of treatment response, using a spatially-independent approach.

METHOD AND MATERIALS

13 GBM patients were enrolled into our multicentre study. All patients completed RT with TMZ. Imaging was performed pre-RT and mid RT. The MRI protocol included a ‘low’ b value acquisition (b= 0s/mm, 50s/mm, 150s/mm, 200s/mm, 500s/mm, 1000s/mm) from which monoexponential diffusion indices ADC and biexponential indices, IVIM parameters D*, D and f were calculated. A ‘high b value’ acquisition (b=0 s/mm, 500s/mm, 1000s/mm, 1500s/mm, 2000s/mm, 2500s/mm, 3000s/mm, 3500s/mm, 4000s/mm) was acquired to allow stretched exponential diffusion indices, DDC and alpha to be derived. FLAIR sequences were used to define ROI and clinical assessment of mid-treatment and end-treatment response using RANO criteria. Histograms were generated from voxels located within manually segmented ROIs defined by increased signal on T2 FLAIR images. Changes in histogram percentile profiles were evaluated across the two timepoints and compared with RANO assessment at the mid treatment and end treatment timepoints.

RESULTS

Following completion of treatment, 5 patients had PD, 4 SD and 4 CR. Patients with PD showed a histogram shift to the left across all diffusion models, in keeping with increasing diffusion restriction and implying increased cellularity. Patients with SD or CR showed little or no shift in the histogram. DDC and f are the most predictive of progression against RANO assessment, and appear superior to routine ADC. Reduction in 75th centile (f) and 95th centile (DDC) are the most sensitive histogram metrics for predicting early progressive disease.

CONCLUSION

Results suggest association between early changes in specific diffusion components and subsequent treatment response. Spatially-independent diffusion parameter comparisons provide unbiased sampling of tumour heterogeneity and abrogate the confound of voxel-to-voxel misregistration due to tumour growth/shrinkage.
NIMG-63. LONGITUDINAL ANALYSIS OF OLIGODENDROGLIOMA GROWTH PATTERN REVEALED SPATIAL HETEROGENEITY AND DIVERSE TREATMENT RESPONSE
Authors: Heiland Dieter , Ohle Robin , Behringer Simon , Beck Juergen , Schnell Oliver
Published: November 2019

Oligodendroglioma are defined by a distinct molecular phenotype marked by 1p19q co-deletion and simultaneous presence of an IDH1/2 mutation. These tumors showed a favorable clinical course and long-term survival of around 15 years. Due to the long course of the disease, prospective studies to determine the effectiveness of different therapeutic strategies are difficult, since the percentage of patients with multiple therapies is high. Here we report a computational approach to map the longitudinal growth pattern, to quantify the effect of therapies on tumor growth and to identify similarities and spatial heterogeneity of oligodendroglioma growth. In our study, we included a cohort of 44 histopathologically and molecularly stratified oligodendrogliomas WHO°II (n=23) and WHO°III (n=21). We started our investigation with the longitudinal tumor segmentation. All volumetric data were pinpointed to the times of tumor therapy within all patients. Next, we extracted first-order features of tumor growth and response to chemo- or radiotherapy as well as resection, resulting in a total number of 98 features. An unsupervised cluster was used to identify similarities between patients, which revealed 3 subgroups. The first subgroup contained patients with predominantly frontal oligodendrogliomas marked by increased response to radiotherapy. The second subgroup included temporal oligodendrogliomas with high response rate to PC/PCV chemotherapy and flagged by epilepsy. The third group was heterogeneous with varying growth behaviors. A survival analysis showed a better separation between low- and high-risk patients based on the growth pattern model, in contrast to the WHO grading system. Taken together, our analysis revealed a novel classification of oligodendroglioma based on the longitudinal growth pattern and therapeutical response. We also detected a spatial difference between frontally or temporally localized oligodendrogliomas. We plan to further investigate molecular data that explain these spatial differences, which also may uncover novel therapeutic strategies.
NIMG-67. DEVELOPMENT OF VERSATILE MACHINE-LEARNING APPROACHES FOR RADIOGENOMICS OF GLIOMA IN DIFFERENT COHORTS
Authors: Takahashi Masamichi , Kawaguchi Risa , Takahashi Satoshi , Miyake Mototaka , Kinoshita Manabu , Ichimura Koichi , Hamamoto Ryuji , Narita Yoshitaka , Sese Jun
Published: November 2019

BACKGROUND

Radiogenomics aims to analyze clinical images and information, and to predict key molecular profiles of tumors. However, imaging protocol is usually different in facilities, and it has been rarely examined whether the performance of developed methods in a dataset is robustly sustained even in other independent datasets. We explored machine learning and matrix decomposition methods using preoperative magnetic resonance images (MRIs) of glioma patients to establish versatile platform regardless of the heterogeneity of the datasets.

METHODS

Preoperative glioma MRIs and clinical information were obtained from public dataset of The Cancer Imaging Archive (TCIA, N=159) and National Cancer Center Hospital (NCC, N=166). More than 16,000 radiomic features were applied for the prediction of tumor grading and IDH mutation status. Accuracy of prediction was evaluated by AUROC (area under the receiver operating characteristic curves).

RESULTS

The performances were comparable between the image features regardless of dimension reduction methods (the best accuracy for tumor grading and IDH status prediction was 0.91 and 0.88, respectively), but they were drastically decreased in the transfer learning (0.70 and 0.69). On the other hand, they were successfully improved by applying matrix decomposition and brain embedding (0.86 and 0.79).

CONCLUSION

Our result and pipeline can be a global benchmark for future studies in heterogeneous datasets. Further evaluation in larger cohorts are planned.
NIMG-70. A LABEL-FREE APPROACH TO ASSESS CHEMOTHERAPY DRUG CONCENTRATION USING CHEMICAL EXCHANGE SATURATION TRANSFER MRI – A FEASIBILITY STUDY
Authors: Kamson David , Grossman Stuart , Han Zheng , Xu Xiang , van Zijl Peter , Liu Guanshu
Published: November 2019

BACKGROUND

Drug delivery is one of the most pressing problems in neuro-oncology as the blood-brain barrier (BBB) uniquely limits penetration of substances into the brain parenchyma. Plasma and CSF drug concentrations are relatively easy to measure, but do not necessarily reflect concentrations in the brain. Furthermore, invasive measurements may be inaccurate in regions of heterogeneous BBB integrity. Advanced non-invasive imaging approaches may help bridge this information gap without the added risk. Chemical exchange saturation transfer (CEST) is an MRI technique that allows in vivo detection of molecules with a suitable hydrogen exchange rate, such as methotrexate (MTX). High-dose MTX is commonly used in oncology and its concentrations in urine (>2000µM), plasma (>1000µM) and enhancing brain tumors (>350µM) are well above the theoretical threshold of CEST. AIM: We aimed to confirm the CEST detectability of MTX in vitro, and to estimate the currently lowest measurable concentrations in solutions mimicking bodily fluids.

METHODS

We used a 9.4T MRI to assess the spectra of MTX at 37°C at various concentrations (0.1–10.0 mM) in a phosphate-buffered saline (PBS) solution at various pH (6.0–8.0), as well as in synthetic urine at pH 6.2.

RESULTS

CEST signals attributable to MTX at 1.5 and 2.7ppm were successfully detected in PBS at concentrations as low as 500µM. The optimal field strength was 3.6µT. While increasing pH increased the detection threshold of the 2.7ppm signal, the 1.5ppm signal was minimally affected by pH within physiologic ranges. In synthetic urine, the MTX CEST signal was well-detectable even at concentrations as low as 200µM.

CONCLUSIONS

These preliminary results suggest that MTX-CEST may be feasible at field strengths achievable in clinical scanners and at MTX concentrations previously measured in enhancing brain tumors treated with high-dose MTX. Further optimization of the technique for in human use is under way.
NIMG-72. PROGNOSTIC VALUE OF [18F]-FDG POSITRON EMISSION TOMOGRAPHY IN PATIENTS WITH RECURRENT GLIOBLASTOMA RECEIVING BEVACIZUMAB
Authors: Graham Maya , Krebs Simone , Bale Tejus , Domfe Kwaku , Lobaugh Stephanie , Zhang Zhigang , Dunphy Mark , Kaley Thomas , Young Robert
Published: November 2019

BACKGROUND

Bevacizumab is used extensively for the treatment of recurrent glioblastoma, and its modification of contrast-enhanced MRI creates a need for alternate prognostic read-outs. We sought to determine the prognostic value of [18F]-FDG (FDG) PET in glioblastoma patients performed during treatment with bevacizumab.

METHODS

We performed an institutional review board approved retrospective study on patients who underwent FDG PET within 4 weeks of a dose of bevacizumab for recurrent glioblastoma. Volumes of interest were placed over one reference lesion as defined by MRI. Maximum standardized uptake value (SUVmax) and peak standardized uptake value (SUVpeak) in this volume of interest were measured on PET, and metabolic tumor volume (MTV), total lesion glycolysis (TLG) and lesion-to-normal contralateral white matter ratios (SUVmax/cWM) were calculated. In addition, tumors were divided into 2 groups based on qualitative uptake pattern: (i) FDG non-avid and (ii) FDG avid. Statistical impact of PET parameters on overall survival (OS) was assessed, as was histopathological correlate of PET findings for patients with pathology available within 3 months of PET.

RESULTS

31 patients were included. Qualitative uptake pattern was significantly associated with OS (p = 0.005), with a median OS of 9.7 months in FDG non-avid patients versus 4.5 months in FDG avid patients. In univariate analysis, SUVmax, SUVpeak and T/N ratio were also significantly associated with OS (p < 0.001). Dichotomizing our sample using a SUVmax cut-off of 15.3 was also predictive of OS (adjusted p = 0.05). Pathology was available for 7 patients (22.6%) and confirmed PET findings.

CONCLUSION

FDG PET is a promising imaging biomarker to predict overall survival in recurrent glioblastoma patients on chronic antiangiogenic therapy, offering a tool for guiding assessment of treatment response in this patient population.
NIMG-74. MULTIPARAMETER MRI INVESTIGATION OF HIGH-GRADE GLIOMA RESPONSE TO CAR T CELL IMMUNOTHERAPY
Authors: Ravi Harshan , Stringfield Olya , De Leon Gustavo , Johnston Sandra , Rockne Russell , Badie Behnam , Brown Christine E , Swanson Kristin , Gatenby Robert , Raghunand Natarajan
Published: November 2019

INTRODUCTION

Immunotherapy with engineered CAR T cells is a promising new therapy for glioblastoma, for which predictive and prognostic biomarkers are needed to inform effective intervention. Recently, our group analyzed standard-of-care (SOC) MRI images of long-term and short-term glioblastoma survivors and identified six intratumoral “habitats” of which “Habitat 6” was correlated with survival at diagnosis in high-grade glioma. Based on the MRI characteristics of “Habitat 6”, viz. high enhancement and high edema, we hypothesized that it could be a marker of tumor immune infiltrates. We are studying longitudinal changes in tumor “habitat” composition on MRIs of subjects with recurrent high-grade glioma treated with CAR T cells engineered to target IL13Ra2.

METHODS

MRI scans of the brain were acquired in 6 subjects at 3.0 T at baseline and various times before and after initiation of CAR T cell therapy. FLAIR, T1W and T1W-CE MRI images were registered to T2W images and six intratumoral “habitats” were computed as per our recently published methodology. The six habitats generated at the end of the tumor segmentation process were: “Habitat 1” (low FLAIR, low enhancement), “Habitat 2” (high FLAIR, low enhancement), “Habitat 3” (low FLAIR, medium enhancement), “Habitat 4” (high FLAIR, medium enhancement), “Habitat 5” (low FLAIR, high enhancement), and “Habitat 6” (high FLAIR, high enhancement).

RESULTS

Analysis of temporal changes in the six “habitats” shows an initial increase in both “Habitat 4” and “Habitat 6” following CAR T cell therapy initiation. Subjects with higher absolute volumes of “Habitat 6” at the baseline (pre-treatment) showed longer overall survival. Overall survival is a function of absolute “Habitat 6” volume at baseline, its direction of change immediately post-therapy, the duration of any increase in “Habitat 6” post-treatment, and the “Habitat 6” to “Habitat 4” ratio. Additional subjects are being evaluated to further understand these preliminary observations.
NIMG-76. RADIOPATHOMICS: INTEGRATION OF RADIOGRAPHIC AND HISTOLOGIC CHARACTERISTICS FOR PROGNOSTICATION IN GLIOBLASTOMA
Authors: Rathore Saima , Nasrallah MacLean , Mourelatos Zissimos
Published: November 2019

INTRODUCTION

Large number of diverse imaging [e.g., multi-parametric MRI (mpMRI), and digital pathology images] and non-imaging (e.g., clinical) biomedical data streams are being routinely acquired as part of the standard clinical workflow for glioblastoma patients. However, under the current clinical practice, these data streams are not collectively used for diagnosis. We sought to assess the synergies between pathologic, and radiomic features by evaluating the predictive value of each group of features and their combinations through a prognostic classifier.

METHODS

The mpMRI (T1,T1-Gd,T2,T2-FLAIR) and corresponding digital pathology images for 135 de novo glioblastoma was acquired from TCIA. An extensive panel of handcrafted features, including shape, volume, intensity distributions, gray-level co-occurrence matrix based texture, was extracted from delineated tumor regions of mpMRI scans. A set of 100 region-of-interest each comprising 1024x1024 that contained viable tumor with descriptive histologic characteristics and that were free of artifacts were extracted from digital pathology images, and were quantified in terms of nuclear texture features, and nuclear intensity and gradient statistics. A support vector regression multivariately integrated these features towards a marker of overall-survival. The accuracy of the predictive model for each group of features, and their combinations, was determined via a 10-fold cross-validation scheme.

RESULTS

The Pearson correlation coefficient between the survival scores predicted by SVR and the actual survival scores was estimated to be 0.75 and 0.77 for radiographic and pathologic data, however, the integration of these data yielded a clear improvement in correlation (0.81), supporting the synergistic value of these features in the prognostic model.

CONCLUSION

Radiomic features extracted from preoperative mpMRI, when used together with digital pathology features, offer synergistic value in assessment of prognosis in individual patients. The proposed radiopathomics marker may contribute to (i) stratification of patients into clinical trials, (ii) patient selection for targeted therapy, and (iii) personalized treatment planning.
NCMP-08. CLINICAL FEATURES OF CAR T-CELL THERAPY NEUROTOXICITY AS POTENTIAL SURROGATE MARKERS FOR PROGRESSION AND OUTCOME
Authors: Yuen Carlen , Artz Andrew , Kelly Thomas , Wu Shasha , Reder Anthony , Rezania Kourosh , Soliven Betty , Xie Tao , Mastrianni James , Park Deric , Kosuri Satyajit , Riedell Peter , Klejch Wesley , Ali Saad , Bishop Michael
Published: November 2019

CAR T-cell therapy related neurotoxicity (NT) is common and can lead to fatalities. Early recognition may improve its management and treatment.

METHODS

Twenty-six patients with relapsed/refractory diffuse large B cell lymphoma who received commercial CAR T-cell therapy (25 axicabtagene ciloleucel [Yescarta®], 1 tisagenlecleucel [Kymriah®]) between December 2017 and September 2018 were assessed for NT based on CARTOX-10 score and Common Terminology Criteria for Adverse Events (CTCAE) version 4.

RESULTS

Twenty-three of 26 (88%) of patients developed NT, which was severe (Grade III-IV) in 8/26 (31%). Severe NT was associated with complete remission compared to progressive disease by both CTCAE (2.4 ±1.1 vs. 1.4 ± 1.3, p = 0.050) and CARTOX-10 score (8.3 ± 1.6 vs. 9.4 ± 1.5, p = 0.040). CARTOX-10 scores were lower for those transferred to the ICU compared to those transferred, respectively, on Days 8 (2.71 ± 4.78 vs. 9.28 ± 2.31, p = 0.010), 9 (2.71 ± 3.96 vs. 9.06 ± 2.50, p = 0.003) and 10 (2.86 ± 4.27 vs. 8.83 ± 3.37, p = 0.002). Depression was associated with poor overall survival (deceased 67% vs. alive 20%, p = 0.00004) and severe NT (severe NT 63% vs. non-severe NT 20%, p = 0.040). EEG findings of frontal intermittent rhythmic delta activity (FIRDA) in 22% (2/9) and triphasic waves in 33% (3/9) were exclusive found in severe NT. Tremulousness was present in 100% of severe NT compared to 67% of non-severe NT patients (p = 0.060). Delirium occurred in 2 patients, both of whom expired with severe NT.

CONCLUSION

Depression, tremor, delirium, encephalopathy, and EEG features of FIRDA and triphasic waves may represent early clinical signs that predict the development of severe NT in off-protocol CAR T-cell therapy. Paradoxically, severe NT is positively correlated with progression free survival and may indicate effective therapeutic response.