bluuebunny/crossref_metadata_2025 huggingface dataset:
PATH-18. INTEGRATING TUMOR MICROENVIRONMENT WITH GENOMIC ABERRATIONS AND TUMOR CLASS IN ADULT GLIAL/GLIONEURONAL TUMORS BY DECONVOLUTION OF BULK METHYLATION DATA
Authors: Singh Omkar , Aldape Kenneth , Pratt Drew
Published: November 2021

It is increasingly recognized that the tumor microenvironment (TME) plays a critical role in the biology of cancer. To better understand the role of non-neoplastic immune cellular components in CNS tumors, we applied a deconvolution approach to bulk DNA methylation array data using methylCIBERSORT on 450k/850k methylation data from a set (n= 4057) of high- and low-grade glial and glioneuronal tumors. Using the cell type proportion data as input, we used dimension reduction (UMAP) to visualize sample-wise patterns of that emerge from the cell type proportion estimations. In glioblastomas (n= 2076) we identified distinct tumor clusters based on immune cell proportion and, interestingly, TME-based cluster groups demonstrated an association with specific genetic alterations such as EGFR amplification and/or CDKN2A/B homozygous deletion. Among 1178 IDH-mutant gliomas, clustering of tumors according to immune cell proportions led to 2 major subgroups, which largely aligned with 1p/19q co-deletion status. Among the non-codeleted tumors (IDH-mutant astrocytomas, N=734), clustering of immune cell decomposition revealed clusters which showed distinct proportions of a key genomic aberration in these tumors (CDKN2A/B loss). To investigate the possible role of monocyte proportion-relative gene expression and promoter methylation of the immune checkpoint PD-L1 and PD-L2 genes, we used a data subset (n=594) samples with matched gene expression profiles. We observed significantly high positive correlations (R=0.54 and 0.68, respectively) between monocyte proportion and expression of PD-L1 and PD-L2, in line with prior reports that monocytic cells can express these immune markers. Consistent with this, we found high negative correlations (R= -0.51 and -0.61, respectively) between monocytes and promoter methylation of PD-L1 and PD-L2, respectively. Overall, the findings highlight specific roles of the TME in biology and classification of adult CNS tumors, where specific immune cell admixtures correlate with tumor types and genomic aberrations.
PATH-21. THE SINGLE-CELL PATHOLOGY LANDSCAPE OF PEDIATRIC GLIOMA
Authors: Messiaen Julie , Nasari Pouya , Van Herck Yannick , Verhaaren Ben , Sebastian Ivey , Milli Giorgia , Bosisio francesca , Pey Jon , De Vleeschouwer Steven , De Vloo Philippe , Depreitere Bart , Vanden Bempt Isabelle , Sciot Raf , Antoranz Asier , Jacobs Sandra , De Smet Frederik
Published: November 2021

High-grade glioma are the main cause of cancer-related death in children. Despite extensive research, their prognosis remains poor with very few treatment options. This can be attributed to the highly heterogeneous and plastic nature of glioma tumor cells and their interactions with the microenvironment, although quantitative data are still largely missing. Here, we used high-dimensional, multiplexed immunohistochemistry to map the spatial, single-cell tissue architecture of 31 pediatric glioma samples covering 9 histologic diagnoses. This novel approach allowed us to map the spatial distribution of the various tumoral subtypes, which typically occur in specific tumoral niches, and how these interact with their local immune-microenvironment. Finally, by aligning these findings to the clinical data of the patients and comparing these to adult glioblastoma, we are now able to more precisely describe the heterogeneous landscape of pediatric glioma at single-cell resolution.
PATH-32. EXTENT, PATTERN, AND PROGNOSTIC VALUE OF MGMT PROMOTOR METHYLATION: DOES IT DIFFER BETWEEN GLIOBLASTOMA AND IDH-WILDTYPE/TERT-MUTATED ASTROCYTOMA?
Authors: Teske Nico , Karschnia Philipp , Weller Jonathan , Siller Sebastian , Dorostkar Mario M , Herms Jochen , von Baumgarten Louisa , Tonn Jörg-Christian , Thon Niklas
Published: November 2021

INTRODUCTION

The cIMPACT-NOW update 6 introduced glioblastoma diagnosis based on the combination of IDH-wildtype (IDHwt) status and TERT promotor mutation (pTERTmut). In glioblastoma as defined by histopathology according to the WHO 2016 classification, MGMT promotor status is associated with outcome. Whether this is also true in glioblastoma defined by molecular markers is yet unclear.

METHODS

We searched the institutional database for patients with: 1.) glioblastoma defined by histopathology; and 2.) IDHwt astrocytoma with pTERTmut. MGMT promotor methylation was analysed using methylation-specific PCR and Sanger sequencing of CpG sites within the MGMT promotor region.

RESULTS

We identified 224 patients with glioblastoma diagnosed based on histopathology, and 71 patients with IDHwt astrocytoma with pTERTmut (32 astrocytomas WHO grade II and 39 astrocytomas WHO grade III). There was no difference in the number of MGMT methylated tumors between the two groups as determined per PCR, and also neither the number nor the pattern of methylated CpG sites differed as determined per Sanger sequencing. Progression-free (PFS) and overall survival (OS) was similar between the two groups. Surgery was associated with improved overall survival in IDHwt astrocytoma with pTERTmut. In patients treated with radiochemotherapy or radiotherapy, higher numbers of methylated CpG sites were associated with favourable outcome in both groups.

CONCLUSION

Extent and pattern of methylated CpG sites are similar in glioblastoma and IDHwt astrocytoma with pTERTmut. In both groups, higher numbers of methylated CpG sites are associated with favourable outcome when radio/chemotherapy is administered. Surgery may form the basis for favourable outcome.
PATH-35. AKT1(E17K) MUTATIONS ARE FREQUENT GENOMIC EVENTS IN CERVICAL SPINAL MENINGIOMAS
Authors: Alkhatib Majd , Schackert Gabriele , Juratli Tareq
Published: November 2021

INTRODUCTION

Spinal meningiomas represent about one-third of all spine tumors. To date, little is known about the molecular profile of spinal meningiomas and their clinical impact. In this study, we correlate clinical parameters with targeted sequencing findings in a well-characterized cohort of 42 patients with spinal meningiomas.

METHODS

Samples from 42 spinal meningiomas (31 females and 11 males) were collected. Targeted sequencing for AKT1 E17K hot spot mutations was performed. Furthermore, clinical and imaging data were collected and correlated with the AKT1 mutation status.

RESULTS

Gross total resection (Simpson grade I /II) was achieved in all patients. The mean follow-up period was 60 months (6 –288 months). None of the patients demonstrated a tumor recurrence. AKT1E17K mutations were detected in 8 patients (19%), in five male and three female patients (p= 0.019). Although the majority of resected meningiomas (n= 28, 66.6%) were located in the thoracic spine, meningiomas originating in the cervical spine harbored significantly more AKT1 E17K mutations (6 out of 14, p= 0.010). Notably, all AKT1 mutated meningiomas arose ventrally or ventrolaterally to the spinal cord. The histologic examination revealed a WHO Grade 1 in 36 meningiomas (85.7%): 21 meningothelial, 8 psammomatous, 5 transitional, 2 fibrous. The remaining six meningiomas were classified as atypical WHO grade 2. Remarkably, AKT1 E17K mutations were significantly related to a meningothelial subtype (p= 0.044).

CONCLUSIONS

Our molecular study demonstrates that AKT1 E17K mutations are a frequent genomic event in spinal meningiomas. The majority of AKT1 mutated meningiomas occurred in male patients, originate in the cervical spine, and exhibit meningothelial histology.
NIMG-01. INTEROBSERVER VARIABILITY OF THE REVISED IMAGING SCORECARD FOR LEPTOMENINGEAL METASTASIS: A JOINT EORTC BRAIN TUMOR GROUP AND RANO EFFORT
Authors: Le Rhun Emilie , Devos Patrick , Winklhofer Sebastian , Lmalem Hafida , Brandsma Dieta , Pérez-Larraya Jaime Gállego , Castellano Antonella , Compter Annette , Dhermain Frederic , Franceschi Enrico , Forsyth Peter , Furtner Julia , Galldiks Norbert , Gempt Jens , Glantz Michael , Hattingen Elke , Hempel Johann Martin , Jaeckle Kurt , Kumthekar Priya , Lukacova Slavka , Minniti Giuseppe , O'Brien Barbara , Postma Tjeerd J , Roth Patrick , Rudà Roberta , Schäfer Niklas , Schmidt Nils Ole , Smits Marion , Snijders Tom , Thust Steffi , Tonn Jörg-Christian , van den Bent Martin , van den Hoorn Anouk , Vogin Guillaume , Preusser Matthias , Wen Patrick , Bendszus Martin , Weller Michael
Published: November 2021

BACKGROUND

Validation of the 2016 LANO MRI scorecard for leptomeningeal metastasis failed for multiple reasons. The objective of this joint EORTC Brain Tumor Group and RANO effort was to validate the feasibility of the revised MRI scorecard for assessing response in leptomeningeal metastasis.

METHODS

Coded paired cerebrospinal MRI of 20 patients with leptomeningeal metastases from solid cancers at baseline and follow-up after treatment and instructions for assessment were provided via the EORTC imaging platform. The kappa coefficient (K) was used to evaluate inter-observer pairwise agreement. Statistical analyses were performed using SAS V9.4 software (Cary, NC). The sponsor of the study was the University Hospital Zurich (2018-00192).

RESULTS

Thirty-five raters participated, including 9 neuroradiologists, 17 neurologists, 4 radiation oncologists, 3 neurosurgeons and 2 medical oncologists. Among leptomeningeal metastases-related items at baseline, the best median concordance was noted for hydrocephalus (K=0.63), and the worst median for spinal linear enhancing disease (K=0.46). The median concordance for overall response was moderate (K=0.44). Notably, the interobserver agreement for the presence of parenchymal brain metastases at baseline was minimal (K=0.29). Significant differences were observed when considering the specialty of the raters. Only 394 of 700 ratings (56%) were fully completed. Among 394 fully completed ratings, perfect concordance was noted in 293 ratings (74%) when comparing the overall response according to the guidelines provided in the scorecard and the overall response provided by the raters. The main discordances were noted for partial response according to the rater versus stable disease according to the guidelines (n=44), followed by progression according to the raters versus stable disease according to the guidelines (n=23).

CONCLUSION

Electronic case report forms with "blocking solutions" are probably required to enforce completeness and quality of scoring. These results confirm the necessity of central review and the need for training of MRI assessment in clinical trials.
NIMG-02. 18F-FLUCICLOVINE POSITRON EMISSION TOMOGRAPHY TO DISTINGUISH TUMOR PROGRESSION FROM RADIATION NECROSIS FOLLOWING STEREOTACTIC RADIOSURGERY FOR BRAIN METASTASIS: A QUALITATIVE ANALYSIS
Authors: Smile Timothy , Tom Martin , Obuchowski Nancy , DiFilippo Frank , Jones Stephen , Suh John , Murphy Erin , Yu Jennifer , Mohammadi Alireza , Barnett Gene , Huang Steve , Wu Guiyun , Johnson Scott , Ahluwalia Manmeet , Peereboom David , Stevens Glen , Chao Samuel
Published: November 2021

PURPOSE/OBJECTIVE(S)

To assess the ability of 18F-Fluciclovine PET/CT to distinguish radiation necrosis (RN) from tumor progression (TP) among patients with brain metastases (BM) treated with stereotactic radiosurgery (SRS) in a prospective pilot study.

MATERIALS/METHODS

Adults with post-SRS BM presenting with follow-up brain MRI equivocal for RN versus TP underwent 18F-Fluciclovine PET/CT within 30 days of equivocal MRI. PET images were reconstructed using a point-spread-function algorithm. Three physician reviewers independently performed qualitative analyses of each lesion using a three-point visual score relative to PET-avidity of blood pool and parotid. Quantitative metrics for each lesion were documented. Reference standard was clinical follow-up with brain MRI until tumor board consensus or tissue confirmation. Nonparametric estimates of area under the receiver operating characteristic curve (AUC) for clustered data were estimated, with diagnostic performance based on visual score.

RESULTS

In 15 subjects with 20 lesions, final diagnosis was RN in 16 (80%) lesions and TP in 4 (20%). Visual score significantly correlated with final diagnosis (AUC range 0.836-0.906 [p≤0.037]). A threshold score of 2 (lesion 18F-fluciclovine uptake above blood pool to parotid) and higher produced sensitivities and specificities of 75-100% and 38-56% respectively among the reviewer majority. Conversely, a threshold of 3 (uptake higher than parotid) produced sensitivities and specificities of 50-75% and 100% respectively.

CONCLUSION

In this prospective pilot, basic visual analysis of 18F-Fluciclovine PET/CT provided high sensitivity and specificity in detection of TP in post-SRS BM based on different threshold scores, suggesting room for visual threshold optimization. A low TP event rate limited the ability to estimate sensitivity/specificity and to perform combined qualitative/quantitative analyses. Further study to refine interpretation criteria is ongoing.
NIMG-11. VOLUMETRIC ENDPOINTS IN DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG): COMPARISON TO CROSS-SECTIONAL MEASURES AND CORRELATION WITH OUTCOMES
Authors: Lazow Margot , Nievelstein Martijn , Lane Adam , Bandopadhayay Pratiti , DeWire-Schottmiller Mariko , Fouladi Maryam , Glod John , Greiner Robert , Hoffman Lindsey , Hummel Trent , Kilburn Lindsay , Leary Sarah , Minturn Jane , Packer Roger , Ziegler David S , Chaney Brooklyn , Black Katie , de Blank Peter , Leach James
Published: November 2021

INTRODUCTION

Cross-sectional tumor measures are used as endpoints in clinical trials of DIPG, but may not capture meaningful changes in disease burden. Volumetric measures may provide a more accurate assessment of tumor growth. We measured the correlation between cross-sectional and volumetric measures and compared their prognostic impact to better understand response evaluation in DIPG.

METHODS

Patients from the International DIPG Registry with diagnostic and post-radiation MRIs were included. Utilizing mint LesionTM software, tumors were manually contoured by an experienced pediatric neuro-radiologist to extrapolate cross-sectional product (CP) and volume measures. Correlation between CP and volume was assessed by linear regression. Landmark analyses were performed to determine differences in overall survival (OS) (via log-rank) between patients classified as progressive disease (PD) versus non-PD according to CP and volumetric measurements at one-, three-, and five-months post-radiation. Imaging consistent with pseudoprogression was designated non-PD. Hazard ratios (HR) for survival after these timepoints were calculated by Cox regression.

RESULTS

A total of 317 MRIs from 46 patients were analyzed. When comparing change from smallest previous tumor size, CP increase of 25% (PD by RAPNO) correlated with volume increase of 28% (R2=0.685). There was no difference in OS between patients classified as PD versus non-PD by CP at one-month, three-months, or five-months post-radiation (p >0.05). However, significant differences in OS were observed between patients classified as PD versus non-PD by volume (28% increase) at one-month (2.7 vs. 12.8 months, p=0.005), three-months (1.9 vs. 10.7 months, p=0.036), and five-months post-radiation (3.7 vs. 9.1 months, p=0.023). PD by volume, but not by CP, was predictive of survival at all timepoints (HR: 5.0, 2.4, 2.4).

CONCLUSIONS

Volumetric assessments of PD correlated better with survival than CP at all post-radiation timepoints. Tumor volume likely represents a more accurate, prognostically-relevant measure of disease burden that deserves investigation in future DIPG trials.
NIMG-14. RESTING STATE EXECUTIVE CONTROL AND SALIENCE NETWORK CONNECTIVITY IN CLINICALLY STABLE LOWER GRADE GLIOMA COVARIES WITH COGNITIVE PERFORMANCE
Authors: Luks Tracy , Villanueva-Meyer Javier , Weyer-Jamora Christina , Brie Melissa , Smith Ellen , Braunstein Steve , Bracci Paige , Chang Susan , Hervey-Jumper Shawn , Taylor Jennie
Published: November 2021

BACKGROUND

Survival outcomes for patients with lower grade gliomas (LrGG) are improving. However, injury from tumor growth and consequences of treatment often leads to impaired cognition, particularly in cognitive domains reliant on distributed functional networks and intact white-matter tracts. Resting state functional MRI (rsfMRI) is a method of investigating the integrity of these functional networks.

METHODS

This study investigated rsfMRI connectivity in 21 patients with clinically stable LrGG compared to age- and gender-matched healthy controls, and associated imaging measures with cognitive outcomes. Data were acquired for 12 cognitive tests administered within one week of imaging. RsfMRI and T1-weighted images for 21 research controls were acquired from OpenNeuro datasets. RsfMRI data were processed and analyzed using the CONN toolbox using CONN’s standard regions of interest (ROI) for the 8 canonical networks as seeds, and cognitive test scores as covariates, with a threshold for T tests of p< .001 uncorrected.

RESULTS

Median age was 48 years old (range 27-67). There were 6 astrocytomas, IDHmut; 3 astrocytomas IDH-wt, 8 oligodendrogliomas, and 4 NOS. Thirteen had left hemisphere tumors (8 frontal, 3 parietal, 2 temporal), and 6 right (5 frontal, 1 temporal). Fourteen had previously recieved radiotherapy. There was significantly lower connectivity in frontoparietal executive control and the salience networks in LrGG patients versus controls. Within patients, lower executive control network connectivity covaried with worse performance on executive measures (FAS, Tower of London, Trails-A, Animal Naming, FrSBe), and attention and working memory measures (Digit Symbol, HVLT). Lower salience network connectivity covaried with poorer performance on executive measures (FrSBe, FAS) and attention and working memory measures (Digit Span, HVLT, WAIS-WM).

CONCLUSION

In clinically stable LrGG, rsfMRI measures of network connectivity are potentially useful markers to monitor and track, given the concordance with cognition, and could help guide cognitive assessment and rehabilitation.
NIMG-17. SYSTEMATIC REVIEW OF LITERATURE EVALUATING MACHINE LEARNING ALGORITHMS TO DEVELOP OUTCOME PREDICTION MODELS IN GLIOMA USING MOLECULAR IMAGING WITH AMINO ACID PET
Authors: Shatalov Julia , Brim W R , Subramanian Harry , Bazaar John , Johnson Michele , Aboian Mariam
Published: November 2021

PURPOSE

Machine learning (ML) algorithms demonstrate accurate prediction of tumor segmentation, molecular pathology, and outcomes in gliomas using MRI and recently application of ML tools has expanded into molecular imaging with PET. We performed a systematic review to evaluate the role and applications of ML in characterization of gliomas with PET.

METHODS

Four databases were searched by medical school librarian and confirmed by an independent librarian: Ovid Embase, Ovid MEDLINE, Cochrane trials (CENTRAL), and Web of Science-Core Collection. The search strategy used keywords and controlled vocabulary combining the terms for: artificial intelligence, machine learning, deep learning, radiomics, magnetic resonance imaging, glioma, and related terms. All articles were reviewed by at least 2 independent reviewers at abstract screening, full text review, data extraction, and bias analysis using TRIPOD.

RESULTS

An initial 11,727 publications were imported to Covidence for screening. After review, 1135 studies moved to full-text review and 715 articles were included. Twelve publications included PET imaging of gliomas. All publications used single-center databases (3-73 patients) with distribution of tracers being [18F]-FDG (1), [18F]-FET (6), [11C]-MET (3), [18F]-FDOPA (1), and [18F]-AMP (1). All but 2 papers used supervised machine learning algorithms. Number of features ranged from 4-19,284. Nine papers manually extracted semiquantitative features TBRmax, TBRmean, SUV, TTP, in addition to demographics. Study outcomes included prediction of treatment response, survival, molecular subtypes, tumor grade, segmentation, and accuracy of image fusion. Accuracy ranged from 0.64-0.95 with AUC 0.43-0.9.

CONCLUSION

ML can be used on small datasets of PET imaging of brain tumors. While majority of the clinical scans are performed with FDG-PET, the machine learning approaches are being applied to mostly amino acid tracers. Extending ML approaches to FDG-PET, which is more common in clinical practice, is recommended. Overall, ML has potential as a useful tool for predicting patient outcomes and improving image postprocessing.
NIMG-31. PROPOSED ORIGINS AND PATHWAYS OF DIFFUSE GLIOMAS REVEALED BY LESION COVARIANCE NETWORKS
Authors: Mandal Ayan , Romero-Garcia Rafael , Seidlitz Jakob , Hart Michael , Alexander-Bloch Aaron , Suckling John
Published: November 2021

Diffuse gliomas have been hypothesized to originate from neural stem cells in the subventricular zone and develop along previously healthy brain networks. Here, we evaluated these hypotheses by mapping independent sources of glioma localization and determining their relationships with neurogenic niches, genetic markers, and large-scale connectivity networks. Using lesion data from a total of 410 patients with high- and low-grade glioma, we identified – and replicated in an independent sample – three lesion covariance networks (LCNs), which reflect clusters of frequent glioma localization. These three LCNs overlapped with the anterior, posterior, and inferior horns of the lateral ventricles respectively, extending into the frontal, parietal, and temporal cortices. The first LCN, which overlapped with the anterior horn, was associated with low-grade, IDH-mutated/1p19q-codeleted tumors, as well as a neural transcriptomic signature and improved overall survival. Each LCN significantly coincided with multiple structural and functional connectivity networks, with LCN1 bearing an especially strong relationship with brain connectivity, consistent with its neural transcriptomic profile. Finally, we identified subcortical, periventricular structures with functional connectivity patterns to the cortex that significantly matched each LCN. These results build upon prior reports of glioma growth along white matter pathways, as well as evidence for the coordination of glioma stem cell proliferation by neuronal activity. Cumulatively, our findings support a model wherein periventricular brain connectivity guides glioma development from the subventricular zone into distributed brain regions.
NIMG-38. MEASURING ADHERENCE TO TRIPOD OF ARTIFICIAL INTELLIGENCE PAPERS IN THE GLIOMA SEGMENTATION
Authors: Tillmanns Niklas , Lum Avery , Brim W R , Subramanian Harry , Lin Ming , Bousabarah Khaled , Malhotra Ajay , cui Jin , Brackett Alexandria , Payabvash Sam , Ikuta Ichiro , Johnson Michele , Turowski Bernd , Aboian Mariam
Published: November 2021

PURPOSE

Generalizability, reproducibility and objectivity are critical elements that need to be considered when translating machine learning models into clinical practice. While a large body of literature has been published on machine learning methods for segmentation of brain tumors, a systematic evaluation of paper quality and reproducibility has not been done. We investigated the use of “Transparent Reporting of studies on prediction models for Individual Prognosis Or Diagnosis” (TRIPOD) items, among papers published in this relatively new and growing field.

METHODS

According to PRISMA a literature review was performed on four databases, Ovid Embase, Ovid MEDLINE, Cochrane trials (CENTRAL) and Web of science core-collection first in October 2020 and a second time in February 2021. Keywords and controlled vocabulary included artificial intelligence, machine learning, deep learning, radiomics, magnetic resonance imaging, glioma, and glioblastoma. The publications were assessed in order to the TRIPOD items.

RESULTS

37 publications from our database search were screened in TRIPOD and yielded an average score of 12.08 with the maximum score being 16 and the minimum score 7. The best scoring item was interpretation (item 19) where all papers scored a point. The lowest scoring items were the title, the abstract, risk groups and the model performance (items number 1, 2, 11 and 16), where no paper scored a point. Less than 1% of the papers discussed the problem of missing data (item 9) and the funding of research (item 22).

CONCLUSION

TRIPOD analysis showed that a majority of the papers do not score high on critical elements that allow reproducibility, translation, and objectivity of research. An average score of 12.08 (40%) indicates that the publications usually achieve a relatively low score. The categories that were consistently poorly described include the ML network description, measuring model performance, title details and inclusion of information into the abstract.
NIMG-45. DIFFUSION MRI AS AN EARLY BIOMARKER OF OVERALL SURVIVAL BENEFIT IN RECURRENT GLIOBLASTOMA TREATED WITH IMMUNE CHECKPOINT INHIBITORS
Authors: Hagiwara Akifumi , Jingwen Yao , Oughourlian Talia , Wang Chencai , Raymond Catalina , Everson Richard , Patel Kunal , Mareninov Sergey , Yong William , Salamon Noriko , Pope Whitney , Nghiemphu Phioanh , Liau Linda , Prins Robert , Cloughesy Timothy , Ellingson Benjamin
Published: November 2021

Diffusion magnetic resonance imaging (MRI) estimates of the apparent diffusion coefficient (ADC) has been revealed to be useful for predicting treatment response in patients with glioblastoma (GBM), with an increase in ADC indicating tumor cell death. The aim of the current study was to investigate whether quantitative changes in diffusion MRI after treatment with immune checkpoint inhibitors (ICI) could predict OS in patients with recurrent GBM. A total of 61 patients were included in this retrospective study with the following inclusion criteria: (i) diagnosis of recurrent GBM treated either with pembrolizumab or nivolumab and (ii) availability of diffusion data in pre- and post-ICI MRI. Tumor volume and median relative apparent diffusion coefficient (rADC) within enhancing tumor with respect to normal-appearing white matter were calculated. Median OS for all patients was 7.6 months (range, 1.0–30.6 months). Results showed that higher post-treatment rADC was associated with significantly longer OS (median, 372 days for rADC ≧ 1.42 versus 211 days for rADC < 1.42; P = 0.01, log-rank test), whereas tumor volume and pre-treatment rADC were not significantly associated with OS. Cox regression analysis revealed post-treatment rADC significantly influences OS (P = 0.02, univariate analysis), even after controlling for age, sex, and IDH status (P = 0.007, multivariate analysis), and additionally controlling for whether surgery was performed after ICI treatment (P = 0.049, multivariate analysis). In conclusion, a high post-treatment rADC may be an early imaging biomarker for identifying OS benefit in recurrent GBM patients receiving ICI treatment.
NIMG-49. A PROSPECTIVE, MULTI-CENTRE TRIAL OF FET-PET IN GLIOBLASTOMA PATIENTS - THE TROG 18.06 FIG STUDY: KEY ASPECTS OF IMAGING AND RADIATION ONCOLOGY CREDENTIALING
Authors: Koh Eng-Siew , Francis Roslyn J , Ebert Martin , Gan Hui , Lee Sze Ting , Lau Eddie , Moore Alisha , Grose Andrew , Rossi Alana , Ng Sweet Ping , Yap June , Ly Tam , Lin Peter , Pinkham Mark B , Ngai Stanley , Yu Christopher , Gorayski Peter , Le Hien , Kirkwood Ian D , Vallat Wilson , Syed Farhan , Krishna Dayanethee , Khan Shahroz , Gill Suki , Thomas Elizabeth , Back Michael , Barnes Elizabeth H , Moffat Bradford A , Scott Fiona , Adda Lucas , Foroudi Farshad , Lourenco Richard De Abreu , Nowak Anna K , Bailey Dale L , Scott Andrew M
Published: November 2021

The FIG study is a prospective non-randomised study now recruiting up to 210 newly diagnosed GBM participants across ten Australian sites. Study outcomes will address the role of [18F] fluoroethyl-L-tyrosine positron emission tomography (FET-PET) in radiotherapy (RT) planning, evaluation of post-treatment changes versus disease progression and prognostication. We describe here the methodology and preliminary outcomes for site credentialing. Eligible participants with GBM undergo FET-PET imaging at three time-points: FET-PET1-post-operative pre-chemo-RT, FET-PET2 acquired one month post-chemo-RT and FET-PET3 (+/-FDG-PET) triggered when clinical and/or radiological (MRI) progression is suspected. Dynamic and static FET-PET images are analysed qualitatively and quantitatively. Radiotherapy is as per standard care with the treating Radiation Oncologist (RO) blinded to FET-PET1. Site nuclear medicine (NM) physicians are required to delineate a biological target volume (BTV) based on FET-PET1 with hybrid RT volumes derived post-hoc. Pre-trial NM quality assurance comprises certification from the Australasian Radiopharmaceutical Trials Network encompassing FET-PET radiochemistry Quality Control and PET camera calibration. Site and central integrated workflows incorporating multi-modality image registration, target volume/region of interest contouring and analysis have been developed. NM benchmarking involves delineation of FET-PET BTVs in 3 cases with another 3 cases addressing response criteria interpretation harmonized across FET-PET, FDG-PET and MRI. Site ROs complete 3 cases involving standard and hybrid target volume delineation based on pre-derived FET-PET volumes. All NM and RO credentialing cases undergo central expert review. To date, of six sites which have submitted full credentialing data, 19/21 RO and 6/6 planning cases were passed. Of 72 NM cases, 18/72 (25%) required resubmission, primarily related to ensuring standardisation of background regions and time activity curve interpretation. The FIG study will be pivotal in establishing the role of FET-PET in GBM management. The robust NM and RO credentialing program will build capacity and expertise in FET-PET production, acquisition and image interpretation.
NIMG-53. RATIO OF T1-WEIGHTED TO T2-WEIGHTED SIGNAL INTENSITY AND IDH MUTATION IN GLIOMA
Authors: Kinoshita Manabu , Uchikoshi Masato , Takano Koji , Sakai Mio , Arita Hideyuki , Nakanishi Katsuyuki , Kanemura Yonehiro , Kishima Haruhiko
Published: November 2021

INTRODUCTION

Identifying IDH mutation status before treatment is essential for Lower-grade glioma (LrGG) treatment. We have previously revealed that IDH mutated LrGG consists of tumor tissues with significantly longer T1 and T2 relaxation time and is a useful radiological feature to identify IDH mutation status. The ratio of T1-weighted to T2-weighted signal intensity (rT1/T2) is a way to retrieve semi-quantitative relaxation time information of the tissue bypassing the need to perform relaxometry. This investigation aimed to elucidate the correlation between rT1/T2 and T1-, T2-relaxation time (-relax) in glioma tissue and to explore the possibility of rT1/T2 as a radiological surrogate marker to identify IDH mutation status in LrGG.

MATERIALS AND METHODS

We analyzed 8 LrGGs (IDHwt:4, IDHmt:2, IDHmt&1p19q-CODEL:2) in which relaxometry was performed. rT1/T2 maps were reconstructed as described in previous literature. Regions-of-interest were designed based on T2WI and FLAIR. The correlations between rT1/T2 and T1- and T2-relax were analyzed. Furthermore, We also investigated the correlation of IDH mutation status and rT1/T2.

RESULTS

106,488 voxels were analyzed. The correlation between rT1/T2 and T1- and T2-relax were rT1/T2=1.6e-0.0003T1-relax and rT1/T2=1.2e-0.002T2-relax (R=0.77 and 0.70). rT1/T2 of IDH-wildtype tumor was significantly higher than that of IDH-mutant tumor (1.0 vs. 0.75, p< 0.0001). Voxel-wise analysis of rT1/T2 map was able to discriminate IDH-wildtype tumor from the mutant tumor with an AUC of 0.82.

CONCLUSIONS

rT1/T2, which can be calculated from MRI acquired during routine clinical practice, is a promising radiological surrogate marker to identify IDH mutation status in LrGG.
NIMG-76. DISCRETE LOWER-GRADE GLIOMA (DLGG) VERSUS INFILTRATIVE LOWER-GRADE GLIOMA (ILGG): CORRELATION OF RADIOLOGICAL CHARACTERISTICS WITH CLINICAL OUTCOMES
Authors: Ali Khan Ahsan , Hamza Bajwa Mohammad , Khan Noman , Khalid Muhammad Usman , Mubarak Fatima , Ather Enam Syed
Published: November 2021

INTRODUCTION

Lower grade gliomas encompass grade 2 and 3 tumors. However, this term is more generalized and does not include the spectrum of radiological and tumor morphological patterns seen. Here we have established two distinct patterns of radiographic appearance seen within lower grade gliomas: ILGG and DLGG. Imaging plays a vital role in diagnosis, surveillance, characterization, and monitoring of intracranial tumors. Of particular importance is the differentiation of tumor features to reliably predict malignancy, tumor grade, possible molecular or genetic features, disease progression and recurrence, potential for malignant transformation, and postoperative outcomes. Our study will look at these radiographic characteristics of diffuse and infiltrating lower grade gliomas and discuss their predictive value. Understanding the distinct nature of these varieties of LGG will help us in surgical decision-making, prognostication, biopsy target and precision medicine.

METHODS

Pre-operative and post-operative MRI images of Grade 2 and 3 tumors were identified and analyzed in order to extract radiographic data, and correlated with patient demographics, clinical outcomes, extent of surgical resection, and molecular genetic analysis.

RESULTS

Out of 35 patients evaluated, 22 (62.9%) were labeled ILGGs and 13 (37.1%) were deemed DLGGs according to the pre-defined criteria. T2 habitat was higher in ILGG (mean = 2162) than DLGG (mean = 1482) as well as size, in cm (6.02 vs. 4.92). ADC habitat, lesion ADC, and percentage of the lesion that showed contrast-enhancement were similar. T2-FLAIR mismatch was significantly higher in ILGG (p = 0.02). Post-operative KPS scores were significantly higher in the DLGG group (p = 0.03).

CONCLUSION

T2-FLAIR mismatch can be a significant classifier for lower-grade gliomas. Our study shows there are differences in tumor morphology of diffuse and infiltrative lower-grade gliomas which can be correlated to outcomes after surgery.

*Indicates corresponding author.
NCMP-01. NOVEL BIOMARKERS FOR RADIATION-INDUCED NEUROTOXICITY
Authors: Makranz Chen , Lubotzky Asel , Zemmour Hai , Shemer Ruth , Glaser Benjamin , Cohen Jonathan , Maoz Myriam , Sapir Eli , Weizman Noam , Feldman John , Lossos Alexander , Dor Yuval , Zick Aviad
Published: November 2021

BACKGROUND

Brain radiotherapy is the main therapeutic modality for brain metastases (BM), but carries short and long term toxicities, termed radiation-induced neurotoxicity (RIN), and classified to acute, early-delayed and late-delayed RIN according to its time onset. Although diagnosis of RIN is crucial for patient management, there is an unmet need for sensitive biomarkers for RIN. Here we report on a novel non-invasive biomarker for detection and monitoring RIN. As radiotherapy is known to induce brain cells apoptosis as well as BBB disruption, we hypothesized that circulating cell free DNA fragments derived from dying brain cells will be elevated in the blood of patients with RIN. Using comparative methylome analysis we identified 13 genomic loci showing brain-specific DNA methylation patterns, including markers for neurons, oligodendrocytes, and astrocytes. We searched for these brain-derived cfDNA (bncfDNA) in plasma samples of patients following brain irradiation.

METHODS

We followed 24 patients treated by brain radiotherapy for BM by clinical and radiological examinations before, during and after treatment. In addition, we serially collected blood samples for DNA analysis, and correlated bncfDNA levels with clinical and radiological assessment.

RESULTS

Patient`s median age was 60 years. Most common primary tumor sites were breast (25%), lung (20.8%) and melanoma (12.5%). RIN was detected in 10 patients (62%). BncfDNA levels increased up to 292.4 fold in acute RIN, up to 138533.1 in early-delayed RIN, and up to 58.4 fold in late-delayed RIN. Resolution of RIN correlated with decrease in bncfDNA. Changes in bncfDNA levels were independent of tumor response and suggested to reflect both symptomatic and asymptomatic RIN.

CONCLUSION

Increase in bncfDNA levels characterizes RIN independent of tumor response. Thus, BncfDNA may serve as a novel biomarker for brain cells death incurred by radiotherapy. Further studies are required to explore the clinical utility of bncfDNA as a RIN biomarker.
NCMP-02. NEUROTOXICITY RELATED TO CAR T-CELL THERAPY IN PATIENTS WITH SECONDARY CENTRAL NERVOUS SYSTEM LYMPHOMA
Authors: Yuen Carlen , Wesley Sarah , Van Besien Koen , Hsu Jing-Mei , Reshef Ran , Iwamoto Fabio , Haggiagi Aya , Magge Rajiv
Published: November 2021

INTRODUCTION

Patients with secondary CNS lymphoma (SCNSL) were excluded from the pivotal trials that led to the approval of chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory (R/R) B-cell lymphomas due to concern for neurotoxicity (NT). Limited evidence exists for axicabtagene ciloleucel (axi-cel, Yescarta®) in SCNSL patients.

METHODS

In this retrospective study, 15 R/R lymphomas patients with SCNSL (14 DLBCL, 1 chronic lymphocytic leukemia) were treated with commercial axi-cel between March 2019 and April 2021 for systemic disease and assessed for NT using the Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) and CTCAE toxicity grading systems.

RESULTS

Seven of 15 patients (47%) developed NT, all of whom had cytokine release syndrome (CRS). Four (27%) developed severe NT (Grade III-IV). In the 8 patients (53%) with active SCNSL, 6 (75%) did not develop NT and 2 (25%) developed severe NT. In the 4 severe NT patients, all had multifocal CNS disease and 3/4 (75%) had leptomeningeal disease. Two thirds of patients previously treated with RT developed severe NT (1 whole brain RT, 1 skull base). The third patient had RT to the eye. Four of 8 (50%) patients with prior intrathecal chemotherapy developed severe NT. Five patients relapsed (3 in the CNS), none of whom had NT. At 11.7 month median follow-up, 8 patients remain alive, 5 are deceased (1 from NT, 3 from progression, 1 from infection), 2 lost to follow-up. The patient who died from NT had prior temporal arteritis. Three additional patients with autoimmune disease did not develop severe NT.

CONCLUSION

In this limited cohort, presence of SCNSL did not increase NT incidence compared to historical outcomes of CAR T-cell therapy patients without SCNSL. This cohort will be compared to CAR T-cell therapy patients without SCNSL. Prospective studies of CAR T-cell therapy in SCNSL patients will be informative.
NCMP-11. SPINAL CORD INFARCT AFTER CAR-T TREATMENT
Authors: Shah rusha , Venur Vyshak , McGranahan Tresa
Published: November 2021

Cortical and subcortical neurotoxicity from CAR-T therapy is a well described complication in literature, with over 40% of patients experiencing at least one neurologic side effect. However, spinal cord toxicity from CAR-T therapy is less well described. To our knowledge, this is the first reported case of a spinal cord infarct following CAR-T therapy. A 44 year old male with primary refractory DLBCL without CNS involvement, which was refractory to R-CHOP, R-ICE, and hyperCVAD part B underwent CD-19 CAR-T treatment. The day after infusion he developed grade 1 cytokine release syndrome (CRS) with fever and up trending inflammatory markers. Infectious work up was negative and he was treated with tocilizumab and dexamethasone. His fever resolved and markers down trended. On day 5 post CAR-T, he became encephalopathic, developed severe back pain, and was unable to move his bilateral lower extremities. He was treated with 2nd and 3rd doses of tocilizumab, dexamethasone and was started on anakinra. Patient’s mental status cleared by day 7 and he was found to have a dermatome sensory level at T10 with flaccid bilateral lower extremity paralysis. MRI Brain was unremarkable, but a spinal MRI showed longitudinally extensive cord edema and diffusion restriction at T10. Due to an initial question of transverse myelitis, he was treated with a 3-day course of IV methylprednisolone, with no improvement in symptoms. CSF studies were unable to be obtained due to his thrombocytopenia. Repeat MRI obtained 10 days after initial imaging showed resolution of cord edema, but continued areas of FLAIR hyperintensity at T10 through the conus. Despite aggressive rehabilitation services, four months later, patient remained paralyzed in his lower extremities with an indwelling foley catheter. He remains in a complete remission.
NCMP-21. IMMUNE-RELATED ACUTE MOTOR AXONAL NEUROPATHY: A SMALL CASE SERIES AND REVIEW OF THE LITERATURE
Authors: Pina Yolanda , Tran Nam , Verma Neha , Vogelbaum Michael , Forsyth Peter , Mokhtari Sepideh , Peguero Edwin
Published: November 2021

BACKGROUND

Immunotherapy revolutionized cancer treatment in the past decade, with a significant increased survival in patients with solid tumors. However, immune checkpoint inhibitors (ICIs) have been associated with a growing number of neurotoxicities, some of which can be fatal if not recognized and treated promptly. Some of these neurotoxicities include very uncommon syndromes like Acute Motor Axonal Neuropathy (AMAN). Herein we present four oncological cases of patients who underwent immunotherapy and developed AMAN.

METHODS

Four patients were diagnosed with immune-related AMAN between 2017 and 2000 at H. Lee Moffitt Cancer Center. Patients were treated with standard of care.

RESULTS

We describe four oncological patients who developed a motor axonal neuropathy (i.e., AMAN) confirmed on nerve conduction studies following 2 cycles of immunotherapy, including a 28 year old woman with melanoma brain metastasis and a 50 year old woman with renal cell carcinoma both treated with ipilimumab and nivolumab, a 32 year old man with Hodgkin lymphoma who was treated with nivolumab and brentuximab, and a 77 year old woman with renal urothelial cancer who was treated with pembrolizumab and cabozantinib. All four patients were promptly recognized as having immune-related neurotoxicity (irNs), were promptly treated (i.e., high dose steroids +/- IVIG +/- other immunomodulators), and significantly improved and have remained stable.

CONCLUSION

This is the first case series of patients with AMAN following two cycles of immunotherapy, who were successfully treated. It is crucial to develop a better understanding of irNs, including those rare conditions that are difficult to diagnose and treat, as the utilization of these immunomodulating therapies continues to expand to include other solid malignancies. Neurologists should be involved early on in any case of suspected irN to assist in the management of these complicated patients and a swift work up should be initiated for timely diagnosis and treatment.
NCOG-05. RISK FACTORS FOR PROLONGED LENGTH OF STAY AND POSTOPERATIVE COMPLICATIONS IN PATIENTS WITH INTRAMEDULLARY SPINAL CORD TUMORS
Authors: Kouam Romaric Waguia , Wang Timothy
Published: November 2021

INTRODUCTION

Primary spine tumors are rare neoplasms that affect about 0.62 per 100,000 individuals in the US. Intramedullary spinal cord tumors (IMSCTs) are the rarest of all primary tumors involving the spine and can cause pain, imbalance, urinary dysfunction and neurological deficits. These types of tumors oftentimes necessitate surgical treatment, yet there is a lack of data on length of stay and complication rates following treatment. Given that treatment candidacy, quality of life, and outcomes are tied so closely to these metrics, it is important to illustrate the risk factors for prolonged length of stay and their association with post-op complications with the ultimate goal of improving patient selection and preoperative optimization.

METHODS

The National Surgical Quality Improvement Program (NSQIP) database was queried for all patients undergoing surgery for treatment of intramedullary spinal cord tumors between 2005 and 2017. Univariate and multivariate analysis were performed to assess patient risk factor influencing prolonged length of stay and post-op complications.

RESULTS

A total of 638 patients were included in the analysis. Pre-operative American Society of Anesthesiology (ASA) physical status classification of 3 and above ( OR 1.89; p=0.0005), dependent functional status ( OR 2.76; p=0.0035) and transfer from facilities other than home ( OR 8.12; p< 0.0001) were independent predictors of prolonged length of stay ( >5 days). The most commonly reported complications were pneumonia (5.7%), urinary tract infection (9.4%), septic shock (3.8%), superficial incisional infection (5.7%), organ or space infection (5.7%), pulmonary embolism (11.3%), DVT requiring therapy (15.1%) and wound dehiscence (5.7%).

CONCLUSION

Our study demonstrated the significant influence of clinical variables on prolonged hospitalization of IMSCT patients. This should be factored into clinical and surgical decision making and when counseling patients of their expected outcomes.
NCOG-13. TUMOR-RELATED MOLECULAR DETERMINANTS OF NEUROCOGNITIVE DEFICITS IN PATIENTS WITH DIFFUSE GLIOMA
Authors: van Kessel Emma , Berendsen Sharon , Baumfalk Anniek , Venugopal Hema , Krijnen Eva , Spliet Wim , van Hecke Wim , Giuliani Fabrizio , Seute Tatjana , van Zandvoort Martine , Snijders Tom , Robe Pierre
Published: November 2021

BACKGROUND

Cognitive impairment is a common and debilitating symptom in patients with diffuse glioma and is the result of multiple factors. We hypothesized that molecular tumor characteristics influence neurocognitive functioning (NCF), and we aimed to identify tumor-related markers of NCF in diffuse glioma patients.

METHODS

We examined the relation between cognitive performance (executive function, memory and psychomotor speed) and intratumoral expression level of molecular markers, in treatment-naive patients with diffuse glioma. We performed a single-center study in a prospectively collected cohort, through a two-step design: (1) differential expression and gene set enrichment analysis (GSEA) to identify candidate oncogenetic markers for cognitive impairment in a hypothesis-free manner. Nineteen molecular markers of interest were derived from this set of genes as well as from prior knowledge; (2) correlation of cognitive performance (executive function, memory and psychomotor speed) to intratumoral expression level of these nineteen molecular markers, measured with immunohistochemistry.

RESULTS

After correcting for tumor volume and location, we found significant associations, between expression level of CD3 and IDH on the one hand with psychomotor speed on the other; between IDH, ATRX, BDNF, CSNK2B, EAAT1, GAT-3, SRF and memory performance; and between IDH, P-STAT5b, CSNK2B and executive functioning. P-STAT5b, CD163, CD3 and SEMA3 were independently associated after further correction for histopathological grade.

CONCLUSION

Several molecular characteristics of gliomas are independent determinants of patients’ cognitive functioning. This suggests that besides tumor volume, location and histological grade, variations in glioma biology influence cognitive performance through mechanisms that include perturbation of neuronal communication. These results pave the way towards targeted cognition improving therapies in neuro-oncology.