bluuebunny/crossref_metadata_2025 huggingface dataset:
PATH-27. INTRAOPERATIVE ASSESSMENT OF IDH MUTATION AS A SURROGATE FOR TUMOR INFILTRATION VIA DESORPTION ELECTROSPRAY MASS SPECTROMETRY IN GLIOMAS
Authors: Brown Hannah , Moniz-Garcia Diogo , Chen Rong , Jentoft Mark , Middlebrooks Erik , Chaichana Kaisorn , Quiñones-Hinojosa Alfredo , Cooks Robert
Published: November 2022

BACKGROUND

Despite advances in cancer biology, surgery and its extent of resection remains the most important prognostic modulator in gliomas, with the distinction between infiltrated and non-infiltrated tissues being an issue at the penumbra. Isocitrate dehydrogenase (IDH) mutation is unique to IDH-mutant glioma cells and can be used as a potential surrogate for tumor infiltration. Here we evaluate desorption electrospray ionization-mass spectrometry (DESI-MS) as a near real-time method for detecting infiltration at the margin of IDH-mutant gliomas.

METHODS

We conducted a prospective study in which DESI-MS analysis was performed on freshly obtained tissue biopsies to detect the presence of 2-Hydroxyglutarate (2HG), with subsequent review of each sample by a board-certified neuropathologist.

RESULTS

A total of 247 biopsies from a 49-patient study were previously collected and analyzed at Indiana University. Assessment of IDH mutation status of 71 core biopsies yielded sensitivity, specificity, and accuracy values of 89, 100, and 94%, respectively. Subsequent improvement of the method, including the measurement of 2HG relative to an internal control (Glutamate, Glu), allowed for detection of IDH-mutant infiltration at surgical margins. We have collected 183 biopsies (116 core and 67 margin) from 23 patients. Preliminary results of IDH mutation assessments of core biopsies indicate 93% sensitivity, 100% specificity, and 98% accuracy and margin biopsies indicate 88% sensitivity, 100% specificity, and 94% accuracy. Tumor infiltration at the margin of the surgical resection by detection of IDH-mut infiltration was detected in 88% of margin biopsies from IDH mutant tumors (30 of 34 biopsies).

CONCLUSION

We present a novel method to allow intraoperative evaluation of IDH mutation presence in glioma margin biopsies. Our method and its ongoing validation identified tumor infiltration beyond surgical margins and serves as a foundation for molecularly guided surgery in IDH-mut gliomas via DESI-MS.
PATH-31. ECDNA PROMOTES TUMORIGENICITY AND INTRATUMORAL HETEROGENEITY IN MEDULLOBLASTOMA
Authors: Chapman Owen , Sridhar Sunita , Wang Shanqing , Mesirov Jill , Chavez Lukas
Published: November 2022

Extrachromosomal circular DNA (ecDNA) is an important driver of aggressive cancers, including medulloblastoma (MB), the most common pediatric brain tumor. To assess the clinical importance of ecDNA in MB, we applied computational methods to detect ecDNA in the genomes of a cohort of 468 MB patients and 31 MB model systems. Among patients, ecDNA was detected in 18% of tumors and carried over twofold greater risk of mortality. Affected genomic loci harbor up to hundredfold amplification of oncogenes including MYC, MYCN, TERT, and other novel putative oncogenes. Between sequential patient biopsies at initial diagnosis and subsequent relapse, we observed structural variation at ecDNA loci and generation of new ecDNA sequences. Among model systems, ecDNA was found in 19 of 31 genomes (61%). Although ecDNA was far more prevalent among MB models than patients, the ecDNA genomic sequences were conserved between most patient-derived xenograft (PDX) models and the human tumors from which they were made. To elucidate the functional regulatory landscapes of ecDNAs in MB, we generated transcriptional (RNA-seq), accessible chromatin (ATAC-seq), and chromatin interaction (Hi-C) profiles of 6 MB tumor samples. In each case, we identified regulatory interactions that cross fusion breakpoints on the ecDNA, representing potential “enhancer rewiring” events which may contribute to transcriptional activation of co-amplified oncogenes. To test this hypothesis, we conducted an in vitro CRISPRi screen targeting regulatory regions on the ecDNA of a MB cell line and identified distal enhancers which promote proliferation. Using single-cell sequencing, we have also developed methods to explore intratumoral heterogeneity of ecDNA in a p53-mutant SHH MB patient tumor and its corresponding PDX model. In summary, our study analyzes the frequency, diversity, and functional relevance of ecDNA across MB subgroups and provides strong justification for continued mechanistic studies of ecDNA in MB with the potential to uncover new therapeutic approaches.
PATH-32. CONCORDANCE FOR CDKN2A/B LOSS AND TERT MUTATION IN WHO 2021 CLASSIFICATION GRADE 3 MENINGIOMAS: A RETROSPECTIVE STUDY
Authors: Yuen Carlen , Pan Peter , Teasley Damian , Miller Michael , Sun Yu , Canoll Peter , Joanta-Gomez Adela , Bargo Alicia , Iwamoto Fabio
Published: November 2022

BACKGROUND

The new WHO 2021 classification included CDKN2A/B loss and TERT mutation as new criteria for Grade 3 meningiomas, but excluded H3K27me3 loss. Malignant behavior may be influenced by DNA methyltransferases (DNMT3A). SUFU mutations may carry a predisposition for multiple meningiomas.

METHODS

In this retrospective study, 228 patients with Grade 2, Grade 3 or recurrent Grade 1 meningiomas with resections from 1990 to July 2021 at Columbia University Medical Center were assessed for recurrence, histologic features, and molecular alterations.

RESULTS

Of 228 patients with meningiomas, 9 were recurrent Grade 1, 9 were Grade 1 transformed to Grade 2, 109 were non-recurrent Grade 2, 77 were recurrent Grade 2, 13 were transformed Grade 2 to Grade 3, and 5 were non-recurrent Grade 3 and 6 were recurrent Grade 3. Median follow-up was 42.0 months. Of the recurrent/transformed tumors, 89 were radiation-resistant. Average mitotic counts for non-recurrent Grade 2 vs. recurrent/transformed Grade 2 and non-recurrent Grade 3 vs. recurrent Grade 3 meningiomas were 4 vs. 5, 24 vs. 27 mitoses/10HPF, respectively. Of 36 meningiomas evaluated with NGS, the most common alterations was NF2 (20/36). CDKN2A/B was lost in 5 meningiomas, three with Grade 2 that transformed to Grade 3 and two with recurrent disease. TERT was mutant in 3/36, 2 of which were Grade 2 that transformed to Grade 3 meningiomas. H3K27M me3 was tested by IHC in 4 patients, 3 with retained staining, all of whom did not recur and 1 with loss of staining in a Grade 1 transformed to Grade 2. DNMT3A was found in 2 tumors, both radiation-induced. SUFU occurred in 3/16, one of each grade, all solitary.

CONCLUSION

In our limited cohort, we observed concordance with the new WHO 2021 criteria for Grade 3 meningiomas
PATH-38. DISSEMINATED “MYXOID GLIONEURONAL TUMOR, PDGFRA P. K385-MUTANT” IN AN ADOLESCENT MANAGED WITH OBSERVATION AND WITHOUT ANY ADJUVANT THERAPY
Authors: Vanan Magimairajan Issai , Macdonald Patrick , Wachnian Cielle , Gianno Francesca , Drimes Tina , Sinha Namita , Hazrati Lili-Naz , Bonanni John
Published: November 2022

INTRODUCTION

Myxoid glioneuronal tumor, PDGFRA p. K385-mutant (MGNT) is a recently described central nervous system tumor entity typically arising from the septum pellucidum and molecularly defined by mutation of the PDGFRA oncogene. The tumor is clinically benign, can be disseminated at presentation and is managed by surgical resection with or without adjuvant therapy (Chemotherapy / Radiation). CASE REPORT: 16yr old female presented to the children’s emergency with 6-week history of increasing intensity of acute on chronic frontal headaches and single episode of seizure like activity. She did not have nausea, vomiting or any cognitive or visual disturbances. Neurological exam was normal with no evidence of papilledema. Magnetic Resonance imaging (MRI) of the brain showed a large intraventricular mass arising from the right lateral ventricle and the septum pellucidum with dissemination into the periventricular white matter, suprasellar region, right thalamus, genu and splenium of the corpus callosum and multiple foci seen in the inferior aspect of the brain stem involving the pons and medulla. There was no evidence of obstructive hydrocephalus and the spine was normal. After an initial endoscopic biopsy failed molecular testing, she underwent an open biopsy which confirmed the diagnosis of MGNT histologically and NGS testing of the tumor revealed mutation at codon 385 (leucine replacing lysine) in the PDGFRA oncogene (k385l). Since the tumor was disseminated and the headache was controlled with symptomatic treatment, she was managed with regular follow up without surgery, adjuvant chemotherapy or radiation. The patient is doing well at 8 months follow up without any symptoms and stable lesions on the MRI.

CONCLUSION

Based on our experience and literature review, MGNT with PDGFRA-k385l mutation is a clinically benign tumor even though it can be disseminated at presentation and can be managed conservatively without any adjuvant therapy.
PATH-45. INTRAEPIGLIOM - RAPID SEQUENCING-BASED DIAGNOSIS OF BRAIN TUMORS
Authors: Kubelt Carolin , Brändl Björn , van Bömmel Alena , Rohrandt Christian , Wang Gaojianyong , Evers Maximilian , Kolkenbrock Stephan , Wong Derek , Danso Dominik , Maicher Andre , Friedrichsen Sönke , Proescholdt Martin , Riemenschneider Markus , Jetzek Ulrich , Meissner Alexander , Yip Stephen , Kretzmer Helene , Synowitz Michael , Müller Franz-Josef
Published: November 2022

The intraoperative diagnosis of brain tumors remains a clinical challenge despite recent technological advances. The current clinical practice differentiates non-surgical brain tumors from those preferably treated with cytoreductive surgery employing intraoperative frozen section diagnostics. A detailed molecular diagnosis required for this classification task within the timeframe of a routine neurosurgical procedure is currently unavailable. We have analyzed a clinical cohort of several brain tumor entities using Nanopore long-read sequencing on two Oxford Nanopore Technologies sequencing platforms (MinION, PromethION). Since currently available molecular cancer classifiers such as the DKFZ methylation profiling classifier cannot be readily adapted to real-time sequencing analysis, we implemented a novel algorithm (MethyLYZR) to predict the underlying cancer type. Publicly available Illumina Infinium array data were used to train the classifier to distinguish 91 brain tumor classes. For validation of classification accuracy, we conducted a comprehensive validation strategy. Both nanopore platforms could sequence more than 5,000 pre-selected CpG within less than 20 minutes for most of our samples. When combining an optimized library preparation protocol with the time used for sequencing the minimal number of CpGs needed for classification, we saw sample-to-answer times of less than 1 hour – in many cases within 45 minutes - from receiving a fresh biopsy to a robust cancer type prediction. Comparing actual and predicted diagnoses resulted in a favorable error rate, indicating potentially highly clinical validity. Our real-time based molecular diagnostic algorithm enables, in most cases, a reliable diagnostic call within the timeframe of a typical neuro-oncological surgery. MethyLYZR as a predictive tool may allow us to adjust the surgical strategy and deliver the prognosis to our patients right after surgery, thus allowing for as-of-yet unexplored opportunities for the intraoperative application of individualized therapeutic modalities.
NIMG-04. LONGITUDINAL TRACKING OF PERITUMORAL EDEMA VOLUME USING PACS-INTEGRATED TOOLS PROVIDES CRITICAL INFORMATION IN TREATMENT ASSESSMENT OF NSCLC BRAIN METASTASES AFTER RADIOSURGERY
Authors: Kaur Manpreet , Petersen Gabriel Cassinelli , von Reppert Marc , Jekel Leon , de Santo Irene Dixe oliveira , Varghese Sunitha , Chiang Veronica , Aboian Mariam
Published: November 2022

PURPOSE

Brain metastases (BM) are the most common intracranial malignancies in adults and mostly originate from lung cancer. Gamma Knife (GK) has become standard of care for BM, however there is insufficient knowledge of the posttreatment volumetric changes of peritumoral edema of BM due to paucity of tools for volumetric segmentation in neuroradiology practice. Recently PACS-integrated tools have become available in select clinical practices facilitating the comparison of posttreatment peritumoral edema volume changes and 2D-based measurements of CE tumor core.

METHODS

Patients with NSCLC BM ≥ 10 mm on T1c+ treated with GK had volumetric measurements for up to 7 follow-ups using a PACS-integrated tool that segments the FLAIR hyperintense region surrounding and including the CE lesion. The 2D and volumetric measurements were compared by creating treatment response curves with incorporation of clinical information including steroid timing.

RESULTS

50 NSCLC BM were included. The median pretreatment peritumoral volume was 8.5 cm3 (IQR 1–47 cm3, n= 36). The volume significantly decreased at 0–90 days (median 1.2 cm3, IQR 0.5–6.1 cm3, n= 31) and between 0-90 and 91-180 days (median 0.8 cm3, IQR 0.3-2.3 cm3, n= 26) post-GK. The time of peak median peritumoral volume increase was at > 365 days (median 1.4 cm3, IQR 0.4–8.1 cm3, n= 19). There was a positive correlation between longest diameter (LD) and peritumoral edema volume (rs= .75, p< .05). At 181–270 days post-GK 50% of BM showed incongruent response course for LD and peritumoral edema volume. The congruence/incongruence ratio of edema/enhancing portion of BM changed over follow-up time.

CONCLUSION

Half of the BM in our study did not show congruent response when comparing posttreatment peritumoral edema volume course to CE lesions in longitudinal assessment. Therefore, there is a critical need for quantitative tools that are incorporated into clinical practice to assess peritumoral edema treatment response.
NIMG-07. APPLYING A GLIOMA-TRAINED DEEP LEARNING AUTO-SEGMENTATION TOOL ON BM PRE- AND POST-RADIOSURGERY
Authors: Kaur Manpreet , Varghese Sunitha , Jekel Leon , Tillmanns Niklas , Merkaj Sara , Bousabarah Khaled , Lin MingDe , Bhawnani Jitendra , Chiang Veronica , Aboian Mariam
Published: November 2022

PURPOSE

Stereotactic radiosurgery (SRS) has become the mainstay to treat BM. Follow-up MRI provides important information on lesion treatment response and guides future therapy planning. Volumetric measurements of BM have shown promise over traditional uni- and two-dimensional measurements in more accurate and repeatable assessment. However, routine clinical use has yet to be achieved because the workflow is laborious. In previous work, we developed a PACS-integrated deep learning algorithm for automatic high- and low-grade glioma 3D segmentation. In this work, we applied this U-Net to segment BM on pre- and post-Gamma Knife (GK) MRI and evaluated the performance.

METHODS

10 pre- and post-GK studies were autosegmented in five randomly selected patients (melanoma n= 3, breast n= 2). The glioma trained algorithm segmented the “Whole Tumor” (tumor core+peritumoral edema on T2w-FLAIR) and “Tumor Core” (CE tumor core+necrosis on SPGR). The AI generated segmentation was then revised as needed by a board-certified neuroradiologist and the dice-similarity-coefficient (DSC) between the revised and automatic volumetric segmentations were calculated.

RESULTS

Four patients had multicentric (2-4 BM) lesions. The mean± SD DSC for Whole Tumor and Tumor Core were 0.92±0.06 and 0.46±0.30 for pretreatment, 0.84±0.09 and 0.41±0.25 for posttreatment BM, respectively. The tool detected lesions with a sensitivity of 45% (5/11) for pretreatment and 50% (3/6) for posttreatment lesions. Three pretreatment and all posttreatment lesions that were not detected by the autosegmentation tool showed a very faint hyperintense peritumoral edema in T2w-FLAIR.

CONCLUSION

Volumetric segmentation of edema on FLAIR using the glioma-trained segmentation algorithm on pre- and post-GK BM did not require major adjustment of segmentation if it detects the lesion. On the other hand, with low sensitivity of lesion detection and low DSC for enhancing component, dedicated training of the algorithm on annotated BM data will be needed.
NIMG-14. RADIOLOGIC ASSESSMENT OF BRAIN METASTASES UNDERGOING LASER INTERSTITIAL THERMAL THERAPY (LITT)
Authors: Sanvito Francesco , Nagaraj Raksha , Sayari Jessica T , Rana Shivam , Raymond Catalina , Cho Nicholas S , Mozaffari Khashayar , Unterberger Ansley , Yang Isaac , Ellingson Benjamin
Published: November 2022

BACKGROUND

Laser Interstitial Thermal Therapy (LITT) is a novel treatment for brain metastases (BMs), and data regarding radiologic changes and long-term efficacy is sparse. This study explored volumetric changes in responding and non-responding BMs and their associations with lesion-specific progression-free survival (PFS-L).

METHODS

Patients with BMs treated with LITT were retrospectively enrolled. 3D volumes-of-interest of the contrast-enhancing BM tissue (CE) on pre-, post-LITT, and follow-up MRI scans were obtained. BMs were followed until progression or censoring. PFS-L was determined using the modified RANO criteria to assess treatment efficacy on each lesion.

RESULTS

Thirty-one BMs (from 30 patients) were preliminarily analyzed. 2 BMs had no follow-up scans. Median follow-up for 29 BMs was 248 days (range 28-2200). Median time to response was 430 days (responders n=7/29), median time to progression was 176 days (progressive disease n=7/29). Pre-LITT CE volume was a predictor of PFS-L (p=0.001), with BMs> 2.5 cc being 14 times more likely to undergo progression. Differences in age and primary tumor site did not impact PFS-L, whereas PFS-L tended to be longer in females (p=0.059), and in frontal and deep grey matter BMs (p=0.11). Post-LITT CE volume was higher than pre-LITT (p< 0.0001, median increase 59%), with no significant differences among responders, stable disease, and progressive disease. In each responding BM, the CE volume shrinkage over time was described by an exponential decay (R2 ranging 0.92-1.0 and half-life ranging 16.55-204 days). All responding BMs showed a pooled exponential decay with R2=0.88 and half-life=75.6 days.

CONCLUSIONS

Our data suggest that smaller BMs may have improved outcomes from LITT treatment. CE volumes may increase in the early post-procedural scans, possibly due to both inflammatory changes and thermal damage. The characterization of the volumetric changes across time for responding lesions may be useful for an early detection of BMs at risk for progression.
NIMG-18. A GROUND TRUTH COMPARISON OF PATHOLOGICALLY CONFIRMED GLIOBLASTOMA MARGINS TO CONTRAST ENHANCEMENT AT AUTOPSY
Authors: Lowman Allison , Bobholz Samuel , Brehler Michael , Duenweg Savannah , Kyereme Fitzgerald , Cochran Elizabeth , Coss Dylan , Connelly Jennifer , Mueller Wade , Agarwal Mohit , Banerjee Anjishnu , LaViolette Peter
Published: November 2022

PURPOSE

Glioblastoma is one of the most common and deadly adult brain tumors. Current standard treatment is surgical resection followed by radiation and concomitant chemotherapy (chemoRT). Glioblastoma progression is monitored using MRI, primarily relying on post-contrast T1-weighted imaging (T1C). Unfortunately, tumor invasion is known to extend beyond traditional contrast enhancement. T1-subtraction (T1S) maps have been introduced as a better tumor volume estimate. In this study we compare T1S map derived tumor annotations to a radiologist for identifying histologically confirmed tumor in patients with differing treatment histories at autopsy.

METHODS

Ten patients with autopsy confirmed glioblastoma and MRI within 1 month of death were recruited for this study. Seven patients received chemoRT combined (chemoRT+) and three patients received no treatment beyond surgery (chemoRT-). Patient’s brains were sliced axially in the same orientation as their final MRI using a patient-specific slicing jig. Large tissue samples were taken, processed, embedded in paraffin, stained for hematoxylin and eosin, and digitized at 40x resolution. Digital images were annotated for infiltrative tumor, pseudopalisading necrosis, and necrosis without palisading cells. T1S and radiologist annotations were created for each patient using their final MRI (mean 18 days prior to death). The annotated histology images were aligned and resampled into MRI space using custom software and the overlap of pathologically confirmed tumor and MRI derived annotations was compared.

RESULTS

T1S maps alone were significantly better at identifying areas of histologically confirmed tumor in chemoRT+ patients compared to chemoRT- patients (p=0.043). T1S derived annotations overlapped with 52% of histologically confirmed tumor in the chemoRT- patients and 78% in the chemoRT+. The radiologist drawn tumor masks were more accurate in chemoRT+ patients, identifying 61% confirmed tumor (trending, p=0.097, chemoRT+=61%).

CONCLUSION

These results demonstrate the difficulty of identifying pathologically confirmed tumor outside contrast enhancement in glioblastoma patients, even in the untreated state.
NIMG-19. IMAGE-BASED MODELING MAP OF EDEMA IS CORRELATED WITH MULTIPLE BLOOD-BRAIN-BARRIER PERMEABILITY RELEVANT TRANSCRIPTOMIC MARKERS IN BRAIN TUMOR PATIENTS
Authors: Jackson Pamela , Ranjbar Sara , Curtin Lee , Bond Kamila , Singleton Kyle , Hawkins-Daarud Andrea , Li Jing , Canoll Peter , Hu Leland , Tran Nhan , Swanson Kristin
Published: November 2022

Brain tumor associated edema is a significant cause of patient morbidity and mortality often requiring continual treatment with differing levels of success across patients. Edema is a broad term that can indicate increased local water as well as diffusely infiltrating tumor cells. Edema is visualized as hyperintense regions on T2-weighted (T2W) magnetic resonance imaging (MRI) and is typically associated with blood-brain barrier (BBB) breakdown and tumor aggressiveness. Understanding the molecular mechanisms driving imaging patterns of “edema” could provide insights into clinical imaging interpretation. We have an ongoing image-guided biopsy study that allows us to link biopsy molecular markers with locoregional MRI patterns of edema. Further, we previously developed a physics-based method to estimate edema abundance (i.e., edema map) from T2W MRIs. Our goal was to identify connections between BBB-associated molecular factors and edema abundance in brain tumors. Our cohort included 38 patients (female: 15, male: 23) with 129 image-guided biopsies (female: 62, male: 67). We correlated image-localized edema map values with the mean transcriptional frequency for 57 genes related to BBB function. Additionally, we examined correlations separately according to patient reported sex (i.e., male and female) and imaging phenotype (i.e., ENH: enhancing and NE: non-enhancing). We utilized multiple comparisons corrections with a 5% false discovery rate to determine significance. For the overall cohort, we observed significant positive correlations for the HIF1A (p< 0.001) and SOX2 markers with edema. For NE samples, significant correlations included APOE (p=0.001), HIF1A (p< 0.001), PIK3CA (p< 0.001), PTCH1 (p< 0.001), and SOX2 (p< 0.001). Amongst female samples, a significant correlation with PTCH1 (p=0.002) was observed. There were no significant correlations noted for male and enhancing sub-cohorts. Significant correlations between molecular markers of BBB and edema map values could lead to clinical biomarkers for edema or tumor aggressiveness.
NIMG-21. INTERIM ANALYSIS OF A PHASE II STUDY OF MULTIPARAMETRIC MR-GUIDED HIGH-DOSE RESPONSE-ADAPTIVE RADIOTHERAPY WITH CONCURRENT TEMOZOLOMIDE IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Kim Michelle , Aryal Madhava , Rosen Benjamin , Parmar Hemant , You Daekeun , Junck Larry , Leung Denise , Umemura Yoshie , Heth Jason , Al-Holou Wajd , Hollon Todd , Wahl Daniel , Lawrence Theodore , Cao Yue
Published: November 2022

BACKGROUND

Biologically-informed radiotherapy (RT) targeting an adversely prognostic hypercellular/hyperperfused imaging phenotype in patients with newly diagnosed glioblastoma (GBM) may improve outcomes by identifying emerging regions of treatment resistance associated with survival (OS), and is under investigation in an ongoing Phase II trial (NCT04574856) of individualized, response-adaptive RT.

METHODS

In this single-arm phase II study, patients with newly diagnosed GBM following resection undergo dose-intensified chemoradiation targeting the residual hypercellular (TVHCV, mean contralateral normal brain+2SD) and hyperperfused tumor volume (TVCBV, contralateral normal frontal grey matter+1SD) identified using high b-value diffusion-weighted and dynamic contrast-enhanced perfusion MRI. The combination of TVHCVCBV (TVHCVCBV) is treated to 50 Gy in 20 fractions (2.5 Gy/fraction), and following mid-RT reassessment, the persistent and developing TVHCVCBV is treated to 30 Gy in 10 fractions (3 Gy/fraction). The primary endpoint is improvement in OS, with planned interim safety analysis.

RESULTS

Since October 2020, 16 of 30 patients have been enrolled. Median age was 58 years (range, 29-75) and 69% were male. No patient underwent biopsy only, and 50% had gross total resection; 23% had MGMT methylated tumors. Median TVHCV/TVCBV was 6.9 cc (range, 1.9-42.8) pre-RT and 30% (range, 1-72%) was nonenhancing. By mid-RT, TVHCVCBV was reduced to 4.2 cc (range, 0.8-34.3) and 47% (range, 3-74%) was nonenhancing. The TVHCVCBV persisting from pre- to mid-RT was 2.3 cc (range, 0-24.2), with an additional 1.8 cc (range, 0.3-20.6) newly developing outside the initial region. All patients underwent adaptive replanning for boost without interruption. Planned interim analysis determined an acceptable rate of neurologic toxicity and safety to continue enrollment.

CONCLUSION

Individualized, response adaptive RT using an advanced imaging biomarker to assess emerging and especially non-enhancing regions of treatment resistance in patients with GBM is feasible, with short term safety in an early cohort and longer-term efficacy outcomes anticipated with ongoing accrual.
NIMG-22. AN AI-BASED COORDINATE SYSTEM ELUCIDATES RADIOGENOMIC HETEROGENEITY OF GLIOBLASTOMA VIA DEEP LEARNING AND MANIFOLD EMBEDDINGS
Authors: Yu Fanyang , Kazerooni Anahita Fathi , Toorens Erik , Akbari Hamed , Sako Chiharu , Mamourian Elizabeth , Bagley Stephen , Binder Zev A , Lustig Robert A , Brem Steven , O’Rourke Donald M , Ganguly Tapan , Bakas Spyridon , Nasrallah MacLean , Chaudhari Pratik , Davatzikos Christos
Published: November 2022

PURPOSE

There is evidence that molecular heterogeneity of glioblastoma is associated with heterogeneity of MR imaging signatures. Modern machine learning models, such as deep neural networks, provide a tool for capturing such complex relationships in high-dimensional datasets. This study leverages recent advances in visualizing neural networks to construct a radiogenomics coordinate system whose axes reflect the expression of imaging signatures of genetic mutations commonly found in glioblastoma.

METHODS

Multi-parametric MRI (mpMRI) scans (T1, T1-Gd, T2, T2-FLAIR, DSC, DTI) of 254 subjects with glioblastoma were retrospectively collected. Radiomics features, including histograms, morphologic and textural descriptors, were derived. Genetic markers were obtained through next generation sequencing (NGS) panel. A multi-label classification deep neural network was trained for predicting mutation status in key driver genes, EGFR, PTEN, NF1, TP53 and RB1. We utilized a nonlinear manifold learning method called Intensive Principal Component Analysis (InPCA), to visualize the output probability distributions from the trained model. The first three principal components (PCs) were selected for constructing the coordinate system.

RESULTS

The axes derived from InPCA analysis were associated with molecular pathways known to be implicated in glioblastoma: (1) Increasing values of PC1 were associated with primary involvement of P53 then RB1 then MAPK then RTK/PI3K; (2) Increasing values of PC2 were associated with primary involvement of RTK then RB1/P53/MAPK then PI3K; (3) Increasing values of PC3 were associated with primary involvement of MAPK then RB1/P53/RTK/PI3K. Imaging features significantly associated with each of three PCs (p< 0.05) were identified by Pearson correlation analysis.

CONCLUSION

Deep learning followed by nonlinear manifold embedding identifies a radiogenomics coordinate system spanned by three components which were associated with different molecular pathways of glioblastoma. The heterogeneity of radiogenomic signatures captured by this coordinate system offers in vivo biomarkers of the molecular heterogeneity of glioblastoma.
NIMG-26. UPTAKE OF [18F]GE-180 IN TSPO PET IS ASSOCIATED WITH SURVIVAL IN PATIENTS WITH RECURRENT GLIOMA
Authors: Quach Stefanie , Holzgreve Adrien , Kaiser Lena , Unterrainer Marcus , Dekorsy Franziska , Nelwan Debie V , Bartos Laura , Kirchleitner Sabrina , Weller Jonathan , Weidner Lorraine , Niyazi Maximilian , Ruf Victoria , Herms Jochen , Stöcklein Sophia , Wetzel Christian , Riemenschneider Markus J , von Baumgarten Louisa , Thon Niklas , Brendel Matthias , Rupprecht Rainer , Bartenstein Peter , Tonn Joerg-Christian , Albert Nathalie
Published: November 2022

OBJECTIVE

The 18 kDa translocator protein (TSPO) is expressed in both activated microglia and glioma cells. Elevated expression of TSPO has been reported to be associated with higher WHO grade. Here we analyze whether TSPO positron emission tomography (PET) signal using the tracer [18F]GE-180 is correlated with clinical outcome in a cohort of patients with recurrent glioma.

METHODS

Patients with suspected glioma recurrence received a [18F]GE-180 TSPO PET. All recurrent tumors were confirmed either by stereotactic biopsy or resection. Maximum standard uptake value SUVmax as well as tumor volume in MRI and, if available, in [18F]FET PET were evaluated together with patient characteristics (age, sex, Karnofsky-Performance score) and neuropathological features (WHO grade, IDH-mutation status). Uni- and multivariate Cox regression and Kaplan-Meier survival analyses were performed to identify prognostic factors for post-recurrence survival (PRS) and time to treatment failure (TTF).

RESULTS

88 consecutive patients were evaluated. TSPO tracer uptake correlated with tumor grade at recurrence (p< 0.05), with no significant differences between IDH-wildtype and IDH-mutant tumors. Within the subgroup of IDH-mutant glioma (n= 46), patients with low SUVmax (median split, ≤ 1.60) had a significantly longer PRS (median 41.6 vs. 25.3 months, p= 0.031) and TTF (32.2 vs 8.7 months, p= 0.001). Also among IDH-wildtype tumors (n= 42), patients with low SUVmax (≤ 1.89) had a significantly longer PRS (median not reached vs 8.2 months, p= 0.002). SUVmax remained an independent prognostic factor for PRS in a multivariate analysis including WHO grade, IDH status and age. Tumor volume defined by [18F]FET PET or contrast-enhanced MRI correlated weakly with TSPO tracer uptake. Treatment regimen did not differ between the subgroups.

CONCLUSION

Our data suggest that uptake of [18F]GE-180 in TSPO PET can add prognostic information in patients with recurrent glioma even in molecular defined subgroups and might serve as an imaging biomarker.
NIMG-27. THE PROGNOSTIC VALUE OF FET PET IN PATIENTS WITH RECURRENT GLIOMA TREATED WITH BEVACIZUMAB
Authors: Werner Jan-Michael , Winkels Myriam , Lohmann Philipp , Ceccon Garry , Wollring Michael , Tscherpel Caroline , Bauer Elena , Goldbrunner Roland , Stoffels Gabriele , Langen Karl-Josef , Fink Gereon R , Galldiks Norbert
Published: November 2022

BACKGROUND

After multiple recurrences in glioma patients, bevacizumab is frequently used as salvage therapy. In this group of patients, we evaluated the prognostic value of amino acid PET using O-(2-[18F]fluoroethyl)-L-tyrosine (FET) before initiation of bevacizumab.

METHODS

We retrospectively identified adult glioma patients at recurrence with (i) at least one or more previous recurrences, (ii) who were treated with bevacizumab, and (iii) who underwent FET PET imaging before bevacizumab initiation. Maximum and mean tumor-to-brain ratios (TBRmax, TBRmean), metabolic tumor volume (MTV), and dynamic parameters (i.e., time-to-peak, slope) were obtained from FET PET. Additionally, contrast-enhancing volumes on MRI were calculated. Threshold values of imaging parameters for evaluating the prognosis were established by ROC analyses using overall survival (OS) of ≥ 6 months as reference. The prognostic value of imaging parameters was subsequently evaluated using the log-rank test and multiple logistic regression analyses.

RESULTS

Twenty-eight patients (glioblastoma, 96%) with a median of 2 recurrences (range, 1-5) were eligible for data evaluation. The patients received a median number of 7 bevacizumab cycles (range, 1-27). The static FET PET parameter TBRmean was the best parameter (threshold, 2.1; AUC, 0.78; P=0.014) to identify patients with a significantly longer OS (8.2 vs. 4.9 months; P=0.044). In contrast, the MTV, contrast-enhancing volume, and dynamic FET PET parameters were not significant. TBRmean remained significant in multiple logistic regression analysis (P=0.031), indicating an independent predictor for OS.

CONCLUSION

Our data suggest that static FET PET allows identifying patients with longer OS before initiation of bevacizumab.
NIMG-29. ASSOCIATION OF PARTIAL T2-FLAIR MISMATCH SIGN AND ISOCITRATE DEHYDROGENASE MUTATION IN WHO GRADE 4 GLIOMA/GLIOBLASTOMA: RESULTS FROM THE RESPOND CONSORTIUM
Authors: Lee Matthew , Sako Chiharu , Patel Sohil , Mohan Suyash , Balana Carmen , Barnholtz-Sloan Jill , Sloan Andrew , Badve Chaitra , Poisson Laila , Griffith Brent , Booth Thomas , Palmer Joshua , Chakravarti Arnab , Bakas Spyridon , Nasrallah MacLean , Choi Yoon Seong , Dicker Adam , Flanders Adam , Shi Wenyin , Mahajan Abhishek , Colen Rivka , Marcus Daniel , Orringer Daniel , Davatzikos Christos , Jain Rajan
Published: November 2022

PURPOSE

T2-FLAIR mismatch (T2FM) is a highly specific imaging biomarker for isocitrate dehydrogenase (IDH) mutation in low-grade gliomas. Previous T2FM studies are inconsistent for glioblastoma (GBM)/grade-4 glioma, partly due to low IDH-mutation prevalence in high-grade gliomas. We leveraged a large multi-institutional GBM/grade-4 glioma cohort to analyze the association of partial T2FM and IDH-mutation (T2-hyperintense, FLAIR-hypointense, nonenhancing, nonedema).

METHODS

We analyzed preoperative MRI of 1500 pathologically confirmed GBM/grade-4 gliomas with known IDH-mutation status from the ReSPOND consortium, consisting of the following institutions (sample size): Ivy GBM Atlas Project (33), Catalan Institute of Oncology (132), Case Western Reserve University/University Hospitals (132), New York University (55), Ohio State University (25), University of Pennsylvania (641), University Hospital Río Hortega (16), Yonsei University Health System (118), The Cancer Imaging Archive (93), Thomas Jefferson University (48), Tata Memorial Hospital (22), University of Pittsburgh Medical Center (156), and Washington University School of Medicine in St. Louis (57). Sequences were co-registered to a common anatomic atlas. Continuous variables were compared by t-test and categorical variables by Χ 2-test.

RESULTS

71 (4.7%) were IDH-mutants, significantly younger (43±1 v. 62±12 years, p=5x10-37), and more likely to exhibit partial T2FM (20% v. 0.4%, p=1x10-43), frontal lobe predominance (68% v. 29%, p=7x10-12), nonenhancing components (T2/FLAIR-intermediate signal, nonedema; 45% v. 9%, p=1x10-22), and cystic components (smooth margins, no/minimal enhancement, homogeneous FLAIR suppression; 17% v. 3%, p=7x10-11) than IDH-wildtypes. 20 cases had partial T2FM (14 IDH-mutant, 6 IDH-wildtype). Sensitivity of partial T2FM for IDH-mutation was 19.7%, specificity 99.6%, positive predictive value 70%, and negative predictive value 96.1%. Subset analysis of 983 IDH-wildtypes with known MGMT methylation status (406 MGMT-hypermethylated) showed frontal lobe predominance was more common in MGMT-hypermethylated than MGMT-unmethylated (39.4% v. 24.3%, p=.02); other imaging characteristics did not significantly differ.

CONCLUSIONS

Partial T2FM is a highly specific imaging biomarker for IDH-mutation in GBM/grade-4 glioma.
NIMG-30. AI-BASED MOLECULAR CLASSIFICATION OF DIFFUSE GLIOMAS USING RAPID, LABEL-FREE OPTICAL HISTOLOGY
Authors: Hollon Todd , Jiang Cheng , Nasir-Moin Mustafa , Kondepudi Akhil , Chowdury Asadur , Al-Holou Wajd , Castro Maria , Lowenstein Pedro , Wadiura Lisa Irina , Widhalm Georg , Neuschmelting Volker , David Reinecke , von Spreckelsen Niklas , Berger Mitchel S , Golfinos John , Hervey-Jumper Shawn L , Camelo-Piragua Sandra , Lee Honglak , Freudiger Christian , Orringer Daniel
Published: November 2022

INTRODUCTION

Molecular classification has transformed the management of brain tumors by enabling more accurate prognostication and personalized treatment. Access to timely molecular diagnostic testing for brain tumor patients is limited, complicating surgical and adjuvant treatment and obstructing clinical trial enrollment.

OBJECTIVE

We aim to develop a rapid (< 90 seconds), AI-based diagnostic screening system that can provide molecular classification of diffuse gliomas and report its use in a prospective, multicenter, international clinical trial of diffuse glioma patients (n = 153).

METHODS

By combining stimulated Raman histology (SRH), a rapid, label-free, non-consumptive, optical imaging method, and deep learning-based image classification, we are able to predict the molecular genetic features used by the World Health Organization (WHO) to define the adult-type diffuse glioma taxonomy, including IDH-1/2, 1p19q-codeletion, and ATRX loss. We developed a multimodal deep neural network training strategy that uses both SRH images and large-scale, public diffuse glioma genomic data in order to achieve optimal molecular classification performance.

RESULTS

One institution was used for model training (University of Michigan) and four institutions (NYU, UCSF, Medical University of Vienna, and University Hospital Cologne) were included for prospective patient enrollment and model testing. Using our system, called DeepGlioma, we achieved an average molecular genetic classification accuracy of 93.2% and identified the correct diffuse glioma molecular subgroup with 91.5% accuracy. DeepGlioma outperformed conventional IDH1-R132H immunohistochemistry (94.2% versus 91.4% accuracy, respectively) as a first-line molecular diagnostic screening method for diffuse gliomas, detecting canonical and non-canonical IDH mutations with high accuracy.

CONCLUSION

Our results demonstrate how artificial intelligence and optical histology can be used to provide a rapid and scalable alternative to wet lab methods for the molecular diagnosis of brain tumor patients during surgery.
NIMG-39. AMINO ACID PET-MRI OF HIGH-GRADE GLIOMA
Authors: Harat Maciej , Rakowska Józefina , Harat Marek , Szylberg Tadeusz , Furtak Jacek , Miechowicz Izabela , Małkowski Bogdan
Published: November 2022

OBJECTIVE

MRI is gold standard for the diagnosis, surgery and radiation therapy of patients with high-grade glioma. Amino acid PET is useful in gliomas without contrast enhancement in MRI but it is unknown whether PET better identifies high-grade foci than T1-sequence with contrast enhancement or improve definition of high grade glioma infiltration related to T2/Flair images.

METHODS

More than 400 biopsy specimens from twenty-three patients with suspected high-grade glioma were examined in this prospective study. Patients meeting the inclusion criteria were referred for hybrid 18F-FET-PET-MRI before stereotactic biopsy. Biopsies were planned based on early FET-PET acquisition 5-15 minutes post injection and MRI. The following biopsy sites were determined in each case: (i) site of contrast enhancement and increased FET uptake; (ii) contrast enhancement but no increase in FET uptake; (iii) increased FET uptake but without contrast enhancement; and (iv) peripheral areas hyperintense in T2 FLAIR without increased FET uptake and contrast enhancement.

RESULTS

In 35% cases, the biopsy result was changed to a higher tumor grade after the inclusion of FET-positive sites. In all cases, high FET uptake was visualized and confirmed outside areas of contrast enhancement on MRI, indicative of high-grade glioma. Results from biopsies based on the FLAIR sequences corresponded to neoplastic lesions in 13 cases (57%), most often with a lower grade than in areas of high FET uptake.

CONCLUSIONS

FET-PET can be used to locate the most malignant areas of contrast-enhancing gliomas and impact the biopsy results. Surgery or radiotherapy planned solely on MRI images may miss parts of tumor presenting highest malignancy. Brain areas hyperintense in T2 FLAIR without increased amino acid uptake are not specific for malignancy in high grade gliomas.
NIMG-43. DIFFUSION BASIS SPECTRUM IMAGING DISTINGUISHES HIGH-GRADE GLIOMA TREATMENT EFFECT FROM TUMOR PROGRESSION
Authors: Han Rowland , Johanns Tanner , Blum Jacob , Ye Zezhong , Sun Peng , Lin Tsen-Hsuan , Kim Albert , Song Sheng-Kwei
Published: November 2022

BACKGROUND

Following standard-of-care chemoradiation therapy for high-grade glioma, it is often challenging to distinguish treatment changes from true tumor progression using conventional magnetic resonance imaging (MRI). Diffusion basis spectrum imaging (DBSI) uses a data-driven multiple-tensor modeling approach to disentangle specific histologic components and structural features present within individual imaging voxels, offering an opportunity to noninvasively differentiate treatment effect from tumor progression. This represents the first study of in vivo longitudinal DBSI for brain tumors in patients.

METHODS

Adult patients were prospectively recruited who met the criteria of known pathological diagnosis of high-grade glioma or glioblastoma (WHO grade III-IV) and undergoing or completing standard-of-care radiation therapy with concurrent chemotherapy. DBSI and conventional MRI data were acquired longitudinally beginning with a 4-week post-radiation therapy MRI until progression as defined by standard RANO criteria or biopsy. DBSI analyses were performed with isotropic diffusion profiles defined as restricted fraction (0 ≤ D ≤ 1.0 μm2/ms) and hindered fraction (1.0 < D ≤ 1.5 μm2/ms).

RESULTS

Eleven patients with contrast-enhancing high-grade gliomas were enrolled between June 2019 and March 2020, with final DBSI data obtained in November 2020. Of these, eight patients had tumor progression, two had treatment effect, and one had stable disease during the study period. Within the contrast-enhancing regions, the DBSI hindered fraction map demonstrated hypointensity for all cases of tumor progression, and hyperintensity for cases of treatment effect. DBSI-based biomarkers were present 0.7 to 12.0 months (median 2.4, IQR 2.8) before definitive diagnosis of treatment effect or tumor progression using conventional methods of MRI and/or biopsy.

CONCLUSIONS

DBSI hindered fraction can distinguish new contrast-enhancing lesions in the setting of high-grade glioma as treatment effect or tumor progression in advance of conventional MRI. Future work will incorporate machine learning algorithms to further improve DBSI-based predictions of tumor histopathology.
NIMG-45. DISTINGUISHING PROGRESSION FROM PSEUDOPROGRESSION IN GLIOBLASTOMA: COMBINED USE OF 18F-FLUCICLOVINE PET AND MULTI-PARAMETRIC MRI
Authors: Nabavizadeh Ali , Bagley Stephen , Ware Jeffrey B , Doot Robert K , Young Anthony , Ghodasara Satyam , Zhao Chao , Anderson Hannah , Schubert Erin , Carpenter Erica L , Till Jacob , Henderson Fraser , Pantel Austin R , Chen Isaac , Lee John Y K , Amankulor Nduka , O'Rourke Donald , Desai Arati , Nasrallah MacLean , Brem Steven
Published: November 2022

PURPOSE

Differentiation of tumor progression (TP) from pseudoprogression (PsP) is a major unmet need in post-treatment glioblastoma (GBM). 18F-Fluciclovine is a synthetic amino acid PET radiotracer with higher uptake in tumor tissue vs. areas of treatment-related change. We investigated the value of 18F-Fluciclovine PET for differentiating PsP from TP independent from and in combination with multi-parametric MRI.

METHODS

We prospectively enrolled 30 patients with GBM with a new or enlarging contrast-enhancing lesion on MRI after chemoradiotherapy who were planned for surgical resection of the lesion. Patients underwent pre-operative 18F-Fluciclovine PET and multi-parametric MRI. Following surgery, the relative percentages of viable tumor and therapy-related changes observed in histopathology were quantified. Patients were categorized as TP if viable tumor represented ≥ 50% of the specimen, mixed TP if < 50% and > 10%, and PsP if ≤ 10%.

RESULTS

18 patients had TP, 4 had mixed TP, and 8 PsP. Patients with TP/mixed TP had a significantly higher 40-50 minutes SUVmax (6.64 + 1.88 vs 4.11± 1.52, p=0.009) and an SUVmax cut-off of 4.66 provided 90% sensitivity and 83% specificity for differentiation of TP/mixed TP from PsP (AUC=0.856). A maximum cerebral blood volume (CBVmax) cut-off of 3.67 provided 90% sensitivity and 71% specificity for differentiation of TP/mixed TP from PsP (AUC=0.779). Combining a 40-50 minutes SUVmax cut-off of 4.662 and a relative CBVmax cut-off of 3.67 provided 100% sensitivity and 80% specificity for differentiating TP/mixed TP from PsP (AUC=0.95). The time activity curve patterns and time to peaks were not different between the groups. Normalization of PET parameters to normal brain parenchyma were not helpful to differentiate the groups due to variability in radiotracer uptake in normal brain between subjects.

CONCLUSION

18F-Fluciclovine PET uptake can accurately differentiate PsP from TP in GBM patients, with even more accurate differentiation achieved when combined with MRI.
NIMG-46. TOWARDS PREDICTING TUMOR AGGRESSIVENESS WITH RADIOPATHOMIC ANALYSIS OF MULTI-PARAMETRIC ANATOMICAL, DIFFUSION-WEIGHTED, AND METABOLIC MRI IN PATIENTS WITH NEWLY-DIAGNOSED GLIOMAS
Authors: Adegbite Oluwaseun , Tran Nate , Molinaro Annette , Phillips Joanna J , Ellison Jacob , Li Yan , Luks Tracy , Shai Anny , Nair Devika , Pedoia Valentina , Villanueva-Meyer Javier , Berger Mitchel S , Hervey-Jumper Shawn L , Aghi Manish , Lupo Janine
Published: November 2022

INTRODUCTION

Pathologically aggressive tumor biology can extend beyond the contrast-enhancing or non-enhancing anatomical lesions in patients with glioma. Identification of malignant regions can help guide diagnosis and subsequent treatment planning. This study leverages a unique multi-parametric MRI dataset with tissue samples of known spatial coordinates to noninvasively predict cellular proliferation (KI-67) and a novel index of tumor aggressiveness (TAI), that combines proliferation, cellularity, and tumor-score.

METHODS

420 tissue samples were collected from 162 patients with newly-diagnosed glioma (47% IDH-wildtype). Clinical imaging consisted of T2-weighted, T2-FLAIR, T1-weighted pre- and post-contrast images, and apparent diffusion coefficient (ADC) and fractional anisotropy (FA) from diffusion-weighted imaging. Mean normalized imaging metrics were quantified from 5mm spheres centered at the location of the tissue sample. A single spectrum was reconstructed at the location of each tissue sample from 3D 1H-MR Spectroscopic Imaging (MRSI) before quantifying normalized metabolite peak-heights for choline, creatine, NAA, lactate/lipid, and relative indices. Univariate mixed-effects linear regression models were employed and features with p< 0.2 were selected for subsequent model building. Support vector machine (SVM), random forest, and gradient boosting machine-learning algorithms were trained and tested on a ⅔-⅓ train-test split with 4-fold cross-validation in training to predict a high/low KI-67 and TAI.

RESULTS

Although none of the individual imaging metrics were significantly associated with KI-67 in the univariate analysis, all diffusion and several MRSI metrics (ncholine, nNAA, CNI, excess choline and creatine) were significantly associated with cellularity. Preliminary multivariate analyses to date suggest that the best radiopathomic model performance is achieved when an SVM was used along with T1-precontrast, nADC, and all metabolite levels (mean cross-validation AUC=0.73 and accuracy=.77).

CONCLUSION

Our results suggest that multi-parametric physiologic and metabolic MRI are useful for radiopathomic-mapping of tumor aggressiveness and are currently being optimized in a larger cohort.