bluuebunny/crossref_metadata_2025 huggingface dataset:
INNV-28. POTENTIAL EFFECTIVE CONSOLIDATION THERAPY WITH SINGLE AGENT IBRUTINIB FOR A CASE WITH PRIMARY CNS LYMPHOMA AFTER INITIAL HD-MTX AND RITUXIMAB INDUCTION THERAPY
Authors: Du Steven , Ko Uvin , Bota Daniela , Kong Xiao-Tang
Published: November 2021

INTRODUCTION

Primary CNS Lymphoma (PCNSL) is a rare and aggressive cancer that originates from lymphocytes and develops in the central nervous system. Standard induction therapy involves high-dose methotrexate (HD-MTX)-based chemotherapy, which achieves complete or partial response in most PCNSL patients. However, there is no standard consolidation therapy. We report one case in which ibrutinib, a Bruton’s tyrosine kinase inhibitor, replaced low-dose WBRT as consolidation therapy after induction by HD-MTX and rituximab. Ibrutinib treatment yielded good tolerance and further resolution of small residue lymphoma.

CASE REPORT

The patient is a 77-year-old female who presented with slurred speech, right-sided weakness, and difficulty word-finding in early 2020. Brain MRI found multifocal lesions, and biopsy of the largest lesion near the left lateral ventricle revealed diffuse large B cell lymphoma. The patient began HD-MTX at 6 g/m2 for the first cycle of induction therapy. She continued HD-MTX every two weeks, but dosage was reduced every cycle due to worsening renal function. Ultimately, MTX was discontinued after 6 cycles. Brain MRI showed significant response after HD-MTX except for small residue lymphoma at the biopsy area. 2nd line regimen rituximab and temozolomide was given to complete induction. Brain MRI was stable, but the small enhancing residue lymphoma at left peri-ventricle area was persistent after the induction therapy (uCR). Ibrutinib as consolidation therapy began after discussion with the patient. The patient tolerated 560 mg ibrutinib for 6 cycles initially, then switched to a reduced dose of 420 mg for cycles 7 and 8 due to neutropenia. Brain MRIs have been stable with resolution of the small lymphoma residue after 6 cycles of ibrutinib. The patient continues ibrutinib for the goal of one year of consolidation therapy.

DISCUSSION

Our case highlights the potential of single-agent ibrutinib as consolidation therapy for PCNSL after HD-MTX and rituximab/temzolomide induction therapy.
INNV-29. BILATERAL PARIETAL LYMPHOMA LESIONS RESPONDED DIFFERENTLY TO HD-MTX AND RITUXIMAB/TEMOZOLOMIDE THERAPY
Authors: Kong Xiao-Tang , Du Steven , Choi Yoon Jae , Bota Daniela
Published: November 2021

INTRODUCTION

Primary CNS lymphoma is a rare aggressive hematological malignancy. Current chemotherapy for induction phase is HD-MTX single agent or HD-MTX based combination regimen. We report a rare case whose left and right parietal lymphoma lesions in the brain responded to different induction therapy regimens during the induction phase.

CASE REPORT

A 43-year-old female presented with seizure and her brain MRI showed bilateral parietal brain lesions in January of 2020. Biopsy and work-up revealed primary CNS diffuse large B-cell lymphoma (DLBCL). The patient underwent HD-MTX therapy. Brain MRI showed clear progression of left parietal lymphoma but stable right parietal lymphoma after two cycles of HD-MTX at 8 g/m2. The treatment was switched to a rituximab 750 mg/m2 weekly and temozolomide 150 mg/m2 daily one-week-on and one-week-off regimen. After 8 weeks, her brain MRI showed nearly complete response of her left parietal lymphoma to rituximab/temozolomide but progression of her right parietal lymphoma. She was switched back to HD-MTX and completed total 8 cycles. Her right parietal lymphoma lesion showed complete response to HD-MTX. The patient is doing well and has been off the treatment over the past 10 months and is waiting for consolidation therapy with autologous stem cell transplantation that has been postponed due to the COVID pandemic.

DISCUSSION

Our case highlights the very rare heterogenous feature of primary CNS lymphoma responding to different treatment regimen. Biopsy of bilateral heterogeneous lesions may be indicated to compare the different molecular features of the lymphoma to find underlying mechanism if they respond to treatment differently. Specific treatment regimen should be selected based on the responsiveness of CNS lymphoma lesions or combination therapy is selected to cover the heterogeneous susceptibility to chemotherapy regimens.
INNV-32. ACCESS TO SPECIALTY RADIATION CARE FOR PATIENTS WITH RESECTABLE BRAIN TUMORS
Authors: Choi Mehee , Martin Brian , Zabramski Joseph , Misell Lisa , Brachman David
Published: November 2021

INTRODUCTION

Many patients with brain tumors face challenges with access to care. For rural patients, prolonged travel times may limit access to appropriate radiotherapy. Radiation centers (RCs) offering specialized brain radiotherapy, e.g., stereotactic radiosurgery (SRS), are geographically limited. Brain brachytherapy at the time of resection offers an option for such patients, but technical challenges have limited the adoption. To address the limitations of traditional brachytherapy, a device with Cs-131 seeds embedded in a bioresorbable collagen tile (GammaTile (GT), GT Medical Technologies, Tempe, AZ) was developed. The device is FDA-cleared for permanent implantation at the time of resection for all recurrent intracranial tumors and newly diagnosed malignant intracranial neoplasms. To investigate if wider availability of this treatment could possibly lower the geographic barrier to access to care, we mapped the US population against existing RCs with brain tumor expertise and neurosurgery centers (NSCs) performing craniotomies.

METHODS

We analyzed 2018 CMS claims data using CPT codes for single- and multi-fraction SRS to identify RCs with brain tumor treatment expertise and mapped these against the population. Using similar methodology, using CPT codes for craniotomies, we identified NSCs, as any facility performing craniotomies is potentially eligible to implant the device.

RESULTS

135 RCs used CPT codes for SRS. 193-, 119-, 82-, and 52-million Americans lived >30-, >60-, >90-, and >120-minutes from one of these centers, respectively. 530 NSCs preform craniotomies, including ≥ 1 in every state, a 4-fold increase over the number of RCs offering SRS.

CONCLUSIONS

For many patients, substantial travel distances limit access to RCs with brain tumor treatment expertise. In contrast, the 530 craniotomy-performing NSCs have far greater geographic dispersion. The option of undergoing brain radiation with GT implantation at the time of brain tumor craniotomy brings treatment closer to millions, ensures compliance, and reduces additional travel for follow-up radiation treatment.
INNV-33. THE IMPACT OF COVID-19 ON NEURO-ONCOLOGY CLINICAL TRIALS DURING WAVE 1 AND WAVE 2 AT A FRONTLINE DETROIT HEALTH CARE SYSTEM
Authors: Alton Joshua , Griffin Carmen , Wigand Amanda , Winters Kenneth , Krozek Emily , Scarpace Lisa , Walbert Tobias , Snyder James
Published: November 2021

In the wake of the Coronavirus disease outbreak (COVID-19), clinical trial operations were significantly impacted following the shutdown of elective healthcare services and even emergency operations. When the pandemic hit Detroit, Michigan in March 2020, the Hermelin Brain Tumor Center (HBTC) at Henry Ford Health System was consumed in COVID-19 emergency care which affected patient enrollment, conduct of trial activities, therapeutic treatment, deviation from protocol requirements, and sponsor-study site contact. The first Metro-Detroit COVID-19 case was confirmed March 10th 2020. At that time there were 18 active brain tumor clinical trials (phase 1 - phase 3) providing anti-cancer therapies. Trial modifications included decentralized operations to buildings with clinic and radiology access away from inpatient COVID-19 care, utilization of telemedicine for non-essential visits, shipping of investigational products to patient home, and in some cases utilization of local results in place of central histopathological confirmation. By April 2020, trials were ranked based on availability of alternative therapies and subject safety in 4 tiers that correlated with subject benefit and impact on care. Trials were given a prioritization level to commence enrollment with priority given to trials where no standard of care exists. Of the HBTC trials, one was graded Tier 1 and most were graded Tier 2. All patients already enrolled continued on study. As restrictions eased, trials were opened in a sequential manner. Changes that were made during the first wave of the pandemic helped to minimize its effect on clinical trial operation and enrollment during the second wave in Fall 2020. Thus, leading toward a decrease in trial deviations and increased enrollment during the 2nd wave. The changes made during the first wave helped to safely continue enrollment and treatment during the second wave and will have a longstanding impact on how clinical trials will be conducted in the future.
INNV-36. NON-INTRUSIVE, NON-INVASIVE AND PATIENT FRIENDLY FOCUSED ULTRASOUND DEVICE AS A DELIVERY VEHICLE FOR CNS TUMORS
Authors: Ramamurthy Bhaskar , Keralapura Mallika , Marshall John , Need Daniel , Dittamore Ryan , Kesari Santosh , Fonkem Ekokobe
Published: November 2021

A major impediment to treatment of brain cancers is the inability to transport drugs across the blood-brain barrier (BBB). The development of an effective, targeted, and non-invasive method to penetrate the BBB to deliver cancer therapeutics is an unmet need in the treatment of brain cancers. Large molecular weight chemo- and immuno-therapies such as doxorubicin and others may be potentially effective against brain cancers if such drugs are sufficiently bioavailable in the brain. Focused ultrasound techniques can safely and transiently open the BBB but current techniques require invasive/intrusive or expensive and high-touch procedures and are not optimal for wide adoption. To address this unmet need, we are developing an innovative technique to non-intrusively, non-invasively and transiently open the BBB in a specified location within the brain using guided ultrasound (US). Our device consists of a proprietary US generator that is controlled by a highly portable system that has a small physical footprint, enabling the US generator and system to be placed in confined spaces such as chemotherapy infusion centers. The US generator is cap-shaped device that is placed on a patient’s head that includes multiple sets of ultrasound transducers that are distributed within the cap according to the anatomy of the skull. With our proprietary technique, we calculate the position of the cap in relation to the internal anatomy in a real-time manner and in a non-intrusive and a non-invasive manner. We have recently concluded an extensive study that resulted in algorithms that can accurately guide the US to various targets within the brain across a spectrum of patients. We also have completed a pilot preclinical study on a large animal demonstrating our ability to open the BBB non-invasively and deposit a drug proxy (gadolinium and Evans Blue).
INNV-37. XCELSIOR: A REAL-TIME, REAL-WORLD LEARNING PLATFORM FOR PATIENTS WITH ADVANCED CANCER
Authors: Stuhlmiller Timothy , Shapiro Mark , Wasserman Asher , Osking Zachary , Shrager Jeff , Federowicz Bryan , Warner Matthew , Friedland Julie , Musella Al , Blondin Nicholas , Fonkem Ekokobe , Wong Eric , Kesari Santosh
Published: November 2021

xCures operates a direct-to-patient, real-world evidence platform for decentralized clinical research. The platform leverages a nationwide observational research protocol (XCELSIOR, NCT03793088) to aggregate, normalize, and analyze N-of-1 clinical outcomes to continuously learn from and inform treatment decisions. Individual data elements are extracted directly from medical documents such as clinic notes, and radiology, genomics, and pathology reports. The data elements are standardized to established biomedical ontologies and stored in a validated and part 11 compliant electronic database, suitable for statistical analyses and regulatory filings. This permits comparison of patient outcomes across institutions and removes the burden of data entry from oncologists and their staff. As an extremely efficient real-world data solution, we have utilized this platform to accelerate both academic- and commercial-sponsored clinical research, prospectively integrating diagnostics and algorithms with interventional treatments. For each patient that participates in XCELSIOR, artificial intelligence-powered clinical decision support algorithms suggest testing and treatment options. These options and supporting treatment rationales are sourced from key opinion leaders, tumor boards, clinical researchers, practicing oncologists, and published literature, and ranked using the real-world outcomes data from the registry. At the conference, we will present an overview of this real-time learning infrastructure and report on clinical case studies for pharma and non-profit groups including over 75 virtual tumor boards and real-world evidence generated from over 150 patients with CNS cancers that we have helped in partnership with Cancer Commons and The Musella Foundation for Brain Tumor Research and Education. Outcomes analyses stratified by therapeutic interventions and biomarkers will be reported, including frequency of adverse events, time to treatment failure, time to disease progression, and overall survival. Interventions include standard-of-care chemotherapies as well as therapies accessed by clinical trial, expanded access, and off-label prescription.
PATH-04. LEPTOMENINGEAL DISEASE IN PATIENTS WITH HISTONE-MUTANT GLIOMAS
Authors: Diaz Maria , Correia Carlos Eduardo Silva , Lin Andrew , Miller Alexandra , Pentsova Elena
Published: November 2021

INTRODUCTION

The 2016 WHO classification describes a subtype of midline gliomas harboring histone 3 (H3) K27M mutations, and the upcoming 2021 edition may include a new subtype of hemispheric diffuse gliomas with H3 G34R/V mutations. Since we began to perform molecular profiling at Memorial Sloan Kettering Cancer Center (MSKCC) we have observed an increased prevalence of leptomeningeal disease (LMD) in this population. However, the incidence and clinical behavior of LMD has not been well defined.

METHODS

This is a retrospective study of patients with H3-mutant gliomas at MSKCC diagnosed from 01/2012 to 02/2021, either by tumor biopsy or by cerebrospinal fluid (CSF). Histone mutations were identified through next-generation sequencing (NGS).

RESULTS

We found 40 patients (pts) harboring H3 mutations (K27M mutations in 31 pts, G34R/V in 8, and both in one), with 2/40 (5%) mutations identified through CSF NGS only and rest in tumor tissue. Median age was 20.5 years (4-70); 25 were male. Tumor location was midline for K27M-mutant tumors (thalamus [N=15], brainstem [N=10], spine [N=5], pineal gland [N=1]) and hemispheric for G34R/V-mutant tumors; tumor with both mutations was thalamic. LMD was diagnosed in 22/40 (55%) pts radiographically, including 19/31 (61%) of K27M-mutant pts and 3/8 (38%) of G34R/V-mutant pts (patient with both mutations did not develop LMD). At analysis, 10 patients remain alive. Median time from diagnosis to LMD was 8.8 months (0-44.4), with median OS of 6.5 months (0.3-34) after LMD diagnosis.

CONCLUSION

More than half of patients with histone-mutant gliomas develop LMD, including over a third of patients with G34R/V mutations. Neuroaxis imaging should be performed in conjunction with CSF studies in histone-mutant gliomas. Besides, CSF NGS represents an important tool to identify molecular profile of tumors when biopsy is not feasible or there is limited tissue for analysis.
PATH-07. INFRATENTORIAL HIGH-GRADE GLIOMAS: NEUROSURGICAL CASE SERIES WITH MOLECULAR ANALYSIS
Authors: Stopa Brittany , Truman Kyla , Villa Genaro , Peruzzi Pierpaolo , Gormley William , Iorgulescu Bryan , Smith Timothy
Published: November 2021

INTRODUCTION

Most high grade gliomas (HGG) are located supratentorially, while less than 1% arise infratentorially. Growing evidence suggests that infratentorial HGGs (iHGG) represent a collection of distinct molecular entities and that further elucidation of their molecular features can help guide management. We perform here a clinical and molecular analysis of our institutional iHGG case series.

METHODS

We retrospectively reviewed iHGG patients treated surgically at Brigham and Women’s Hospital (1992-2020), and evaluated their history of prior malignancies, tumor location, treatment, molecular profile, tumor recurrence, and survival. iHGG were identified by review of pathology records, using WHO Histologic Grading Criteria as grade III-IV gliomas located infratentorially. Molecular analysis data was obtained from pathology records.

RESULTS

Among 37 iHGGs, 16 (43%) were glioblastomas, 11 (30%) were anaplastic astrocytomas, 2 (5%) were diffuse midline gliomas, 2 (5%) were infiltrating gliomas, 2 (5%) were anaplastic ependymomas, 1 (3%) was an anaplastic oligodendroglioma, and 3 (8%) were HGG not otherwise specific. Sixteen (43%) patients were female, median age was 49 years. Fifteen patients had history prior malignancy, 11 of which received radiation and 8 chemotherapy. Surgical resection of iHGG included gross total resection in 4 (11%) and subtotal in 33 (89%). Twenty-one patients (57%) received adjuvant radiation and 19 (51%) chemotherapy. At follow-up, 13 (35%) patients demonstrated symptomatic deterioration, 15 (41%) were stable, and 7 (19%) were improved. Seven patients (19%) experienced recurrence at a mean time of 19 months, and one-year survival was 35%. Molecular analysis revealed 7/15 (47%) tumors were MGMT promoter methylated, IDH was mutated in 3/24 (13%), EGFR was amplified in 3/10 (30%), CDKN2A/B homozygous deletion in 4/7 (57%), TP53 was mutated in 14/15 (93%), and H3K27M was present in 4/10 (40%).

CONCLUSIONS

iHGGs demonstrate substantial distinction from their supratentorial counterparts. Herein we examined their clinical course, molecular features, management, and outcomes.
PATH-08. PROGNOSTIC IMPLICATIONS FROM LONG-TERM SURVIVORS (LTS) OF GLIOBLASTOMA
Authors: Briceno Nicole , Abdullaev Zied , Vera Elizabeth , Choi Anna , Christ Alexa , Grajkowska Ewa , Leeper Heather , Levine Jason , Lindsley Matthew , Reyes Jennifer , Boris Lisa , Burton Eric , Lollo Nicole , Panzer Marissa , Penas-Prado Marta , Pillai Valentina , Theeler Brett , Wu Jing , Polskin Lily , Papanicolau-Sengos Antonios , Quezado Martha , Aldape Kenneth , Gilbert Mark , Armstrong Terri
Published: November 2021

Glioblastoma (GBM) is the most aggressive primary brain malignancy with < 45% living a year beyond diagnosis which drops to 7% at five years. However, there have been reports of long-term survivors (LTS) living three to ten years beyond diagnosis. Few studies have reported on molecular factors in tumors from LTS cohorts. We identified GBM (IDH1/2 wildtype) patients living at least 3 years post diagnosis (N=25), including 16 with pre-treatment tumor tissue, from our Natural History Study. Available pre- or post-treatment tumors were analyzed with targeted panel sequencing and methylation analysis for classification, MGMT promoter status and copy number changes. Classical clinical prognostic features such as limited resection or older age did not preclude long-term survival as patients with tumor biopsy (n=1) or subtotal resection (n= 5) and patients > 60 were included in the LTS cohort. Furthermore, tumors with molecular features typically associated with poor prognosis were also in this GBM LTS group. MGMT promoter was unmethylated in 17% of tumors; EGFRvIII mutation in 13%, EGFR amplification in 33%, CDKN2A homozygous loss in 30% and complete chromosome 7 gain with 10 loss in 55%. Additionally, the methylation classifier found a higher-than-expected incidence of mesenchymal tumors (29%) and RTK II (57%). Tumors had a higher percent of TP53 mutations (44%) but lower pTERT (76%) compared to TCGA. These data suggest an individual patient’s prognosis cannot easily be predetermined based on classical clinical and molecular data. This underscores the need for further analyses to discover additional factors leading to their unexpected, prolonged survival and elucidate the role of factors typically associated with poor prognosis. Future work will include RNA-sequencing and germline whole genome sequencing to determine tumor specific gene expression and identify any possible genomic alterations that confer improved survival.
PATH-11. PDGFA INITIATES ABERRANT MITOSIS AND MALIGNANT TRANSFORMATION OF NEURAL PROGENITOR CELLS
Authors: Blough Michael , Omairi Hiba , Grisdale Cameron , Cairncross J Gregory
Published: November 2021

BACKGROUND

Imagining ways to prevent or treat glioblastoma (GBM) have been hindered by a lack of understanding of its pathogenesis. Although platelet derived growth factor-A (PDGFA) overexpression may be an early event, critical details of the biology of GBM, and tools to study its initiation have been lacking. Indeed, many PDGF-driven models replicate its microscopic appearance, but not genomic architecture. Recently, we reported an in vitro model of GBM initiation that overcomes this barrier to authenticity.

METHODS

We used a method developed to establish neural stem cell cultures to investigate the effects of PDGF-A on cells derived from the subventricular zone (SVZ), a putative region where the cells of origins for GBM are derived. We micro-dissect SVZ tissue from p53-null and wild-type adult mice, culture cells in media supplemented with PDGF-A, and assess cell viability, proliferation, mitotic capacity, and genome stability.

RESULTS

Paradoxical to its canonical role as a growth factor, we observe abrupt and substantial cell death in PDGF-A. Abnormal mitosis was the first observable alteration and occurred immediately in cells of both p53 wild-type and null genotypes: wild-type cells did not survive in PDGF-A, whereas a fraction of null cells evade apoptosis. Evading cells displayed attenuated proliferation accompanied by early chromosomal gains and losses. After approximately 100 days in PDGF-A, surviving cells suddenly proliferate rapidly, acquire growth factor independence, and become tumorigenic in immune-competent mice. Transformed cells continue to display highly abnormal mitotic phenotypes with complex karyotypes similar to GBM, had a neural progenitor cell (NPC) lineage profile, and were resistant to PDGFR-alpha inhibition.

CONCLUSION

Abnormal mitosis induced by PDGF-A initiates and perpetuates the genome instability that transforms p53-null neural progenitor cells to yield cancers with the types of recurring chromosomal gains and losses that characterize human GBM.
PATH-17. POSSIBLE ASSOCIATION BETWEEN OLIGODENDROGLIAL HISTOLOGICAL FEATURES OF IDHMUT/CODEL LOWER GRADE GLIOMAS AND PATIENT'S FAVORABLE PROGNOSIS, BUT NOT IN IDHMUT/NONCODEL AND IDH-WILDTYPE TUMORS
Authors: Pareira Eriel , Shibuya Makoto , Ohara Kentaro , Nakagawa Yu , Kanazawa Tokunori , Kamamoto Dai , Kato Yasutaka , Aimono Eriko , Yoshida Kazunari , Nishihara Hiroshi , Sasaki Hikaru
Published: November 2021

Comprehensive diagnostic using histological and molecular characteristics began to be implemented in WHO 2016 but the relevance of oligodendroglial histological features to patients’ prognoses is still controversial. To elucidate the connection between oligodroglial histology and patient’s prognoses we analyzed 93 LrGGs resected for about 2 decades were reassessed for histological features based on WHO2007 with special interest to pure oligodendroglial diagnosis (namely, oligodendroglioma or anaplastic oligodendroglioma) and presence of classic for oligodendroglioma (CFO) features. Those histological features, patients’ OS, and tumor chromosomal/genetic characteristics were correlated each other in each of the 3 IDH-1p/19q based molecular groups. The reassessed morphology-based diagnosis was shown to be most strict for astrocytic, but loosened for oligodendroglial tumors as compared with the original institutional diagnoses and WHO2016. The pure oligodendroglial diagnosis by reassessment was associated with longer OS in IDHmut/codel group, but not in IDHmut/noncodel and IDH-wildtype groups. The presence of CFO was not associated with patients’ OS in any molecular groups. Gain of 8q was associated with the oligodendroglial diagnosis in IDHmut/noncodel group. Neither the oligodendroglial diagnosis nor CFO was predictive for the methylation status of the MGMT gene in any of the 3 molecular groups. NGS of the IDHmut/codel tumors suggested that mutations in the FUBP1 and CIC genes might be associated with poor prognosis. The oligodendroglial histological feature is not independently predictive for either patients’ prognosis or chemotherapeutic response in LrGGs, except the oligodendroglial diagnosis in IDHmut/codel tumors.
PATH-30. RAPID AND LOW-COST LIQUID BIOPSY-BASED METHOD FOR SCREENING AND MONITORING OF GBM BY MASTER REGULATORY GENE MARKERS IN GBM STEM-LIKE CELLS
Authors: Tran David , Liu Tianyi , Le Son
Published: November 2021

BACKGROUND

Current liquid-based cancer screening relies on massive deep NGS to detect rare cancer-derived genetic materials - a costly method fraught with high false-negative and false-positive rates. We aim to develop a non-NGS-centered, AI-directed liquid-based detection of GBM stem-like cells (GSCs).

METHODS

Utilizing a robust AI suite, NETZEN, we defined a common master regulatory gene network (MRGN) of the GBM state in GSCs. Since master regulators (MRs) in MRGN are developmentally restricted, their chromosomal loci are accessible in GSCs but not in normal cells. Downstream factors in MRGN are massively overexpressed in GSCs compared to normal cells. Thus, we measured the following in PBMCs from healthy controls spiked with known quantities of GSCs and patients with GBM: 1) accessibility of MR genes using transposase/transposons carrying unique barcodes to be inserted into the MR’s predetermined accessible locations, and 2) expression of downstream factors using nested qRT-PCR.

RESULTS

We characterized 10 MRs in GSCs with ≥1 promoter region that is hypomethylated and accessible (by ATACseq) in GBM/GSCs per GSE70175-92460 (19 samples) and GSE67633-96088 (14 samples), or hypermethylated and inaccessible in lymphocytes/PBMCs per GSE98837 (6) and GSE74912 (13). Using barcoded transposons, we specifically disrupted 4 MR’s accessible foci only in GSCs, not in PBMCs. We also identified 50 downstream factors with the top 20 having 3 to 5-orders-of-magnitude higher mean expression in GSCs compared to PBMCs (GSE79362-86884, 451 samples). Currently our method has a detection limit of 0.2-1 GSC per 106 PBMCs. Using the first iteration, we detected MRGN of the GBM state in blood samples of 14 of 14 GBM patients before resection, compared to none of 15 healthy donors.

CONCLUSIONS

Chromosomal accessibility and signal amplification in MRGN of GSCs provide powerful substrates for a non-NGS, low-cost, liquid-based GBM detection system with high sensitivity and specificity. Further testing and optimization are ongoing.
PATH-36. INTRATUMOR HETEROGENEITY AND BIOINFORMATIC DIFFERENCES INFLUENCE MENINGIOMA MOLECULAR CLASSIFICATION
Authors: Vasudevan Harish , Choudhury Abrar , Hilz Stephanie , Villanueva-Meyer Javier , Chen William , Lucas Calixto , Braunstein Steve , Oberheim-Bush Nancy Ann , Butowski Nicholas , Pekmezci Melike , McDermott Michael , Perry Arie , Solomon David , Magill Stephen , Raleigh David
Published: November 2021

Molecular alterations such as CDKN2A inactivation and TERT promoter mutation are new criteria for grade 3 meningiomas in the 5th edition of the WHO Classification of Tumors of the Central Nervous System. However, consensus approaches to identify copy number variants (CNVs) and short somatic variants in meningiomas are lacking. Here, we performed integrated DNA methylation profiling, RNA-sequencing, and targeted DNA mutational profiling on 10 stereotactically-collected, regionally-distinct samples from 4 meningiomas. Targeted DNA sequencing revealed numerous private short somatic variants from multiple sites within individual meningiomas, including a TERT promoter mutation in only 1 of 2 samples from the same tumor. DNA methylation profiling revealed differences in biologic groups and immune cell enrichment between regionally-distinct samples within individual meningiomas. CNV status was evaluated using DNA methylation profiling and RNA sequencing on 14 stereotactically-collected, regionally-distinct samples from 2 meningiomas. Phylogenetic architectures from DNA methylation profiling and targeted DNA sequencing were highly concordant and shared 99.12% of CNVs while RNA sequencing identified only 39% of the CNVs called from DNA based approaches. Finally, CNV analysis based on single-cell RNA sequencing revealed partially overlapping CNVs across meningioma cells within an individual tumor, suggesting subclonal populations may influence CNV-based meningioma molecular classification and underlie limitations in defining CNVs from bulk RNA-sequencing. In sum, these data highlight the relative strengths and weaknesses of various approaches for molecular analysis of meningiomas complicated by intratumor heterogeneity due to non-tumor cells and subclonal populations of meningioma cells. Future efforts to incorporate molecular analysis into the diagnostic paradigm for meningiomas may require orthogonal validation across multiple platforms or image-guided meningioma sampling to select the most aggressive regions for molecular profiling.
PATH-37. DISTINCT GENOMIC SUBCLASSES OF HIGH-GRADE/PROGRESSIVE MENINGIOMAS: NF2-ASSOCIATED, NF2-EXCLUSIVE, AND NF2-AGNOSTIC
Authors: Williams Erik , Santagata Sandro , Wakimoto Hiroaki , Barker Fred , Brastianos Priscilla , Cahill Daniel , Ramkissoon Shakti , Alexander Brian , Juratli Tareq
Published: November 2021

BACKGROUND

Genomic studies of high-grade/progressive meningiomas have reported a heterogeneous mutation spectrum. Here, we present a genomic survey of one of the largest multi-institutional cohorts of high-grade/progressive meningiomas to date.

METHODS

850 high-grade/progressive meningiomas, including 441 WHO grade 2 and 176 WHO grade 3 meningiomas and 220 progressive WHO grade 1 meningiomas, were tested as part of a clinical testing program by hybridization capture of 406 cancer-related genes. Information from histopathology review and patient clinical data was assessed.

RESULTS

Genomic analyses converged to identify at least three distinct patterns of biologically-aggressive meningiomas. The first and most common contained NF2-mutant tumors (n = 426, 50%), was associated with male sex (64.4%, p = 0.0001) and often harbored additional mutations in CDKN2A/B (24%), and the chromatin regulators ARID1A (9%), and KDM6A (6%). A second group (NF2-agnostic) featured TERTp (n = 56) or TP53 mutations (n = 25) and were either NF2-mutant or wild-type, and displayed no association with either sex. The remaining group generally lacked NF2 mutations, and accounted for 40% of the cases-with three subgroups. One consistent primarily of grade 3 lesions harboring alterations in chromatin regulators BAP1 (n = 22) or PBRM1 (n = 16). A second subgroup contained AKT1 (n = 26), PIK3CA (n = 14) and SMO (n = 7) mutant skull-based meningiomas, and a third mixed subgroup included 237 meningiomas with a heterogeneous spectrum of low frequency and non-recurrent alterations.

CONCLUSIONS

Our findings indicate that the patterns of genomic alterations in high-grade/progressive meningiomas commonly group into three different categories. The most common NF2-associated canonical group frequently harbored CDKN2A/B alterations, which is potentially amenable to targeted therapies. An NF2-agnostic group harbored frequent TERTp and TP53 mutations. The final subclass, distinct from the canonical NF2 mutant associated pathway, was partly characterized by BAP1/PBRM1 alterations (rhabdoid/papillary histology) or skull-base disease.
PATH-40. SPORADIC NF2 WILD-TYPE MULTIPLE MENINGIOMAS HARBOR DISTINCT DRIVER MUTATIONS
Authors: Prilop Insa , Pinzer Thomas , Cahill Daniel , Brastianos Priscilla , Schackert Gabriele , Juratli Tareq
Published: November 2021

OBJECTIVE

Multiple meningiomas (MM) are rare and present a unique management challenge. While the mutational landscape of single meningiomas has been extensively studied, understanding the molecular pathogenesis of sporadic MM remains incomplete. The objective of this study is to elucidate the genetic features of sporadic MM.

METHODS

We identified nine patients with MM (n=19) defined as ≥2 spatially separated synchronous or metachronous meningiomas. We profiled genetic changes in these tumors using next-generation sequencing (NGS) assay that covers a large number of targetable and frequently mutated genes in meningiomas including AKT1, KLF4, NF2, PIK3CA/PIK3R1, POLR2A, SMARCB1, SMO, SUFU, TRAF7, and the TERT promoter.

RESULTS

Most of MM were WHO grade 1 (n= 16, 84.2%). Within individual patients, no driver mutation was shared between separate tumors. All but two cases harbored different hot spot mutations in known meningioma-driver genes like TRAF7 (n= 5), PIK3CA (n= 4), AKT1 (n= 3), POLR2A (n=1) and SMO (n= 1). Moreover, individual tumors differed in histologic subtype in 8/9 patients. The low frequency of NF2 mutations in our series stands in contrast to previous studies that included hereditary cases arising in the setting of neurofibromatosis type 2 (NF2).

CONCLUSIONS

Our findings provide evidence for genomic inter-tumor heterogeneity and an independent molecular origin of sporadic NF2 wild-type MM. Furthermore, these findings suggest that genetic characterization of each lesion is warranted in sporadic MM.
PATH-43. RAMAN SPECTROSCOPY AS A TOOL IN NEUROSURGERY
Authors: Borgmann Felix Kleine , Klamminger Gilbert Georg , Mombaerts Laurent , Klein Karoline , Jelke Finn , Mirizzi Giulia , Slimani Redouane , Pilot Michel , Husch Andreas , Mittelbronn Michel , Hertel Frank
Published: November 2021

BACKGROUND

Raman Spectra have been shown to be sufficiently characteristic to their samples of origin that they can be used in a wide range of applications including distinction of intracranial tumors. While not replacing pathological analysis, the advantage of non-destructive sample analysis and extremely fast feedback make this technique an interesting tool for surgical use.

METHODS

We sampled intractanial tumors from more than 300 patients at the Centre Hospitalier Luxembourg over a period of three years and compared the spectra of different tumor entities, different tumor subregions and healthy surrounding tissue. We created machine-learning based classifiers that include tissue identification as well as diagnostics.

RESULTS

To this end, we solved several classes in the intracranial tumor classification, and developed classifiers to distinguish primary central nervous system lymphoma from glioblastoma, which is an important differential diagnosis, as well as meningioma from the surrounding healthy dura mater for identification of tumor tissue. Within glioblastoma, we resolve necrotic, vital tumor tissue and peritumoral infiltration zone.We are currently developing a multi-class classifier incorporating all tissue types measured.

CONCLUSIONS

Raman Spectroscopy has the potential to aid the surgeon in the surgery theater by providing a quick assessment of the tissue analyzed with regards to both tumor identity and tumor margin identification. Once a reliable classifier based on sufficient patient samples is developed, this may even be integrated into a surgical microscope or a neuronavigation system.
PATH-45. APOLLO: RAMAN-BASED PATHOLOGY OF MALIGNANT GLIOMA
Authors: Lita Adrian , Sjöberg Joel , Filipescu Stefan , Celiku Orieta , Petre Luigia , Gilbert Mark , Noushmehr Houtan , Petre Ion , Larion Mioara
Published: November 2021

BACKGROUND

DNA methylation is an essential component for integrative diagnosis in glioma. Methylation subtype prediction of gliomas is currently done via sample extraction of high-quality of reasonable amount of DNA (~1ug), methylome profiling, followed by probe identification, curation and subsequent analysis via different random forest classifiers. However, the DNA methylation classification is not always available for all the samples.

METHODS

Raman Spectroscopy performed of the regions of interest using 1mm2 FFPE tissue spots from 45 patient samples with LGm1 to LGm6 methylation subtypes. Spectral information was then used to train a convolutional neural network (CNN) and develop a prediction algorithm. 70 % of dataset - model training while the remaining 30% for validation. Supervised wrapper methods and random forests were used to identify the top 109 most discriminatory Raman frequencies out of 1738.

RESULTS

We identified the most discriminatory features from these analyses and demonstrated that these frequencies show differential spectral intensities for these frequencies depending upon the glioma subtypes across the larger areas of the tissue. We compared the results of the Ward linkage clustering with the separation induced by the “frequency criterion”, an empirical observation that Raman spectra of tumor spots are characterized by intensities higher than 5000 on some of the frequencies from 1463 to 1473. For each of the 45 samples we ran Ward linkage clustering with a variable number of clusters (from 2 to 7), with the majority cluster corresponding to tumor spots and the others corresponding to (various types of) non-tumor spots. We found that the majority cluster matches very well the tumor spots characterized by the frequency criterion, The average accuracy over all samples was 90:3%, the average precision was 99:6% and the average recall was 90:2%. For most samples, two clusters were sufficient to distinguish between tumor and non-tumor spots with accuracy.
NIMG-04. PREDICTING THE BRAF MUTATIONAL STATUS IN PATIENTS WITH MELANOMA BRAIN METASTASES USING RADIOMICS - A BICENTRIC STUDY
Authors: Meissner Anna-Katharina , Gutsche Robin , Galldiks Norbert , Kocher Martin , Juenger Stephanie T , Eich Marie-Lisa , Wendl Christina , Goldbrunner Roland , Ruge Maximilian , Mauch Cornelia , Proescholdt Martin , Grau Stefan , Lohmann Philipp
Published: November 2021

BACKGROUND

The BRAF V600E mutation is present in approximately 50% of patients with melanoma and is an important prerequisite for a response to targeted therapies such as BRAF inhibitors. In the majority of patients, the BRAF mutational status is based on the analysis of tissue samples from the extracranial primary tumor only. Since the extracranial and intracranial BRAF mutational status may be discrepant, the additional information on the BRAF mutational status of melanoma brain metastases would be of clinical value, e.g., for the prediction of response to targeted therapies. Here, we evaluated the potential of MRI radiomics for the determination of the intracranial BRAF mutational status in patients with melanoma brain metastases.

PATIENTS AND METHODS

Fifty-nine patients with melanoma brain metastases from two university hospitals (group 1, 45 patients; group 2, 14 patients) were operated with subsequent genetic analysis of the intracranial BRAF mutational status. All patients underwent structural MRI preoperatively. Areas of contrast enhancement were manually segmented and analyzed. Group 1 was used for model training and validation, group 2 for model testing. After image preprocessing and radiomics feature extraction, a test-retest analysis was performed to identify robust features prior to feature selection. Finally, the best performing radiomics model was applied to the test data. Diagnostic performances were evaluated using receiver operating characteristic (ROC) analyses.

RESULTS

Twenty-two patients (49%) in group 1, and 6 patients (43%) in group 2 had an intrametastatic BRAF V600E mutation. Using the best performing six parameter radiomics signature, a linear support vector machine classifier yielded an area under the ROC curve (AUC) of 0.92 (sensitivity, 83%; specificity, 88%) in the test data.

CONCLUSION

The developed radiomics classifier allows a non-invasive prediction of the intracranial BRAF V600E mutational status in patients with melanoma brain metastases and may be of value for treatment decisions.
NIMG-09. DETECTION OF ASYMPTOMATIC MALIGNANT LESIONS BY [18F]FDG PET/MRI IN CHILDREN AND ADOLESCENTS WITH NEUROFIBROMATOSIS TYPE 1
Authors: Baumgartner Alicia-Christina , Platzgummer Hannes , Aszmann Oskar , Amann Gabriele , Berghoff Anna , Kasprian Gregor , Traub-Weidinger Tatjana , Azizi Amedeo A
Published: November 2021

BACKGROUND

Plexiform neurofibromas (PN) are a hallmark feature of Neurofibromatosis type 1 (NF1). 10% of PN undergo malignant transformation. As malignant peripheral nerve sheath tumors are a leading cause of death in NF1-patients, early detection of malignancy is essential. 2-deoxy-2-[ 18F]fluoro-D-glucose [18F]FDG PET/CT imaging is used in patients with NF1 to judge malignant transformation. AIMS: The present study evaluated [18F]FDG PET/MRI in pediatric NF1 patients at high risk for MPNST and its utility as a possible screening tool for malignant transformation of yet asymptomatic lesions.

METHODS

Patients aged 0-25 with symptomatic and asymptomatic neurofibromas who underwent PET/MRI from 2014 to 2021 were included. Chart review of imaging data, clinical and histological findings was performed retrospectively.

RESULTS

41 patients (18 female) with a median age at first PET/MRI of 16.87 years (6.21-24.41) were included. 40 lesions were operated as indicated by clinical (e.g. pain, rapid growth) or imaging findings. Based on histopathological analysis 7 lesions in 4 patients were categorized as malignant, 3 as atypical neurofibromatous neoplasms of uncertain biologic potential (ANNUBP). 4/7 malignant and 2/3 ANNUBP lesions were asymptomatic (i.e. without rapid growth, pain, neurologic dysfunction). 5/7 symptomatic tumors were without significant FDG-PET and proven benign by histology. 18 lesions (2 symptomatic) in 9 patients that showed an increased uptake suspect of malignant transformation were histologically classified as benign. None of the patients died during follow-up, 1 symptomatic MPNST patient received postsurgical radio- and chemotherapy.

CONCLUSION

Our data indicate that malignant transformation of PN also occurs in asymptomatic patients. [18F]FDG PET/MRI is feasible in pediatric and adolescent patients with the tumor predisposition syndrome NF1 and is an alternative to PET/CT when assessing for malignancy thereby drastically reducing radiation exposure. Early detection through screening of high-risk NF1 patients with [18F]FDG PET/MRI could potentially increase overall survival by facilitating early curative resection.
NIMG-28. PROSPECTIVE HISTOPATHOLOGY-VALIDATED MACHINE LEARNING FOR DISTINGUISHING TRUE PROGRESSION FROM TREATMENT-RELATED CHANGES IN GLIOBLASTOMA PATIENTS
Authors: Akbari Hamed , Kazerooni Anahita Fathi , Bakas Spyridon , Sako Chiharu , Mamourian Elizabeth , Rudie Jeffrey D , Shukla Gaurav , Bagley Stephen J , Desai Arati , Brem Steven , Lustig Robert A , Wolf Ronald L , Bilello Michel , O’Rourke Donald M , Mohan Suyash , Nasrallah MacLean , Davatzikos Christos
Published: November 2021

PURPOSE

Decision making about the best course of treatment for glioblastoma patients becomes challenging when a new enhancing lesion appears in the vicinity of the surgical bed on follow-up MRI (after maximal safe tumor resection and chemoradiation), raising concerns for tumor progression (TP). Literature indicates 30-50% of these new lesions describe primarily treatment-related changes (TRC). We hypothesize that quantitative analysis of specific and sensitive features extracted from multi-parametric MRI (mpMRI) via machine learning (ML) techniques may yield non-invasive imaging signatures that distinguish TP from TRC and facilitate better treatment personalization.

METHODS

We have generated an ML model on a retrospective cohort of 58 subjects, and prospectively evaluated on an independent cohort of 58 previously unseen patients who underwent second resection for suspicious recurrence and had availability of advanced mpMRI (T1, T1-Gd, T2, T2-FLAIR, DTI, DSC). The features selected by our retrospective model, representing principal components analysis of intensity distributions, morphological, statistical, and texture descriptors, were extracted from the mpMRI of the prospective cohort. Integration of these features revealed signatures distinguishing between TP, mixed response, and TRC. Independently, a board-certified neuropathologist evaluated the resected tissue by blindly classifying it in the above three categories, based on mitotic figures, pseudopalisading necrosis, geographic necrosis, dystrophic calcification, vascular changes, and Ki67.

RESULTS

Tissues classified as TRC by the neuropathologist were associated with imaging phenotypes of lower angiogenesis (DSC-derived features), lower cellularity (DTI-derived features), and higher water concentration (T2, T2-FLAIR features). Our ML model characterized TP with 78% accuracy (sensitivity:86%, specificity:70%, AUC:0.80 (95%CI, 0.68-0.92)) and TRC with 81% accuracy (sensitivity:80%, specificity:81%, AUC:0.87 (95%CI, 0.72-1.00)).

CONCLUSION

Our proposed ML model reveals distinct non-invasive markers of TP and TRC, directly associated with histopathological changes in prospective glioblastoma patients. Reliable stratification of TP and TRC entities may help to noninvasively determine whether the course of treatment should change.
NIMG-32. THE FEDERATED TUMOR SEGMENTATION (FETS) INITIATIVE: THE FIRST REAL-WORLD LARGE-SCALE DATA-PRIVATE COLLABORATION FOCUSING ON NEURO-ONCOLOGY
Authors: Baid Ujjwal , Pati Sarthak , Thakur Siddhesh , Edwards Brandon , Sheller Micah , Martin Jason , Bakas Spyridon
Published: November 2021

PURPOSE

Robustness and generalizability of artificial intelligent (AI) methods is reliant on the training data size and diversity, which are currently hindered in multi-institutional healthcare collaborations by data ownership and legal concerns. To address these, we introduce the Federated Tumor Segmentation (FeTS) Initiative, as an international consortium using federated learning (FL) for data-private multi-institutional collaborations, where AI models leverage data at participating institutions, without sharing data between them. The initial FeTS use-case focused on detecting brain tumor boundaries in MRI.

METHODS

The FeTS tool incorporates: 1) MRI pre-processing, including image registration and brain extraction; 2) automatic delineation of tumor sub-regions, by label fusion of pretrained top-performing BraTS methods; 3) tools for manual delineation refinements; 4) model training. 55 international institutions identified local retrospective cohorts of glioblastoma patients. Ground truth was generated using the first 3 FeTS functionality modes as mentioned earlier. Finally, the FL training mode comprises of i) an AI model trained on local data, ii) local model updates shared with an aggregator, which iii) combines updates from all collaborators to generate a consensus model, and iv) circulates the consensus model back to all collaborators for iterative performance improvements.

RESULTS

The first FeTS consensus model, from 23 institutions with data of 2,200 patients, showed an average improvement of 11.1% in the performance of the model on each collaborator’s validation data, when compared to a model trained on the publicly available BraTS data (n=231).

CONCLUSION

Our findings support that data increase alone would lead to AI performance improvements without any algorithmic development, hence indicating that the model performance would improve further when trained with all 55 collaborating institutions. FL enables AI model training with knowledge from data of geographically-distinct collaborators, without ever having to share any data, hence overcoming hurdles relating to legal, ownership, and technical concerns of data sharing.