bluuebunny/crossref_metadata_2025_split huggingface dataset:
PATH-26. COMPLEMENTARY CLASSIFICATION APPROACH TO RESOLVE LOW-SCORE RESULTS FROM THE DKFZ METHYLATION CLASSIFIER FOR CNS TUMOR DIAGNOSTICS
Authors: Singh Omkar , Pratt Drew , Abdullaev Zied , Quezado Martha , Aldape Kenneth , Cimino Patrick 
Published: November 2022

Abstract
DNA methylation-classification using the DKFZ CNS tumor classifier is highly useful, but experience indicates that approximately one-third of clinical cases do not reach the confidence threshold (0.84) for a definitive match. A low-confidence score can be observed for a variety of reasons, and addressing such instances is not always clear. We developed a complementary classification approach that differs from the DKFZ classifier in several important ways. First, it utilizes a new reference set of several thousand samples, utilizing the entire ~850k probe set on the EPIC array. Second an alternative classification approach, it establishes multiple (50) classifiers by dividing the probes into 50 independent bins, allowing dual measurements of both an overall confidence score, as well as a consistency score. To evaluate this approach, we first evaluated a set of well-classified samples (N=521, DKFZ family score &gt; 0.84) as ground-truth, showing that our bin-based approach was equivalent (100% accuracy) in well-classified samples. Second, we then evaluated a set (n=329) of samples that did not match to the 0.84 threshold on the DKFZ classifier. Using cutoff of 0.8 consistency score and 0.7 confidence score, we identified 99/329 cases with a match. To evaluate the potential ground-truth of our findings, orthogonal data was used to validate matches in our classifier. For example, many of our matches to GBM showed the expected abnormalities (combined +7/-10 CNV and TERT promoter mutation). Two cases that received low-score IDH-glioma matches by DKFZ matched to K27-altered-DMG in our classifier and were later shown to harbor the H3-K27M mutation. One case that received a low-score suggestion of GBM-MES on DKFZ matched in our classifier to PXA; this was then shown to harbor the expected BRAFV600E mutation. Overall, our method may add to and complement the DKFZ classifier as a means to resolve a subset of otherwise difficult-to-classify CNS tumors.
PATH-28. DIFFERENCES IN METHYLATION PROFILES BETWEEN LONG-TERM SURVIVORS AND SHORT-TERM SURVIVORS OF IDH WILD-TYPE GLIOBLASTOMA
Authors: van der Meulen Matthijs , Ramos Ronald , Voisin Mathew , Patil Vikas , Wei Qingxia , Singh Olivia , Climans Seth , Kalidindi Navya , Or Rosamarylin , Diamandis Phideas , Munoz David , Zadeh Gelareh , Mason Warren 
Published: November 2022

Abstract

INTRODUCTION
Patients with glioblastomas (GBM) have an overall survival (OS) of approximately 15 months. However, approximately 5% of patients survive much longer, with an OS of &gt; 5 years. This study examines the differences in methylation profiles between long-term survivors ( &gt; 5 years, LTS) and short-term survivors (&lt; 1 year, STS) with an isocitrate dehydrogenase (IDH) wild-type GBM.

METHODS
In a multicenter retrospective analysis, we identified 25 long-term survivors with a histologically confirmed GBM. These were age and sex-matched to a short-term survivor. The methylation profiles of all 50 samples were analyzed with EPIC 850k, classified according to the DKFZ methylation classifier, and the methylation profiles of all IDH wild-type LTS vs STS were compared.

RESULTS
After methylation profiling, 16/25 LTS and 23/25 STS were confirmed to be IDH wild-type GBMs, all with copy number gains of chromosome 7 and loss of chromosome 10. There were no significant differences between tumour purity or GBM subtype between LTS and STS. LTS had significantly increased MGMT promoter methylation (p = 0.01), and higher FGFR3-TACC3 (p = 0.03), compared to STS. STS had significantly more often a CDKN2A/B loss (p = 0.01) and higher levels of NF1 (p = 0.02), compared to LTS. There were no significant CpGs identified between LTS vs STS at an adjusted p-value of 0.05. Unadjusted analyses identified key pathways and biological processes involved in both LTS and STS. The top pathway in LTS was the Hippo signaling pathway and the Wnt pathway. The top pathway in STS was GPCR ligand binding and cell-cell signaling.

CONCLUSION
A small group of patients with IDH wild-type GBM survive more than 5 years. While there are few differences in the global methylation profiles of long-term survivors compared to short-term survivors, our study highlights potential pathways involved in aggressive and senescent GBMs.
PATH-30. BIOLOGIC AND CLINICAL SIGNIFICANCE OF NEOPLASTIC AND IMMUNE CELL STATES IN GROUP3 AND GROUP 4 MEDULLOBLASTOMA
Authors: Asanigari Saleembhasha , Mehani Bharati , Wu Di , Chung Hye-Jung , Aldape Kenneth 
Published: November 2022

Abstract
Medulloblastoma (MB) is a heterogeneous malignant childhood brain cancer, classified into four molecular subgroups, WNT, SHH, Group3, and Group4, based on transcriptional, genetic, and clinical features. We aimed to understand the tumor microenvironment of Group 3 and Group 4 tumors utilizing single-cell transcriptome data. We identified four neoplastic cell states, including stemness (TNF-α), proliferative, mesenchymal and quiescence, and 11 broad lymphoid and myeloid cell types from single-cell transcriptomes. We applied CIBERSORTx to enumerate cell type proportion and CODEFACS on 73 bulk MB RNAseq profiles to determine cell type-specific abundance and gene expression profiles. We noted significant associations (both positive and negative) between the abundance of neoplastic cell states and microenvironmental cell types in both group3 and group4 MB. For example, the invasive cell state negatively correlated with dendritic cells in Group3 and Group4 tumors, but the invasive cell state was oppositely correlated with a macrophage subset in group 3 versus group 4 tumors, Survival analysis showed a significant association of higher proliferative cell state with poorer survival in Group3 MB while in group4 elevated invasive cell state, as well as elevated α, NK, and CD4-T cell abundance showed trends for poorer prognosis. Using Ecotyper, we determined cellular ecotypes based on cell type-specific transcriptome states. An ecotype containing B cell, hematopoietic, dendritic, and proliferative cell states was associated with poor prognosis in group3 and group4 tumors. We further analyzed ligand-receptor interaction between cell type states of poor prognosis ecotype; and found several interactions between ligands from immune cells (SEMA4G, LAMB2) and receptors on neoplastic cells (PLXNB2). Conversely, extracellular matrix ligands on neoplastic cells (COL1A1/2 and FN1) were found on this analysis potentially associated with integrin receptors on immune cells. Overall, our study highlights the potential biologic and clinical significance of neoplastic and immune cell states in group3/4 MB.
PATH-35. HYPERMITOTIC MENINGIOMAS HARBOR DNA METHYLATION SUBGROUPS WITH DISTINCT BIOLOGICAL AND CLINICAL FEATURES
Authors: Choudhury Abrar , Chen William , Lucas Calixto-Hope , Magill Stephen , Raleigh David 
Published: November 2022

Abstract
Meningiomas are the most common primary intracranial tumors, and treatments for meningiomas are limited to surgery and radiotherapy. Clinically tractable biomarkers for meningiomas are under development, and multiple retrospective studies have reported genetic, epigenetic, or gene expression grouping schemes shedding light on meningioma biology, outcomes, or druggable dependencies. Here we report biologically distinct subgroups within the Hypermitotic meningioma DNA methylation group, validating an architecture that unifies contrasting theories of meningioma biology. To do so, we re-analyzed meningioma DNA methylation profiles from a discovery cohort (n=200) and an independent, consecutive validation cohort (n=365). Median follow-up was 5.6 years for 388/142/35 WHO grade 1/2/3 meningiomas. Copy number variants (CNVs) were calculated for all meningiomas, and RNA sequencing was performed on the discovery cohort. Unsupervised hierarchical clustering of β methylation values was performed on the discovery cohort, controlling for artifacts and inaccurate β methylation values due to the presence of CNVs. As previously reported, meningioma clustering was validated with the validation cohort and revealed 3 DNA methylation groups (Merlin-intact, Immune-enriched, or Hypermitotic) that were associated with distinct biological drivers, clinical outcomes, and therapeutic vulnerabilities. Further analysis using RNA sequencing revealed differential enrichment of FOXM1 target genes across 2 subgroups of Hypermitotic meningiomas. Gene expression programs in these subgroups were concordant with Proliferative or Hypermetabolic meningiomas reported by other investigators. Analysis of meningiomas by DNA methylation subgroup conserved biological features distinguishing DNA methylation groups, including CNVs deleting NF2, immune cell enrichment, or lymphatic gene expression. Analysis of clinical outcomes suggested subgroups may refine prediction of postoperative 5-year local freedom from recurrence (54.1% for Hypermetabolic vs 5.9% for Proliferative) or overall survival (82.2% for Hypermetabolic vs 21.8% for Proliferative) within DNA methylation groups. In summary, meningioma DNA methylation groups and the subgroups they harbor provide a framework unifying contrasting theories of meningioma biology.
PATH-39. A 44-YEAR-OLD FEMALE WITH DICER1-MUTANT PRIMARY INTRACRANIAL SARCOMA WITH IMAGING NEAR END OF LIFE
Authors: Lowman Allison , Winiarz Aleksandra , Bobholz Samuel , Kyereme Fitzgerald , Duenweg Savannah , Coss Dylan , Cochran Elizabeth , Charlson John , Connelly Jennifer , LaViolette Peter 
Published: November 2022

Abstract
DICER1-mutant intracranial sarcomas were recently defined by WHO in the 2021 CNS tumor classifications. Currently there is a lack of literature describing the clinical nature of this disease. Here we present a case of primary intracranial sarcoma with DICER1 mutation and unknown etiology. A 44-year-old female presented with aphasia and right-sided weakness. Clinical imaging confirmed the presence of a hemorrhagic mass in the left frontal lobe and superior falx. The patient underwent two surgical resections, but a clear diagnosis was difficult to make due to heterogenous histological features and inconclusive genomic testing. The surgical samples were sent to the National Institute of Health where genetic testing indicated a DICER1 E1813D mutation with high allele frequency (97%), a TP53 mutation with high allele frequency (95%), and a high variant allele frequency NF1 splice site mutation (96%). This resulted in a diagnosis of DICER1-mutant primary intracranial sarcoma. The patient was treated with temozolomide, bevacizumab, and CPT-11. 382 days after the mass was originally identified, the patient died. A detailed analysis of the radiographic images was performed by creating T1-weighted post-contrast enhancement maps (T1C) and T2-weighted fluid attenuated inversion recovery (FLAIR) hyper-intensity maps for each timepoint. We plotted these volumes over time alongside the patient’s treatment history. Large spikes in T1C and FLAIR volume were seen 4 days prior to initiation of temozolomide and 31 days after CPT-11 treatment was ended. At the final clinical MRI, both volumes were about 4 times greater than that of the initial scan. Despite this disease’s aggressive nature, it can be difficult to accurately diagnose, due in part to very few studies investigating the clinical features of this rare tumor. With the addition of this diagnosis to WHO CNS5, future studies should examine the behavior of these tumors, aiding in earlier diagnosis and improvement of treatment guidance.
PATH-41. THE DEVELOPMENT OF PRIMITIVE NEURONAL COMPONENT AT FIRST PROGRESSION OF MALIGNANT GLIOMA, A CASE SERIES
Authors: McGranahan Tresa , Costanza Katelyn , Cimino Patrick 
Published: November 2022

Abstract
A subset of malignant gliomas are found to have solid-looking primitive nodules which confer a diagnosis of glioblastoma with primitive neuronal component (GBM-PNC). These tumors are associated with higher rates of isocitrate dehydrogenase (IDH) mutations and increased responsiveness to platinum-based therapies, however they are also associated with a high rate of cerebrospinal fluid (CSF) dissemination. We review four patients treated at our institution with a prior diagnosis of malignant glioma who were found to have GBM-PNC at resection of recurrent disease and evaluate the clinical significance of the development of a primitive neuronal component. Of the 4 patients, 3 had previously been diagnosed with glioblastoma with a disease-free interval after radiation and temozolomide of 17.8 years, 2.4 years, and 1.6 years. The 4th patient was diagnosed 2 years prior with a WHO grade 2 IDH mutant astrocytoma and had only been treated surgically prior to disease progression. At recurrence, all patients developed cystic masses adjacent to prior surgical site in frontal lobe and/or temporal lobe. While no patients had spinal cord symptoms, as a result of the primitive component found at re-resection 3 out of 4 patients underwent spinal cord imaging. Two patients were found to have cauda equina enhancement favored to represent CSF dissemination. This is in line with the 40% CSF dissemination reported in other case series of diagnosis of GBM-PNC and far greater than 1.1% reported for glioblastoma. In this case series, the of development of primitive neuronal component at malignant glioma recurrence was associated with radiographic appearance of a cystic mass with significant vasogenic edema as well as high rates of CSF dissemination. The clinical implication of platinum responsiveness will also be presented.
PATH-42. DIAGNOSIS AND PROGNOSTICATION OF AN ATYPICAL ADULT PRESENTATION OF DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMOR (DLGNT) BY METHYLATION PROFILING
Authors: Karbhari Nishika , Thomas Alissa 
Published: November 2022

Abstract

BACKGROUND
Diffuse leptomeningeal glioneuronal tumors (DLGNT) are rare central nervous system tumors first described in the 2016 WHO classification. A paucity of data exists on this tumor. This case describes an adult presentation of DLGNT, a classically pediatric tumor, and highlights the importance of genetic and epigenetic analyses in neuro-oncologic diagnoses. CASE: A 22-year-old male presented with shoulder paresthesias and back pain, progressing to bilateral leg weakness. Spine MRI demonstrated an enhancing intramedullary T8 lesion, prompting urgent laminectomy and resection. Frozen section suggested a glial neoplasm. Four-month follow-up MRI spine showed leptomeningeal dissemination at the C-spine and caudal thecal sac. CSF analysis revealed 110 mg/dL protein, 2 cells/mcl, and negative cytology. NCI methylation profiling demonstrated 1p deletion and KIAA1549:BRAF fusion, consistent with DLGNT, subtype 1, with MAPK pathway activation; Ki-67 index was 30%. Treatment with binimetinib was initiated. After 1 month of therapy, the patient is tolerating treatment and strength is improving.

DISCUSSION
This case describes a rare presentation of a rare tumor. DLGNT, subtype 1, has a median age of diagnosis of 5 years and an indolent course. We describe an adult patient with molecular features consistent with DLGNT subtype 1, but a high proliferative index suggesting a more aggressive growth potential. In this case, methylation profiling aided in diagnosing the tumor type and guided treatment. The KIAA1549:BRAF fusion is an activating mutation in the MAPK pathway, and binimetinib was selected as a MEK inhibitor with high CNS penetration. To our knowledge, this is the first case of an adult-onset DLGNT treated with binimetinib. Based on our single patient experience, we would advocate for methylation profiling for rare CNS tumor entities.
PATH-46. COMPUTATIONAL HISTOPATHOLOGY INFORMED RAPID TARGETED NANOPORE SEQUENCING ENABLES AFFORDABLE NEXT DAY REPORTING OF COMPREHENSIVE MOLECULAR MARKERS FOR CNS TUMOUR DIAGNOSTICS
Authors: Patel Areeba , Dogan Helin , Jung Alexander , Seferbekova Zaira , Payne Alexander , Ritter Michael , Schrimpf Daniel , Stichel Damian , Hamelmann Stefan , Blume Christina , Euskirchen Philipp , Goidts Violaine , Sill Martin , Pfister Stefan , Loose Matthew , Wick Wolfgang , von Deimling Andreas , Jones David T , Schlesner Matthias , Gerstung Moritz , Sahm Felix 
Published: November 2022

Abstract

BACKGROUND
Integrative brain tumour diagnostics indisputably requires comprehensive reporting of molecular markers. The 2021 WHO classification of central nervous system (CNS) tumours substantially increased the set of markers for routine evaluation, with greater significance to DNA methylation analysis in diagnostics. Limited by investment and batching, smaller labs and clinics might suffer major delays in delivering clinical decisions. To make precision diagnostics accessible, we introduce an integrated computational histopathology and adaptive nanopore sequencing workflow for next day CNS tumour diagnostics.

METHODS
We used CNS-CHiP- a multitask deep transfer learning model to predict key molecular alterations and methylation classification from H&E stained CNS tumour slides. For further characterisation and subtyping, we used the predictions to formulate a custom panel for each patient. Targeted sequencing and analyses were performed using Rapid-CNS2- a custom neurooncology nanopore sequencing pipeline for parallel copy-number, mutational and methylation analysis that is flexible in target selection with no additional library preparation and can be initiated upon receipt of frozen sections. Sequencing was performed on a portable MinION or GridION.

RESULTS
We demonstrate our workflow on diagnostic samples received by the Department of Neuropathology, University Hospital Heidelberg. CNS-CHiP predicted multiple pathognomonic alterations (eg. IDH mutation, 7 gain/10 loss) with reasonable accuracy. This provided basic information regarding the tumor type instantly. Personalised panels enabled small target sizes, resulting in low sequencing time (up to 24h) and competitive costs. The GPU-accelerated bioinformatics pipeline reduced analysis time from &gt; 24h to &lt; 3h.

CONCLUSIONS
Our workflow harnessing histology-based molecular predictions to instruct targeted nanopore sequencing can be set up with low initial investment and has the potential to facilitate reporting of molecular results on the next day of sample collection. CNS-CHiP combined with Rapid-CNS2 thus aims to make CNS tumour diagnostics affordable and accessible to smaller hospitals and labs especially in low- and middle-income countries.
NIMG-12. DSC-MRI PERFUSION IMAGING IN UNTREATED BRAIN METASTASES USING THE CONSENSUS ACQUISITION PROTOCOL: A MULTI-SITE BENCHMARK STUDY
Authors: Kohn Sarah , Prah Melissa , Kong Min , Phung Daniel , Urcuyo Javier , Ye Jason , Attenello Frank , Mendoza Jesse , Shiroishi Mark , Hu Leland , Schmainda Kathleen 
Published: November 2022

Abstract

INTRODUCTION
DSC-MRI perfusion methods are commonly used to evaluate both primary and metastatic brain cancer with the creation of maps of relative cerebral blood volume (rCBV). Recently, guidelines were established to ensure a standard DSC-MRI acquisition protocol that reduces inter-site variability. The purpose of this study was to initiate the determination of rCBV benchmark values using the DSC-MRI consensus protocol in treatment-naïve brain metastases.

METHODS
Patients from three sites with treatment-naïve, contrast-enhancing brain metastases on MRI were considered for inclusion in this retrospective study. The MRIs included pre- and post-contrast T1w(T1+C) images obtained after administration of gadolinium-based contrast agent (GBCA) (0.1 mmol/kg), which serves as the recommended preload for the DSC-MRI data collection. A 2nd GBCA dose (0.1 mmol/kg) was administered 40-60sec after the collection of baseline GRE-EPI images using recommended settings (FA=60o, TE/TR=30ms/1100-1250ms) for 120s. Calibrated pre/post T1w difference maps (dT1) were used for delineation of enhancing lesion, and standardized (calibrated) rCBV (sRCBV) created. Mean sRCBV for metastases were compared to normal appearing white matter (NAWM) and treatment-naive glioblastoma (GBM) from a previous study. Pairwise comparisons were performed using the Mann-Whitney nonparametric test.

RESULTS
N=52 patients with primary histology of lung (n=27); breast (n=6); skin (n=7); gastrointestinal (GI: n=3) and genitourinary (GU: n=9) cancers were included in comparison to GBM (n=31). The mean sRCBV for all metastases (1.77+/-1.05) is significantly lower (p=0.0003) than for GBM (2.67+/-1.34) but with both statistically greater (p&lt; 0.0001) than NAWM (0.706+/-0.163). Individually, lung (1.47+/- 0.61), breast (2.275+/-0.87), skin (2.10+/-1.22), GI (1.91+/- 0.64) and GU (2.01+/-0.63) mean sRCBV are statistically greater than for NAWM.

CONCLUSION
Using the consensus DSC-MRI acquisition protocol confirms use of sRCBV to identify biologically active, treatment-naive brain metastases setting benchmark values for future applications.
NIMG-16. COMPARISON OF A STIR- AND T1-WEIGHTED-BASED RADIOMICS MODEL TO DIFFERENTIATE BETWEEN PLEXIFORM NEUROFIBROMAS AND MALIGNANT PERIPHERAL NERVE SHEATH TUMORS IN NEUROFIBROMATOSIS TYPE 1 (NF1)
Authors: Ly Ina , Liu Tianyu , Cai Wenli , Michaels Olivia , Kwon Daniel , Bredella Miriam , Jordan Justin , Borcherding Dana , Boswell Demetrius , Burgess Crystal , Chi Ping , de Blank Peter , Dombi Eva , Hirbe Angela , Korf Bruce , Lee Shernine , Mautner Victor , Melecio-Vázquez Mairim , Mulder Zachary , Pollard Kai , Pratilas Christine , Salamon Johannes , Srihari Divya , Steensma Matthew , Widemann Brigitte , Blakeley Jaishri , Plotkin Scott 
Published: November 2022

Abstract

BACKGROUND
Plexiform neurofibromas (PNF) and malignant peripheral nerve sheath tumors (MPNST) are best visualized on short TI inversion recovery (STIR) sequences on MRI. However, STIR sequences are not routinely acquired in the clinical setting. T1-weighted pre-contrast (T1W) sequences are more standardly obtained but provide insufficient contrast for tumor identification. We developed a radiomics model based on STIR and T1W sequences to differentiate between NF1-associated PNF and MPNST.

METHODS
Using a 3D quantitative imaging analysis software (3DQI), 68 MPNST and 79 PNF from 134 participants at nine centers were segmented on STIR sequences (if available) or T2 fat-saturated or T1-weighted fat-saturated post-contrast sequences. Tumor regions of interest were co-registered to T1W sequences. Standard pre-processing included N4 bias field correction, intensity normalization (mean 120 SI, SD 80 SI), and resampling (1 mm3 voxel resolution). 107 radiomic features were extracted using PyRadiomics. To classify tumors as PNF or MPNST, we applied the Boruta algorithm and correlation removal for selection of important features. A Random Forest model was built using the top five selected features. The data were divided into a training/validation and test set (7:3 ratio). Five-fold cross-validation was performed and repeated 100 times. Model performance was evaluated using AUC, sensitivity, specificity, accuracy, and 95% CI.

RESULTS
For the STIR-based model, AUC was 0.856 (95% CI 0.727-0.984), sensitivity 0.6, specificity 0.833, and accuracy 0.727 in the test set. For the T1W-based model, AUC was 0.867 (95% CI 0.743-0.990), sensitivity 0.8, specificity 0.79, and accuracy 0.794 in the test set.

CONCLUSIONS
Our radiomics models demonstrate high and comparable performance to distinguish between PNF and MPNST on STIR and T1W sequences. Our inclusion of multicenter MRIs enhances model generalizability. These models can potentially be integrated into the radiologic workflow to help clinicians in the early identification of MPNST or pre-malignant atypical neurofibromas on clinical MRIs.