bluuebunny/crossref_metadata_2025_split huggingface dataset:
PATH-09. NEXT-GENERATION SEQUENCING OF GLIOBLASTOMA MULTIFORME ‘EXTREME RESPONDERS’
Authors: Zameer Mohammed , Fives Cassie , Peters Niamh , Birmingham Niamh , Collins Dearbhaile , O’Reilly Seamus , Bambury Richard 
Published: December 2020

Abstract

BACKGROUND
Glioblastoma Multiforme (GBM) is the most common primary brain among adults. Despite steady advances in treatment, the outcome remains universally lethal. Median overall survival in a population-based study is approximately 10 to 12 months. Prognostic factors in GBM patients include age, performance score, extent of surgical resection, IDH1 mutation status and MGMT methylation status. Survival &gt; 2 years is rare; for the purpose of this study we have defined these patients ‘extreme responders.’ This study aims to identify genomic signatures and gene alterations that may have contributed to ‘extreme response’ to standard adjuvant chemoradiotherapy.

METHODS
A total of 12 out of 141 primary GBM patients were identified as ‘extreme responders’ as part of a retrospective chart review between 2005 - 2016. Of the 12 suitable for NGS testing, 9 were analyzed using the Foundation One CDx® (next-generation sequencing platform) which interrogates 324 genes, microsatellite status and tumour mutational burden (TMB). Baseline demographics, clinical characteristics, and NGS results were compared.

RESULTS
Of the 9 patients tested, over half were female (5, 55%) and median age at diagnosis was 53 years. Gross total resection was performed at diagnosis in 3 cases. MGMT status was available for 5 patients and was methylated in 3. NGS results revealed: MSI stable in all patients, median TMB 3 muts/Mb and most common gene alterations were TP53 (5/9); ATRX (4/9); EGFR (3/9); CDKN2A/B (3/9); IDH1(3/9); PIK3R1(3/9) and PTEN (3/9).

CONCLUSION
Acknowledging the fact that our sample size was small and no control group was tested, our study infers a higher incidence of IDH1, TP53 and ATRX mutations which are more common in secondary glioblastomas and this may be a contributing factor towards longer survival in our cohort. We did not identify any universal molecular marker predictive of improved prognosis or exquisite sensitivity to chemoradiotherapy.
PATH-10. EFFECTS OF 19q-LOSS IN IDH-MUTATED ASTROCYTOMAS ON BETTER PROGNOSIS AND OLIGODENDROGLIOMA-LIKE MORPHOLOGY
Authors: Otani Ryohei , Uzuka Takeo , Higuchi Fumi , Matsuda Hadzki , Tanaka Shota , Mukasa Akitake , Kim Phyo , Ueki Keisuke 
Published: December 2020

Abstract
We previously reported that there was a subgroup of IDH-mutated astrocytomas harboring only 19q-loss showing oligodendroglioma-like morphology and significantly longer overall survival (OS) compared with 19q-intact astrocytomas. To further explore the biological characteristics of this possible subgroup and obtain insight into the mechanism of their clinical behavior, we compared gene expression pattern between five 19q-loss and five 19q-intact IDH-mutated astrocytomas by microarray analysis. Comparing expression level of each genes between 19q-loss and 19q-intact astrocytomas,136 up-regulated genes and 203 down-regulated genes were extracted. Gene expression patterns of 19q-loss astrocytomas were partially different from that of 19q-intact astrocytomas. More down-regulated genes distributed on 19q and 4p, and more up-regulated genes distributed on 4q. Multiple genes associated with stem cell maintenance were down-regulated in 19q-loss astrocytomas, and genes associated with glioma progression were differentially expressed. Comparing expression patterns among 19q-loss astrocytomas and other IDH-mutant glioma subgroups using TCGA datasets by t-SNE analysis revealed that expression pattern of 19q-loss astrocytomas did not shift to that of oligodendrogliomas with 1p/19q codeletion but were a subgroup in astrocytomas. These results indicated that 19q-loss in astrocytomas was an acquired event different from 1p/19q codeletion in oligodendrogliomas, and better prognosis morphological features in 19q-loss astrocytomas were derived from differentially expressed genes associated with stem cell maintenance and glioma progression.
PATH-12. TEMOZOLOMIDE-INDUCED HYPERMUTATION IS ASSOCIATED WITH HIGH-GRADE TRANSFORMATION, DISTANT RECURRENCE AND REDUCED SURVIVAL IN INITIALLY LOW GRADE IDH-MUTANT GLIOMAS
Authors: Yu Yao , Villanueva-Meyer Javier , Chang Susan , Grimmer Matthew , Hilz Stephanie , Solomon David , Choi Serah , Wahl Michael , Mazor Tali , Hong Chibo , Shai Anny , Phillips Joanna , McDermott Michael , Haas-Kogan Daphne , Taylor Jennie , Butowski Nicholas , Clarke Jennifer , Berger Mitchel , Costello Joseph , Bush Nancy Ann Oberheim 
Published: December 2020

Abstract
Temozolomide, a commonly used alkylating agent, can induce somatic hypermutation in gliomas. The prevalence and implications of this phenomenon are not well characterized. Using targeted and whole exome sequencing from a cohort of 82 patients with recurrent IDH-mut LGG, we evaluated the clinical implications of hypermutation. Hypermutation was identified at transformation in 57% of recurrent gliomas exposed to TMZ and occurred for both IDH-mutant astrocytomas (52%) and oligodendrogliomas (64%). Among astrocytomas, receipt of radiotherapy prior to transformation was associated with decreased risk of hypermutation (11% vs 70%, p=0.0052), but this trend was not observed for oligodendrogliomas (78% vs 54%, p=NS). Among hypermutated tumors, 94% were transformed to higher WHO grades. Hypermutation was associated with transformation to higher WHO grade (OR 12.0 95% CI 2.5-115.5, p=0.002) and shorter survival after transformation (HR 2.1, 95% CI 1.1-4.0, p=0.018) compared with non-hypermutated transformed tumors. It remained prognostic (controlling for grade, molecular subtype, age, and prior radiotherapy. Patients with transformation to glioblastoma had poor survival regardless of hypermutation (p=0.78). Multivariate models were validated using an external, independent dataset (Harrel’s C=0.72). Strikingly, hypermutated tumors were also associated with development of discontiguous disease after transformation (3-year CI 41% vs 8% p=0.005), including ependymal and leptomeningeal distributions and four cases of spinal dissemination that were not observed in non-hypermutated tumors. These data have significant implications for management of IDH-mut LGG at recurrence.
PATH-15. DEEP LEARNING ENABLED PREDICTION OF ISOCITRATE DEHYDROGENASE MUTATION STATUS FROM DIGITAL HISTOPATHOLOGY DATA IN GLIOBLASTOMA
Authors: Kebir Sied , Blau Tobias , Lazaridis Lazaros , Schmidt Teresa , Keyvani Kathy , Sure Ulrich , Stuschke Martin , Kleinschnitz Christoph , Scheffler Björn , Glas Martin 
Published: December 2020

Abstract

BACKGROUND
The determination of isocitrate dehydrogenase (IDH) mutation status plays a crucial role in the diagnosis of glioblastoma. Depending on the age of the patient and the result of the immunohistochemical analysis, additional DNA sequencing may be required to determine IDH mutation status. As DNA sequencing results can occasionally take several days until available, there is a need for inexpensive and fast non-invasive methods. In this work, we investigated whether IDH mutation detection by artificial intelligence (deep learning) from digitized hematoxylin-eosin (H&E) stained sectional specimens is feasible.

METHODS
Patients with histologically confirmed glioblastoma from The Cancer Genome Atlas cohort were included if digitized H&E stained whole-slide scans with corresponding information on IDH status were publicly available. The total cohort was subdivided into a training, validation, and test cohort in a ratio of 44:33:23. Whole-slide scans were partitioned into tiles of fixed size and used to train a Resnet-34 convolutional neural network. The evaluation of the trained model was performed once on the test cohort using Receiver Operating Characteristic analysis and Area-Under-The-Curve (AUC) metric. To ascertain which regions of the H&E specimens were decisive for the determination of IDH status, the Grad-CAM method was used.

RESULTS
124 patients were included, 29 of which were IDH mutant. The digitized H&E slides had an average size of 2.5 gigabytes per image file and approximately 1000 tiles per slide were prepared. The prediction AUC of the trained model was 0.94. The duration of IDH prediction was about 3.5 seconds per slide. The Grad-CAM evaluation confirmed that the model mainly used cellular regions to collect decision-supporting information.

CONCLUSIONS
This pilot study shows the promising potential of deep learning for the prediction of IDH mutation status from digitized H&E scans in glioblastoma. To confirm these data, testing this model on an independent cohort is needed.
PATH-16. COMPREHENSIVE GENOMIC PROFILING ACCURATELY DETERMINES 1p19q CODELETION STATUS IN GLIOMAS
Authors: Sharaf Radwa , Pavlick Dean C , Frampton Garrett M , Cooper Maureen , Jenkins Jacqueline , Alexander Brian , Cloughesy Timothy , Yong William , Liau Linda , Nghiemphu Phioanh , Ji Matthew , Lai Albert , Albacker Lee A , Ramkissoon Shakti H 
Published: December 2020

Abstract

BACKGROUND
Genomic profiling of gliomas is vital to ensure diagnostic accuracy, inform prognosis, and identify therapeutic options for primary and recurrent tumors. The integration of genomic biomarkers into brain tumor classification has improved the diagnostic accuracy and led to the development of molecularly stratified clinical trials.

DESIGN
Comprehensive genomic profiling (CGP) was performed on FFPE material from 310 (162 FoundationOne® and 148 FoundationOne® CDx) samples of brain tumors with available 1p19q FISH results, initially diagnosed by submitting institutions based on histology. Via CGP, we analyzed tumors in up to 395 cancer-associated genes (including IDH1/2) and predicted 1p19q codeletion using a custom research-use only algorithm. Progression-free (PFS) and overall survival (OS) were determined for 519 patients based on computationally predicted 1p19q codeletion status.

RESULTS
For all samples, regardless of their IDH1/2 mutation status, concordance between 1p19q status based on FISH and our algorithm was 97.1%, (301/310), with a positive predictive value (PPV) of 100% (133/133) and sensitivity of 93.7% (133/142). All discordant samples were called as positive for codeletion by FISH and negative by our CGP-based algorithm. Discordant samples were either IDH1/2 wild-type (2) or IDH1/2, ATRX, and TP53 altered (7), consistent with the genomic profile of diffuse astrocytomas. For IDH1/2-mutated samples, concordance was 96.7% (238/246). In the clinical outcomes dataset, median PFS was 35 months for the codeletion group compared to 13 months for the non-codeletion group (hazard ratio (HR): 0.60; 95% CI: 0.40-0.88; p=0.009). Similarly, median OS was 160 and 34 months respectively for codeleted versus intact (HR: 0.46; 95% CI: 0.28-0.76; p=0.002).

CONCLUSIONS
1p19q codeletion status derived from CGP is highly concordant with FISH results suggesting that CGP-derived 1p19q codeletion status may be a reliable substitute for traditional FISH testing. Patients with CGP-derived 1p19q codeletion showed increased PFS and OS compared to non-codeleted counterparts.
PATH-18. A MULTI-CENTER CASE SERIES OF ADULT K27M MUTATED DIFFUSE MIDLINE GLIOMAS REVEALING A POPULATION UNIQUE FROM PAEDIATRIC CASES
Authors: Yuile Alexander , De Silva Madhawa , Kastelan Marina , Cheung Veronica , Sy Joanne , Buckland Michael , Drummond Jamie , Back Michael , Wheeler Helen 
Published: December 2020

Abstract

BACKGROUND
Histone mutations in the K27M gene were first described in 2014, and incorporated into the WHO CNS tumour classification system in 2016. They are typically associated with diffuse midline gliomas (DMG). Presenting symptoms vary greatly, with some experiencing significant delay in diagnosis. Median survival is only 9-12 months for these patients. Biopsy samples are small, and in some due to location, not performed. Although data is predominately based on the paediatric population, DMGs are seen in both adolescence and adults. In this multi-site retrospective study, we describe 11 adult patients with K27M DMG gliomas across two tertiary Neuro-Oncology services in Sydney, Australia. To the authors’ knowledge we present the largest known collection of adult K27M cases in the Asia-Pacific region with correlation of treatment, clinicopathologic and radiologic features with outcomes.

METHODS
The glioma databases of Royal North Shore Hospital (RNSH) and Royal Prince Alfred Hospital (RPAH) between January 2009 and March 2020 were interrogated to identify patients. Selection criteria included patients aged ≥ 18 years who presented with a DMG, had undergone biopsy, and had confirmed K27M via next generation sequencing. Clinicopathologic, radiologic and treatment outcomes were extracted for correlation.

RESULTS
Eleven patients fitting the selection criteria were identified and reported. The median age at diagnosis was 30 years and 4 were female. Five presented with hydrocephalus, the most common presenting symptoms were headaches and nausea and/or vomiting (n= 4 and n= 2 respectively). The median progression-free survival was 13 months (4-31 months) and the median overall survival was 23 months (4-59 months).

CONCLUSION
This case series reports the outcomes of older patients with K27M. The clinical course demonstrated suggests a divergence from paediatric biology. Ongoing studies are required to further characterise the histopathological and clinical differences of these tumours in older patients.
PATH-20. A CASE REPORT OF NOVEL BCR-ABL1 FUSION IN GLIOBLASTOMA, IDH-WILD TYPE
Authors: Ahn Hyungmin , Sang Lee Kyu , Choe Gheeyoung 
Published: December 2020

Abstract
In recent years, molecular tests have become essential to diagnose brain tumor. Although numerous molecular studies of glioblastoma have been conducted, pathogenesis of glioblastoma has not been fully identified. Present report is an extraordinary case of glioblastoma, IDH-wild type with BCR-ABL1 fusion. The BCR-ABL1 fusion is also called ‘Philadelphia gene’ and have never been found in solid tumors other than hemato-lymphoid malignancies. A 63-year-old man presented with clumsy and inappropriate word symptoms a week ago. Magnetic resonance imaging test revealed a 6.6 x 5.0 cm heterogeneously enhancing mass in the left temporal lobe and the patient underwent tumorectomy. Microscopically, tumor showed increasing cellularity, marked nuclear atypia and brisk mitosis. Microvascular proliferation and necrosis was present that can be diagnosis as glioblastoma. In addition, tumor showed strong GFAP positivity which indicated the glial differentiation. There is no evidence of diagnosis as another tumor including metastatic carcinoma or hemato-lymphoid malignancy. Interestingly, BCR-ABL1 fusion was detected in next generation sequencing test. The BCR-ABL1 fusion was a novel finding in glioblastoma, thus additional fluorescence in situ hybridization tests were conducted for confirmation BCR-ABL1 fusion and the same alteration was found. The patient had no leukemic presentation in the blood test, radiologic test and clinical symptom. Notably, this is the first case report that glioblastoma has the BCR-ABL1 fusion.
PATH-24. DETECTION OF POINT MUTATIONS AND GENE FUSIONS FROM CIRCULATING CELL-FREE DNA (CFDNA) OF GLIOBLASTOMA (GBM) PATIENTS
Authors: Frenkel-Morgenstern Milana , Palande Vikrant , Detroja Rajesh , Gorohovski Alessandro , Glass Rainer , Flueh Charlotte , Kanner Andrew A , Laviv Yoseph , Nof Sagi Har , Levy-Barda Adva , Benouaich-Amiel Alexandra , Yust-Katz Shlomit , Kurtz Marina , Perez Shira , Shay Dorith Raviv , Siegal Tali 
Published: December 2020

Abstract

BACKGROUND
GBM is characterized by intratumoral heterogeneity. Tumor heterogeneity, clonal diversity and mutation acquisition hamper the ability to tailor personalized therapy for GBM. Tumor sampling has limited ability to accurately capture the molecular landscape of the tumor and to disclose acquired molecular aberrations. Mutation analysis of cfDNA is a non-invasive procedure which may overcome these limitations as it may reflect the real composition of the tumor and track the molecular evolution. We sequenced cfDNA of GBM patients and assessed mutation patterns and fusion genes.

METHODS
We collected blood and respective tumor samples from 27 GBM patients and blood samples from 14 healthy controls. Tumor DNA, cfDNA and WBC DNA were sequenced using deep sequencing procedures. The data were analyzed for detection of single nucleotide polymorphism (SNPs) and gene-gene fusions.

RESULTS
GBM cfDNA concentrations were significantly elevated (median: 23.63 ng/mL; range 12.6–137) compared to healthy controls (median 2.06; range 1.68–7.62) (p &lt; 0.0001). We identified unique SNPs in each glioma patient’s cfDNA and the corresponding tumor DNA including the top-10 most frequently mutated genes in GBM. For example, mutation of TP53 was detected in18.75%; EGFR in 37.5%; NF1-12.5%; LRP1B-25% and IRS4 in 25%. For gene-gene fusion we used the in-house fusion gene database, ChiTaRS 5.0, and identified fusions in cfDNA and tumor DNA. Thus, KMT2A-FLNA was the most frequent fusion found in 16.4% of samples. BCR-ABL1 in 8.82% and FGFR1-BCR in 2.94%. Other fusions included COL1A1-PDGFB (5.88%), NIN-PDGFRB (5.88%), KIF5B-RET (5.88%) and also TPM3-ROS1(2.94%), TFG-ALK(2.94%), MSN-ALK (2.94%) and NPM1-ALK (2.94%) which may be targeted by brain penetrating drugs that are ROS1 and ALK inhibitors.

CONCLUSIONS
Our study suggests that plasma cfDNA analysis may help to uncover real time mutational and gene fusion status of GBM by a non-invasive procedure. It may identify drug targets based on personalized gene-gene fusions.
PATH-40. INTRAGENIC DMD DELETIONS ARE THE MOST COMMON RECURRENT GENOMIC ALTERATIONS IN ESTHESIONEUROBLASTOMA
Authors: Juratli Tareq , Nayyar Naema , Young Michael , Subramanian Megha , Brastianos Priscilla , Lin Derrick 
Published: December 2020

Abstract

INTRODUCTION
Esthesioneuroblastoma (ENB) is a rare, malignant neuroectodermal tumor of the olfactory epithelium. To date, a few recurrent genetic alterations have been identified in ENB. Here, we sought to examine the genomic signature on a series of clinically well-characterized aggressive ENB samples.

METHODS
We performed whole-exome sequencing in a cohort of 26 ENB samples from 12 patients, containing 11 matched primary-metastatic samples. Additionally, targeted sequencing was carried out in all samples to determine TERT promoter hotspot mutations. Furthermore, we performed immunohistochemistry (IHC) using an antibody that recognizes the dystrophin central rod domain in all available specimens.

RESULTS
Our cohort consisted of 9 male and 3 female patients with a median age of 66 years at first diagnosis (4- 77 years). One patient was staged Kadish B at the time of diagnosis and eleven were staged Kadish C. The median overall survival was 3.85 years (0.3 – 16 years). Consistent with previous findings, each tumor exhibited a different mutational signature and the mutational landscape appears to be predominantly driven by copy number variations. Interestingly, we detected intragenic deletions in dystrophin (DMD) as the most common and consistent alteration in ENB patients (in 11 of 12 patients, 91.6%). DMD deletions, when identified within the primary ENB, were preserved in all subsequent metastatic lesions. Moreover, DMD deletions where concurrently identified in three cases with multiple metastases. IHC revealed the concurrent loss of dystrophin expression, the protein encoded by DMD, in all cases with DMD deletions. Otherwise, no other recurrent genomic findings were detected, including TERT promoter mutations.

CONCLUSIONS
Our findings validate previously described DMD deletions as the most common recurrent genomic alteration in primary ENB. Furthermore, our data demonstrate that DMD deletions were perpetuated in subsequent metastatic lesions, and when identified in any metastasis, were present in other metastases from the same patient.
PATH-43. TARGETED GENOMIC ANALYSIS OF PRIMARY ADULT BRAIN TUMORS: A SINGLE INSTITUTIONAL EXPERIENCE OF 26 CASES
Authors: Hirani Samina , Thurlapati Aswani , Bhayani Shahzeem , Greer Adam , Mills Glenn 
Published: December 2020

Abstract

BACKGROUND
In the United States, primary brain tumors comprise 2% of all cancers with an alarming 5-year survival rate of 35% [1,2]. To aid histopathological diagnosis, genomic profiling of tumors using next generation sequencing (NGS) has allowed more accurate molecular subclassification of tumors and identification of novel, subtype specific therapies in management [3]. We present single institutional data of molecular gene profiles in patients with adult primary brain tumors. Understanding the genetic landscape of these tumors will help determine molecular targets for currently available drugs and open new avenues for further drug development [4].

METHODS
We retrospectively reviewed all primary brain tumor patients seen at LSU Health Science Center Shreveport who underwent NGS from July, 2017 to July, 2019. After reviewing a total of 44 patient charts, 26 were identified to have all the data required for our analysis. Standardized genetic sequencing reports made by molecular pathologists were used. Genetic mapping was performed and descriptive analysis was done using Statistical Analysis System (SAS).

RESULTS
Demographic characteristics of our patients consist of 50% males, 15% African American with an average age of diagnosis 59. The histopathological types diagnosed include 65% glioblastoma-multiforme and others comprising of gliosarcoma, pilocytic astrocytoma, ganglioma, oligodendroglioma, anaplastic oligodendroglioma, anaplastic ganglioma, meningioma, hemangiopericytoma, and astroblastoma. In 23% of patients, the results of gene sequencing in addition to histopathology impacted the clinical management by improving subclassification and in identifying targetable mutations. 42% of our patients found to have targetable mutations.

CONCLUSION
In the era of precision oncology, targeted gene sequencing of adult primary brain tumors may aid in diagnosis beyond histopathology by identifying the genetic landscape of tumors and molecular targets for individualized therapies.