bluuebunny/crossref_metadata_2025_split huggingface dataset:
PATH-27. GIANT CELL GLIOBLASTOMA DOES NOT REPRESENT A DISTINCT TUMOUR ENTITY BUT STRATIFIES INTO DIFFERENT GENETICALLY DEFINED SUBTYPES
Authors: Wiedey Anna , Dörner Evelyn , zur Mühlen Anja , de Azevedo Pinto Maria , Kramm Christof , Waha Andreas , Pietsch Torsten 
Published: November 2019

Abstract

BACKGROUND
Giant cell glioblastoma (G-GBM) is a rare variant of glioblastoma (GBM) characterized by large often multinucleated tumour cells. G-GBM occurs most frequently de novo; in contrast to IDH wildtype GBM they carry TP53 mutations in high frequency.

METHODS
We collected 58 G-GBM from 25 children and 33 adults diagnosed at the Brain Tumor Reference Center of the German Society of Neuropathology and Neuroanatomy (DGNN) in Bonn, and performed a systematic histological, immunohistochemical and genetic analysis by molecular inversion probe array assay, panel next generation sequencing and pyrosequencing.

RESULTS
78.4% of G-GBM carried mutations of TP53. Five G-GBM represented IDH-mutated gliomas, 5 cases had H3F3A-G34, and 3 had H3-K27M mutations. The vast majority (75%) lacked IDH or histone gene mutations. In these, chromosome 7 showed a copy number gain in 2/3 of the cases in contrast to the other molecular types. TERT promotor mutations occurred only in adult patients at a frequency of 35.5%. Similarly, chromosome 1q gain, 10 and 13 loss was more frequent in tumours of adult patients. MGMT promotor was methylated in 30.6 % of G-GBM. As a potential therapeutic target, PDGFR-alpha was found expressed in the vast majority of cases and its gene showed copy number gain in 34.5%.

CONCLUSIONS
In summary, G-GBM is a histological phenotype most likely related to p53 dysfunction but can occur in different genetically defined GBM entities (IDH-, histone gene mutated or in IDH/histone wildtype GBM). (supported by grants from the Deutsche Kinderkrebsstiftung and the Medical Faculty of the University of Bonn, BONFOR)
PATH-30. TARGETED THERAPIES FOR PEDIATRIC LOW-GRADE GLIOMAS: A CASE SERIES
Authors: Shah Nidhi , Walter Andrew , Kaur Gurcharanjeet 
Published: November 2019

Abstract
Pediatric central nervous system (CNS) malignancies are the most common malignancies of childhood. The standard treatment plan for most CNS malignancies involves surgery, chemotherapy, radiation, and/or a combination of above therapies. Unresectable symptomatic low grade gliomas, such as pilocytic astrocytomas and gangliogliomas, are slow growing tumors that are typically responsive to a single course of intravenous chemotherapy, but in select patients these WHO grade I or II tumors can recur and be refractory to multiple courses. Molecular diagnostics can offer valuable insight into the tumor microenvironment, where targeted therapies can be offered for specific actionable mutations. Here we report a case series of 3 pediatric patients, with unique CNS malignancies, currently on targeted therapies for tumor-specific somatic mutations. Patient A is a 5 year old male with unresectable Neurofibromatosis-1 related plexiform neurofibroma of the nasopharyngeal space as well as optic pathway glioma, with a mutation of the MAPK/ERK pathway. Patient B is a 6 year old male with recurrent, refractory pilocytic astrocytoma of the optic pathway and hypothalamus, with progression through several courses of intravenous chemotherapy, noted to have somatic NACC2-NTRK mutation. Patient C is a 17 year old female with unresectable, pontomedullary ganglioglioma, noted to have BRAF-V600E mutation. Patient A is treated with Selumetinib, for about 6 months, with near resolution of nasopharyngeal mass. Patient B is treated with Larotrectinib, for about 3 months, with stability of clinical symptoms. Patient C is treated with Vemurafenib, for about 10 months, with stability of lesion size and patient-reported clinical improvement. No adverse events were noted for any of these patients and all medications were administered orally. Significant improvement in quality of life was reported, as they did not have central lines or bone marrow suppression. Targeted inhibitors provide a reasonable treatment option for relapsed, refractory CNS malignancies with actionable mutations.
PATH-38. ROSETTE-FORMING GLIONEURONAL TUMOR IS DEFINED BY FGFR1 ACTIVATING ALTERATIONS WITH FREQUENT ACCOMPANYING PI3K AND MAPK PATHWAY MUTATIONS
Authors: Calixto-Hope Lucas , Lee Julieann , Sloan Emily , Hofmann Jeffrey , Van Ziffle Jessica , Onodera Courtney , Grenert James , Devine Patrick , Kline Cassie , Banerjee Anu , Clarke Jennifer , Taylor Jennie , Ann Oberheim-Bush Nancy , Buerki Robin , Butowski Nicholas , Chang Susan , McDermott Mike , Aghi Manish , Theodosopoulos Philip , Hervey-Jumper Shawn , Berger Mitchel , Raffel Corey , Gupta Nalin , Kleinschmidt-DeMasters Bette , Wood Matthew , Grafe Marjorie , Guo Hua , Sun Peter , Torkildson Joseph , Cooney Tabitha , Fata Cynthia , Scharnhorst David , Samuel David , Bannykh Serguei , Khatib Ziad , Maher Ossama , Chamyan Gabriel , Pelaez Liset , Brathwaite Carole , Jin Lee-way , Lechpammer Mirna , Born Donald , Vogel Hannes , Lee Han , Phillips Joanna , Pekmezci Melike , Bollen Andrew , Tihan Tarik , Perry Arie , Solomon David 
Published: November 2019

Abstract

BACKGROUND
Rosette-forming glioneuronal tumor (RGNT) is an uncommon CNS tumor originally described in the fourth ventricle characterized by a low-grade glial neoplasm admixed with a rosette-forming neurocytic component.

METHODS
We reviewed clinicopathologic features of 42 patients with RGNT. Targeted next-generation sequencing was performed, and genome-wide methylation profiling is underway.

RESULTS
The 20 male and 22 female patients had a mean age of 25 years (range 3–47) at time of diagnosis. Tumors were located within or adjacent to the lateral ventricle (n=16), fourth ventricle (15), third ventricle (9), and spinal cord (2). All 31 tumors assessed to date contained FGFR1 activating alterations, either in-frame gene fusion, kinase domain tandem duplication, or hotspot missense mutation in the kinase domain (p.N546 or p.K656). While 7 of these 31 tumors harbored FGFR1 alterations as the solitary pathogenic event, 24 contained additional pathogenic alterations within PI3-kinase or MAP kinase pathway genes: 5 with additional PIK3CA and NF1 mutations, 4 with PIK3CA mutation, 3 with PIK3R1 mutation (one of which also contained focal RAF1 amplification), 5 with PTPN11 mutation (one with additional PIK3R1 mutation), and 2 with NF1 deletion. The other 5 cases demonstrated anaplastic features including hypercellularity and increased mitotic activity. Among these anaplastic cases, 3 harbored inactivating ATRX mutations and two harbored CDKN2A homozygous deletion, in addition to the FGFR1 alterations plus other PI3-kinase and MAP kinase gene mutations seen in those RGNT without anaplasia.

CONCLUSION
Independent of ventricular location, RGNT is defined by FGFR1 activating mutations or rearrangements, which are frequently accompanied by mutations involving PIK3CA, PIK3R1, PTPN11, NF1, and KRAS. Whereas pilocytic astrocytoma and ganglioglioma are characterized by solitary activating MAP kinase pathway alterations (e.g. BRAF fusion or mutation), RGNT are genetically more complex with dual PI3K-Akt-mTOR and Ras-Raf-MAPK pathway activation. Rare anaplastic examples may show additional ATRX and/or CDKN2A inactivation.
PATH-41. LONGITUDINAL MATCHED MUTATIONAL ANALYSIS IN RECURRENT AND MULTIFOCAL GLIOMAS
Authors: Daher Ahmad 
Published: November 2019

Abstract
Re-resection of recurrent gliomas and multifocal gliomas are relatively uncommon resulting in limited understanding of the molecular profile of gliomas in those settings. Here we present a comprehensive mutational analysis via next generation sequencing (NGS) of 20 gliomas from 9 patients treated at our institution: one recurrent oligodendroglioma, one secondary glioblastoma (GBM), five locally recurrent primary GBMs, and two multifocal recurrent primary GBMs. Tumor mutational burden (TMB) range was 1.8–60.6 mutations/megabase (mt/Mb). Elevated TMB was seen in the initial (49.2 mt/Mb) and recurrent (60.6 mt/Mb) secondary GBM samples and in the distal recurrent GBM sample (50.9 mt/Mb) of one of the two patients with multifocal recurrent disease, suggesting a temozolomide-induced hypermutated state. Interestingly, the elevated TMB in the patient of multifocal recurrence occurred 5 years after completing 12 cycles of TMZ and was seen in the distal but not local focus of disease recurrence where TMB remained at 1.8 mt/Mb. The patient with multifocal (right frontal and right temporal) GBM at diagnosis developed recurrence in the temporal location only. NGS of the 2 resected tumors revealed 4 common somatic mutations, 3 mutations unique to the right frontal lesion and 8 mutations unique to the right temporal lesion. Additionally, our oligodendroglioma who was heavily treated in the six years prior to his last recurrence retained 4/6 of the initial somatic mutations and acquired 5 new ones upon the last recurrence. This analysis further highlights glioma spatiotemporal heterogeneity and the linear and divergent evolution upon disease recurrence and in the multifocal pre-treatment and recurrent settings. We also show that extensive oncogenic alterations can occur upon glioma recurrence, which is a major therapeutic barrier in managing recurrent disease, a barrier that can render the initial genomic profile of the disease, the basis of molecularly targeted therapy in the majority of cases, less meaningful.
PATH-54. MULTI-DIMENSIONAL MOLECULAR CHARACTERIZATION OF PATIENT-MATCHED MEDULLOBLASTOMA AT DIAGNOSIS AND RELAPSE
Authors: Kumar Rahul , Deng Maximilian , Smith Kyle , Liu Anthony P Y , Rudneva Vasilisa , Dhall Girish , Kleese Laura , Bowers Daniel , Chintagumpala Murali , Leary Sarah , Nazarian Javad , Orr Brent , Robinson Giles , Pfister Stefan , Korshunov Andrey , Gajjar Amar , Jones David , Northcott Paul 
Published: November 2019

Abstract

INTRODUCTION
Recurrent medulloblastoma (MB) confers an abysmal prognosis with ~10% 5-year overall survival. Optimal treatment paradigms for relapsed disease are largely unknown. Conservation of molecular subgroup at relapse has been described and divergent clonal evolution implicated, yet multi-dimensional molecular characterization of larger cohorts are warranted to substantiate these findings and to disclose potential mechanisms underlying treatment failure and disease recurrence.

METHODS
A multi-institutional series of 85 patient-matched, primary MBs and their relapses was profiled by DNA methylation array (Illumina 450K/850K). Entity and molecular subgroup classifications were assigned using random forest tumor classifiers (Molecular Neuropathology v.11b4). Genome-wide copy-number aberrations were also inferred from these data while parallel next-generation (whole-exome or targeted panel) sequencing on the majority of the cohort facilitated inference of somatic driver mutations.

RESULTS
Comprised of WNT (1%), SHH (41%), Group 3 (22%), Group 4 (35%), primary tumors largely retained subgroup affiliation at relapse with the notable exception of 14% of cases. The majority (8/12) of discrepant classifications were determined to be secondary glioblastomas, while three Group 4 primary tumors relapsed as Group 3. Amongst conserved pairs, copy-number analyses suggest somatic clonal divergence between primary MBs and their respective relapses with an average of 0.8 (range 0–5) primary-specific and 2.0 (range 0–11) relapse-specific cytogenetic alterations. Despite high global methylation correlations between primary/relapse pairs (median 0.95), epigenetic evolution at relapse is suggested by the lower degree of conservation amongst promoter-associated probes (median 0.83, p < 2.2e-16).

CONCLUSION
Secondary malignancy, particularly glioblastoma, may masquerade as relapsed MB, highlighting the utility of molecular characterization for relapsed disease and necessity for vigilant clinical surveillance. By deciphering the evolution of MB from diagnosis to relapse, a fundamental understanding of disease pathogenesis may be garnered, motivating rational and targeted clinical interventions in early therapy and at the time of relapse.
NIMG-02. NON-INVASIVE DETECTION OF IDH MUTANT 1p19q NON-CODELETED GLIOMAS USING THE T2-FLAIR MISMATCH SIGN
Authors: Foltyn Martha , Natalia Nieto Taborda Karen , Neuberger Ulf , Reinhardt Annekathrin , Brugnara Gianluca , Unterberg Andreas , Debus Jürgen , Herold-Mende Christel , von Deimling Andreas , Wick Wolfgang , Bendszus Martin , Kickingereder Philipp 
Published: November 2019

Abstract

OBJECTIVE
To assess the validity and pathophysiology of the T2/FLAIR mismatch sign for non-invasive identification of IDH-mutant 1p/19q non-codeleted glioma.

METHODS
MRI scans from 408 consecutive patients with newly diagnosed glioma (113 lower-grade glioma and 295 glioblastoma) were evaluated for the presence of a T2/FLAIR-mismatch sign (defined as complete/near-complete hyperintense signal on T2w, simultaneous hypointense signal on FLAIR except for a hyperintense peripheral rim) by two independent reviewers. Sensitivity, specificity, accuracy, positive and negative predictive value (PPV, NPV) were calculated to assess the performance of the T2/FLAIR-mismatch sign for identifying IDH-mutant 1p/19q non-codeleted tumors. An exploratory analysis of spatial differences in ADC and rCBV values comparing the FLAIR-hypointense core vs. hyperintense rim in cases with presence of a T2/FLAIR-mismatch sign was performed.

RESULTS
There was substantial interrater agreement to identify the T2/FLAIR-mismatch sign (Cohen’s Kappa = 0.75 [95% CI 0.57–0.93]). The T2/FLAIR-mismatch sign was present in 12 cases with lower-grade glioma (10.6%), all of them were IDH-mutant, 1p/19q non-codeleted tumors (sensitivity=10.9%, specificity=100%, PPV=100%, NPV=3.0%, accuracy=13.3%). The T2/FLAIR-mismatch sign was not identified in any other molecular subgroup, especially not in any of the IDH-mutant glioblastoma cases (n=5). In tumors with T2/FLAIR-mismatch sign the ADC values were significantly lower in the rim as compared to the core (p=0.0005) whereas there was no difference in rCBV values (p=0.4258).

CONCLUSION
This study confirms the high specificity of the T2/FLAIR-mismatch sign for non-invasive identification of IDH-mutant 1p/19q non-codeleted gliomas, although sensitivity is low and applicability is limited to lower-grade gliomas. The identified spatial differences in ADC values between the core and rim of tumors with a T2/FLAIR-mismatch sign potentially reflects differences in tumor cellularity and microenvironment.
NIMG-04. MRI CHARACTERISTICS, TREATMENT APPROACH, PATTERN OF RELAPSE AND SURVIVAL FOR MULTICENTRIC GLIOBLASTOMA. A RETROSPECTIVE MONOCENTRIC STUDY
Authors: Benouaich-amiel Alexandra , Khasminsky Vadim , Gal Omer , Weiss Tamara , Fichman Suzana , Siegal Tali , Yust-Katz Shlomit 
Published: November 2019

Abstract

INTRODUCTION
Multicentric glioblastoma (m-GBM) is a rare GBM variant (6–13% of all GBM cases). Published data is scarce and focus largely on enhancing foci. We performed a retrospective study to determine the incidence, imaging characteristics, treatment, pattern of relapse and prognosis of m-GBM.

METHODS
The neuropathological database of our institution was surveyed for histological diagnosis of adult GBM diagnosed between 01/01/2015 and 31/05/2018. All pre-operative MRI were reviewed to identify patients with m-GBM (defined as well separated enhancing and non-enhancing tumor foci). Medical records and follow-up MRI studies were reviewed to retrieve the data.

RESULTS
Of the 167 patients with newly diagnosed GBM, 14 (8%) presented with m-GBM. All of them had at least one enhancing lesion. The total number of lesions was 37 (19 enhancing and 18 non-enhancing) with a median number of lesions per patient of 2 (range 2 to 4). Median age at diagnosis was 66 (range: 49–79) years. MGMT status was known for 10 patients (5 methylated and 5 un-methylated). Nine patients underwent resection of the enhancing component whereas 5 patients had a biopsy. Median follow up was 14.3 (range: 2–30) months. All but one patient were treated by concurrent radiotherapy with temozolomide. All enhancing lesions were included in radiation field, whereas 4 of the 18 Flair lesions were not. Median progression free survival was 6.2 (range: 0–13.3) months. Six of the 18 non-enhancing tumor foci eventually displayed contrast enhancement during the follow-up. At last follow up, 12 patients died, with an overall survival of 12.3 months. Information regarding radiation fields, pattern of progression and molecular profile will be presented at the meeting.

CONCLUSION
m-GBM presents therapeutic dilemmas regarding the optimal therapeutical approach. Better understanding of the disease course and pattern of progression may help to optimize the therapeutic approach implying particularly to non-enhancing tumor foci.
NIMG-15. DEUTERIUM METABOLIC IMAGING (DMI) MEASURES THE WARBURG EFFECT IN BRAIN TUMORS
Authors: Corbin Zachary , Prado Isabel , Fulbright Robert , Rothman Douglas , de Graaf Robin , De Feyter Henk 
Published: November 2019

Abstract

INTRODUCTION
Metabolic changes in cancer have gained renewed interest as potential diagnostic and prognostic markers. The tendency to favor glycolysis in the presence of oxygen has been coined the Warburg Effect. We developed a magnetic resonance-based method that illustrates this metabolic shift. Deuterium Metabolic Imaging (DMI) observes glucose metabolism by tracing deuterium-labeled downstream metabolites, effectively representing the Warburg Effect. This pilot study uses DMI to visualize in vivo the Warburg Effect in subjects with brain tumors.

METHODS
We screened Yale Neuro-Oncology patients, excluding those with diabetes and MRI contraindications. Recruited subjects orally consumed 0.75g/kg of [6,6’-2H2]-glucose dissolved in water. Imaging studies were performed using a 4T magnet interfaced to a Bruker spectrometer. All data were analyzed in Matlab 8.3. Deuterium-labeled metabolite levels were overlaid on MRI to generate amplitude color maps for glucose, glutamate+glutamine (Glx), lactate, and the lactate/Glx ratio, representing the Warburg Effect.

RESULTS
Six brain tumor subjects were imaged. Age ranged from 53 to 72 years, and five subjects were men. Diagnoses included 4 glioblastomas (GBMs), 1 anaplastic oligodendroglioma (AO), and 1 meningioma. DMI mapping revealed regional differences between tumor sites and contralateral areas. All GBMs showed the Warburg Effect, while the AO and meningioma did not.

CONCLUSION
The Warburg Effect was not evident in DMI of every high-grade brain tumor, as it was not observed in the WHO grade III AO. While this tumor has a lower WHO grade than GBM, we speculate that this discrepancy relates to its molecular characterization, including an IDH1 R132H mutation, MGMT methylation, and 1p/19q codeletion. The brain tumor treatment paradigm is shifting from one based upon WHO grade to one centered around molecular features. We believe DMI provides detailed metabolic information about tumor aggressiveness, which may be linked to molecular characteristics, underscoring its clinical relevance for brain tumor diagnosis and management.
NIMG-35. QUANTITATIVE ESTIMATION OF PROGRESSION-FREE SURVIVAL BASED ON RADIOMICS ANALYSIS OF PREOPERATIVE MULTI-PARAMETRIC MRI IN PATIENTS WITH GLIOBLASTOMA
Authors: Fathi Kazerooni Anahita , Rathore Saima , Akbari Hamed , Rudie Jeffrey , Sako Chiharu , Min Ha Sung , Mamourian Elizabeth , Bakas Spyridon , Shukla Gaurav , Bilello Michel , Davatzikos Christos 
Published: November 2019

Abstract

PURPOSE
Glioblastoma managed with maximal resection and adjuvant chemoradiation has large heterogeneity at the time of tumor recurrence (progression-free survival, PFS). Upfront identification of patients with shorter than median PFS, may facilitate better personalization of treatment, such as patient stratification into clinical trials for treatment intensification and/or supportive care. The aim of the current study was to build a radiomics model that can reliably predict PFS in patients with glioblastoma at the time of initial diagnosis. EXPERIMENTAL DESIGN: A total of 66 de novo glioblastoma patients in a single institution who underwent gross total resection followed by standard adjuvant chemoradiation, were found to have pathologically confirmed recurrence. Patients who had sufficient follow-up MRI to reliably determine PFS and available pre-surgical multi-parametric MRI (mpMRI) (T1, T1Gd, T2, T2-FLAIR, DTI, DSC-MR images) were included. The patients were stratified into two classes of “short PFS (≤7 months, n=35)” and “long PFS (≥9 months, n=19)”. An extensive set of features was extracted from preoperative mpMRI scans, including shape and volumetric measures computed for different tumorous regions, and characteristics derived from histograms and gray-level co-occurrence matrix (GLCM). Predictive modeling for discrimination of patients with short from those with long PFS was performed using a 10-fold cross-validated support vector machine classifier.

RESULTS
An accuracy of 79.6% was achieved for prediction of short and long PFS (sensitivity=83%, specificity=74%, AUC=0.86 [95%CI: 0.76–0.96]; short-PSF was considered the positive class). The patients with shorter PFS showed markedly higher cell density in the nonenhancing tumor (DTI), higher neo-angiogenesis in the enhancing tumor (DSC-MRI, T1Gd), lower water concentration in the enhancing tumor region (T2), and higher maximum enhancement (calculated by the subtraction of T1 from T1Gd) in the edema region.

CONCLUSION
Quantitative assessment of preoperative mpMRI provides accurate prediction of PFS for patients with glioblastoma, which can aid in personalized treatment planning.
NIMG-36. EVALUATION OF [18F]DASA-23 FOR NON-INVASIVE MEASUREMENT OF ABERRANTLY EXPRESSED PYRUVATE KINASE M2 IN GLIOMA: FIRST-IN-HUMAN STUDY
Authors: Patel Chirag , Beinat Corinne , Haywood Tom , Murty Surya , Xie Yuanyang , Recht Lawrence , Nagpal Seema , Thomas Reena , Khalighi Mohammad , Gandhi Harsh , Holley Dawn , Gambhir Sanjiv 
Published: November 2019

Abstract

OBJECTIVES
We developed 1-((2-fluoro-6-(fluoro-[18F])phenyl)sulfonyl)-4-((4-methoxyphenyl)sulfonyl)piperazine ([18F]DASA-23) as a novel radiopharmaceutical to measure pyruvate kinase M2 levels by positron emission tomography (PET). PKM2 catalyzes the final step in glycolysis, the key process of tumor metabolism. PKM2 is preferentially expressed by glioblastoma (GBM) cells with minimal expression in the healthy brain, making it an important biomarker of cancer glycolytic re-programming. Here, we report the first evaluation of [18F]DASA-23 in human healthy volunteers and subjects with low-grade (LGG) and high-grade glioma (HGG).

METHODS
[18F]DASA-23 was synthesized under GMP conditions. Brain [18F]DASA-23 PET/MRI scans (3T) were performed in human healthy volunteers (n=5) and subjects with LGG (n=3) and HGG (n=2). The PET imaging duration was 60 min and standardized uptake value (SUV) calculations were performed on the 30–60 min summed images. The maximum SUV in the tumor (TumorSUVmax) and contralateral white matter (WMSUVmax) were calculated.

RESULTS
[18F]DASA-23 specific activity was 2961±873 mCi/µmol (n=10) with radiochemical purity >95%, injected mass of 1.8±0.7 mcg, and dose of 0.3±0.02 mcg per kg body weight. In healthy volunteers, [18F]DASA-23 crossed the intact blood-brain barrier and was rapidly cleared through the bladder and also showed uptake in the gallbladder, liver, and intestines over time. [18F]DASA-23 was found to be intact in plasma up to 10 min post-injection and 75% intact at 30 min post-injection. In subjects with glioma, TumorSUVmax was significantly greater in HGG (2.2±0.4, n=2) compared to LGG (0.8±0.3m n=3), p=0.02. In this early human series, the normalized ratio of TumorSUVmax/WMSUVmax was not significantly different between subjects with HGG (2.0±0.6) and LGG (1.0±0.4), p=0.1.

CONCLUSION
[18F]DASA-23 is a promising new imaging agent for the non-invasive delineation of LGG and HGG based on aberrantly expressed PKM2. An ongoing study is evaluating the utility of this agent in additional patients with intracranial malignancies (NCT03539731).