bluuebunny/crossref_metadata_2025 huggingface dataset:
INNV-35. INTRODUCING THE EDUCATIONAL NEURO-ONCOLOGY APP
Authors: Alnahhas Iyad
Published: November 2019

BACKGROUND

The purpose of the Neuro-Oncology Trials App is to promote evidence-based practice in neuro-oncology and educate learners about the clinical trials that have been completed in the field. Evidence-based practice means consulting the literature when treating patients and applying the results of well-designed clinical trials to questions that we encounter in clinical practice. Being well versed in the literature is essential for high-quality patient care.

METHODS

We have developed a reference tool in the form of a smartphone app to provide easily-searched, easy-to-read detailed summaries of the methodology and results of selected pivotal clinical trials in the field of neuro-oncology.

RESULTS

The Neuro-Oncology Trials App includes summaries of select published clinical trials in the field of neuro-oncology. The topics include newly diagnosed glioblastoma, recurrent glioblastoma, low-grade gliomas, primary central nervous system lymphoma and management of gliomas in the elderly. The app includes an intuitive search function that facilitates looking up trials by: tumor histology, names of authors, names of journals, names of chemotherapy medications and acronyms of names of trials. Finally, it is continually updated and made available free of charge to users.

CONCLUSIONS

The Neuro-Oncology Trials App is ideal for practitioners at all levels and learners (medical students, residents and fellows) to look up information and quick summaries of trials in neuro-oncology when seeing patients in clinics or during rounds. The Neuro-Oncology App is soon to be available on the Apple and Android stores.
MNGI-03. ESTROGEN HORMONE REPLACEMENT THERAPY IN INCIDENTAL MENINGIOMA - A GROWTH RATE ANALYSIS
Authors: Kamson David , Yuen Carlen , Castillo Saavedra Laura , Jenkins Vogel Tilley , Merrell Ryan , Walker Matthew
Published: November 2019

BACKGROUND

Meningiomas are common intracranial neoplasms with female predominance and sharply rising incidence in the perimenopausal years. As they often express estrogen receptors, hormone replacement therapy (HRT) poses a theoretical risk inducing accelerated growth. Although HRT has been linked to slightly increased incidence, its actual effect on meningioma growth-rate had not been studied in a clinical population. AIM: We aimed to retrospectively compare tumor characteristics and grow-rates of incidental meningiomas of those with a ≥6-month history of estrogen-based HRT (e-HRT) before or during surveillance compared to those without (no-HRT).

METHODS

Forty females with e-HRT and 80 age-matched HRT-naïve females were identified from the NorthShore Incidental Meningioma Database. Tumor characteristics and diameters were analyzed on initial and all follow-up MRIs. Progression-free survival (PFS) was assessed.

RESULTS

Twenty-one patients completed e-HRT before, 10 started before and continued during, and 9 started e-HRT during surveillance. Patient and radiographic characteristics were similar between the groups (mean age 62y in both, parity; tumor calcification, T2W-intensity), whereas those with e-HRT had significantly lower body weight (68±16kg vs. 77±21kg; p=0.01) and tended to have longer follow-up (6.7±3.9yrs vs. 5.3±3.9yrs; p=0.07). Those with e-HRT had significantly smaller meningiomas (13±6mm vs. 16±9mm at diagnosis and 15±7mm vs. 19±11mm at end of follow-up; p=0.03 for both), and slower absolute grow-rates (0.5±0.8 vs 1.0±2.1mm/year; p=0.05) than those of no-HRT. Proportional growth-rate differences were not significant (3.3%/year vs. 5.4%/year p >0.05). Subgroup analyses showed no difference between vaginal vs. oral/subcutaneous/transdermal route e-HRT vs. no-HRT. PFS defined by RECIST1.1, RANO and clinical (new symptoms or treatment) criteria were 11.1, 6.6 and 14.7years in e-HRT versus 10.5, 5.4 and 11.4years in no-HRT. None of the differences were significant (log-rank p >0.1).

CONCLUSIONS

In this preliminary analysis, those with e-HRT had smaller tumors that grew slower, suggesting that e-HRT may be safe in incidental meningioma.
MNGI-07. TRIMETHYLATED H3K27 AND EZH2 EXPRESSION IN MENINGIOMA: CORRELATION WITH TENDENCY TO RECUR
Authors: Calatozzolo Chiara , Patanè Monica , Farinotti Mariangela , DiMeco Francesco , Finocchiaro Gaetano , Pollo Bianca
Published: November 2019

Meningiomas are the most frequent primary CNS tumors, usually benign (WHO grade I), but in the 25–30% more aggressive tumors (grade II-III). Histopathological criteria (WHO 2016) are unsatisfactory to recognize meningiomas with tendency to recur. Recent studies have identified some mutations associated with histological features and location (i.e. BAP1 mutation in rhabdoid subtype), while risk stratification schemes based on DNA methylation subgroups have been proposed. Epigenetic modifications of histones play a pivotal role in tumorigenesis, the methylation of lysine 27 (K27) of histone H3 controlled by EZH2 subunit of PRC2 complex. BAP1 could be also involved in epigenetic regulation of PRC2 complex. The deregulation of H3K27 methylation has been found associated with recurrence risk in grade II meningiomas. Aim of the present study was to evaluate histone H3 methylation profile in a group of meningiomas of different grade with follow-up longer than 10 years, comparing non-recurrent to recurrent ones. We performed an immunohistochemical study on 145 meningiomas (50 grade I, 80 grade II and 15 grade III), investigating the expression of trimethylated H3K27 (H3K27me3), EZH2 and BAP1. The results were related to clinical data obtained from our Institutional Tumor Registry and evaluation of clinical reports. We observed a loss of H3K27me3 expression only in grade II and III meningiomas in 18% of cases, without correlation with tendency to recur. EZH2 showed increased percentage of positive nuclei related to the grade. In the group of grade I meningioma EZH2 expression was associated to recurrences. We didn’t observe loss of BAP1 expression. In conclusion, our data suggest that immunohistochemical evaluation of H3K27me3 and EZH2 could be a useful tool to better stratify meningioma with high risk of recurrence. Moreover, EZH2 could be of interest as therapeutic target. Molecular investigations in a larger cohort are needed to confirm these results.
PATH-03. DIFFERENCES IN CLINICAL COURSE OF GROUP-A AND GROUP-B POSTERIOR FOSSA EPENDYMOMA (PFA, PFB) AS DEFINED BY H3K27ME3 IMMUNOHISTOCHEMICAL ANALYSIS
Authors: Yonezawa Ushio , Yamasaki Fumiyuki , takano Motoki , Taniguchi Hiroki , Sugiyama Kazuhiko , Kurisu Kaoru
Published: November 2019

PURPOSE

Posterior fossa ependymoma is classified as PFA and PFB based on underlying genetic/mutational characteristics, and PFA is reported to have poor prognosis compared to PFB. Recently, immunohistochemical findings of negative H3K27me3 have been reported to suggest PFA and attracted the attention as a surrogate marker. We classified our cases into PFA and PFB guided by immunohistochemical staining results of H3K27me3 and examined their clinical course.

MATERIALS AND METHODS

Between 1999 and 2018, 17 cases of posterior fossa ependymoma were treated at our institute. Negative immunostaining for H3K27me3 was classified as PFA, and positive as PFB. We evaluated age, gender, pathological diagnosis, progression free survival (PFS) and overall survival (OS) in both groups.

RESULTS

Nine cases were classified as PFA and eight as PFB. The median age of the PFA group was 4 years-old, 4 males, 5 females, pathological diagnosis was ependymoma in 5, and anaplastic ependymoma in 4 cases. The median follow-up period was 50 months, recurrence was confirmed in 5 cases (56%), PFS was 27.6 months. Three of the 5 patients who relapsed died (33%), and the OS was 50 months. The median age of the PFB group was 50 years, 4 males and 4 females, the pathological diagnosis was ependymoma in 6, and the anaplastic ependymoma in 2 cases. The median follow-up period was 111 months, recurrence was observed in 2 cases (25%), PFS was 98 months and all patients were alive during the period of this research.

CONCLUSION

Immunohistochemical results of H3K27me3 correlated with prognosis, implying the possibility of it being a surrogate marker of posterior fossa ependymoma.
PATH-06. A TARGETED NGS-BASED OVERALL SOLUTION TO SUPPORT DIAGNOSTICS AND THERAPY PREDICTION IN NEUROONCOLOGY: CONSIDERATIONS FOR A FLEXIBLE AND COST-EFFICIENT PLATFORM CHOICE AND PANEL DESIGN
Authors: Riemenschneider Markus , Rudolf Andras , Hau Peter , Pukrop Tobias , Kölbl Oliver , Corbacioglu Selim , Brawanski Alexander , Proescholdt Martin , Lorenz Julia
Published: November 2019

Continuous updates add novel molecular markers to the WHO classification of CNS tumors. Additionally, molecularly informed trials may provide the basis for the introduction of additional predictive biomarkers. All these developments will prospectively require molecular testing to a yet unknown extent and still pose challenges to many neuropathology labs. Some of the relevant alterations (e.g. C11orf95-RELA) are hard to assess or complex subclassifications (e.g. for medulloblastomas) are required. Some labs rely on a two-tiered approach: i) methylation arrays for tumor classification and ii) targeted NGS panel sequencing for identifying actionable mutations. However, high initial investment and annual costs for running two platforms in parallel hinder a fast expansion of the new techniques in the breadth of neuropathology. We decided to focus on the sole use of the relatively cost-efficient Mini-Seq NGS platform (Illumina). First, we designed a DNA panel (FFPE, HaloPlex, Agilent; no Covaris required) that is suited for detection of DNA mutations, copy number alterations and chromosomal alterations (459 kbp, 58 genes, 4082 SNPs, 98.83% coverage). We successfully used this platform to support tumor classification in astrocytomas, oligodendrogliomas, meningiomas and medulloblastomas and identified actionable targets of clinical use. We then designed a RNA panel (FFPE, Sure Select, Agilent) that detects gene fusions and covers a broad range of alterations particularly relevant to pediatric tumors (e.g. pediatric glioblastomas, ependymomas, CNS PNETs) (148 kbp, coding sequence of 31 genes, 99.88% coverage). With these two panels we cover the most relevant molecular alterations in the field of neurooncology. The cost-efficient and flexible single platform approach enables state-of-the-art molecular diagnostics in virtually every neuropathology lab in a quality-controlled manner. Functionality is guaranteed for future revisions of the WHO classification as novel biomarkers can be easily included in an adapted panel design.
PATH-19. TUMOR HETEROGENEITY IN GLIOMAS: A PILOT STUDY OF HISTOPATHOLOGY-ASSOCIATED PROTEOME PROFILES ASSESSED BY LIQUID CHROMATOGRAPHY TANDEM MASS SPECTROMETRY OF FFPE SAMPLES
Authors: Paixao Becker Aline , Hlavin Bell Erica , Jaharul Haque S , McElroy Joseph , Fleming Jessica , Han Chunhua , Popp Illinca , Prinz Marco , Staszewski Ori , Grosu Anca , Chakravarti Arnab
Published: November 2019

Herein, we aimed to scrutinize tumor heterogeneity of infiltrative gliomas based on histopathological phenotypes, through proteomic profiling of formalin-fixed, paraffin embedded (FFPE) tissue. FFPE tissues are promising samples for proteomic studies, which can support the elucidation of glioma evolution and identify therapeutically vulnerable proteins and signaling pathways that drive recurrence and resistance mechanisms. We represented 2–3 adjacent, phenotypically distinct areas from 12 grade II-IV gliomas diagnosed according to the 2016 WHO classification, in a total of 35 samples (1.0mm cores), that were analyzed employing liquid chromatography tandem mass spectrometry (LC-MS/MS) for label-free expression proteomics. The statistical analysis was performed using R and Qlucore™ omics explorer software. Overall, 9222 peptides were mapped to 1758 non-redundant proteins, 320 of which had a significant (p< 0.05) differential expression in glioblastomas versus lower grade gliomas (Wilcoxon test comparing average expression). Principal component analysis (PCA) of the whole set of proteins showed clustering of the samples by tumor grade and IDH status. Unsupervised hierarchical analysis of the most significantly expressed proteins (p= 0.01, FDR= 0.05) showed that IDHwt gliomas had high expression of proteins related to cell movement, DNA structure, and fatty acid metabolism throughout the samples. IDHmut gliomas largely displayed high expression of mitochondrial enzymes related to energy production and neurotransmitter metabolism, with subsets closely related to 1p19q status and histological grade. Importantly, we demonstrated that LC-MS/MS analysis of FFPE core samples is feasible and enables recognition of different proteome signatures across histopathological phenotypes within a single tumor. This is the first study, to our knowledge, exploring proteome profiles addressing histopathological heterogeneity in gliomas by LC-MS/MS analysis of FFPE samples, which warrants further validation in independent datasets including ones that utilize frozen specimens. FUNDING: R01CA108633, R01CA169368, RC2CA148190, U10CA180850-01 (NCI), Brain Tumor Funders Collaborative Grant, and the Ohio State University CCC (all to AC).
PATH-24. CXCR4 IS A POTENTIAL THERAPEUTIC TARGET FOR GLIOBLASTOMA AND DIFFUSE INTRINSIC PONTINE GLIOMAS
Authors: Zorofchian Soheil , Zhu Ping , Takayasu Takeshi , Rios Adan , Quezado Martha , Esquenazi Yoshua , Ballester Leomar Y
Published: November 2019

Glioblastoma (GBM) is the most common adult malignant brain tumor with poor prognosis and Diffuse Intrinsic Pontine Glioma (DIPG) is a pediatric type of glioblastoma for which there is no effective therapy. CXCR4, a G-protein coupled receptor, has been shown to play a role in GBM invasion, cell survival, proliferation and angiogenesis. A CXCR4 inhibitor (AMD3100/Plerixafor) has been suggested as a potential therapeutic strategy for GBM with an isolated case report of a long-term survivor and an ongoing clinical trial evaluating its effects in GBM patients. However, there is a poor understanding of the expression of CXCR4 in GBM and DIPGs. In this study, we evaluated the expression of CXCR4 in 21-DIPG and 36-GBM cases. In GBMs, CXCR4 was expressed in 5.6% of cases in tumor cells and in 19.4% of cases in endothelial cells in blood vessels. In DIPGs, we observed expression of CXCR4 in 28.6% of cases in tumor cells and in 14.3% of cases in endothelial cells. We observed absence of CXCR4 expression in all IDH-mutant GBMs. There was no correlation between CXCR4 or EGFR expression, p53-mutations or H3F3A p.K27M mutations in DIPGs. There was a trend of poorer prognosis in CXCR4 positive DIPGs but the difference did not reach statistical significance. Furthermore, we evaluated the effects of Plerixafor in the survival of DIPG and U87-GBM cell lines and observed a dose-dependent reduction in cell viability. RT-PCR and immunohistochemistry of DIPG cells showed variable CXCR4 expression in the cell lines that did not correlate with sensitivity to Plerixafor. In conclusion, in vitro experiments show that the CXCR4 inhibitor Plerixafor is a potential therapeutic strategy for GBM and DIPGs. However, CXCR4 is not universally expressed in glioblastomas and its expression should be considered in clinical trials that evaluate the efficacy of CXCR4 inhibitors in GBM and DIPGs.
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

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

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

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

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

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

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

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

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

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

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).
NIMG-44. NON-INVASIVE ADVANCED IMAGING METRICS PROVIDE POTENTIAL BIOMARKERS FOR GBM BIOLOGICAL HETEROGENEITY AND IMMUNE LANDSCAPE VARIANCE
Authors: Kersch Cymon , Muldoon Leslie , Fu Rochelle , Claunch Cheryl , Neuwelt Edward , Barajas Ramon
Published: November 2019

BACKGROUND

Treatment of glioblastoma multiforme (GBM) is complicated by extensive tumor heterogeneity. We hypothesize that transcriptomic analysis of brain tumor regions with different magnetic resonance imaging (MRI) characteristics will define specific biological processes, providing a non-invasive method for tumor characterization and stratification.

METHODS

Previously at the University of California San Francisco, treatment naïve GBM tissue from gadolinium contrast enhancing lesion (CEL) and non-enhancing lesion (NCEL) regions were stereotactically sampled; prior to resection, relative cerebral blood volume (rCBV) and apparent diffusion coefficient (ADC) were determined. The tissue samples were characterized by immunohistochemistry and assessed for gene expression by microarray analysis. We correlated gene expression patterns in the CEL, NCEL, and non-tumor gliotic brain samples with multimodal physiological imaging metrics and immunohistochemical phenotypes. Gene expression networks were probed using Gene Set Enrichment Analysis. Key immunologic genes were examined individually.

RESULTS

Samples with differing MRI and histological phenotypes demonstrated transcriptomic variance reflecting distinct biological networks. We found significant differences in immune pathways, with immune gene signature prominent in CEL areas, moderate in NCEL and low in gliotic non-tumor brain. Within homogenously enhancing areas of CEL and NCEL there was underlying heterogeneity detectable by variable rCBV, ADC and histological phenotypes, which correlate with differing gene expression profiles indicative of biological and immunological tumor microenvironments. Increasing rCBV was correlated with an anti-inflammatory immune response in the CEL and a pro-inflammatory immune response in the NCEL. ADC was negatively correlated with cell cycle and immune networks in CEL, while NCEL ADC was positively correlated with immune processes. GBM samples with the mesenchymal molecular subtype had the greatest immune response.

CONCLUSIONS

Multimodal MRI features identify regionally diverse transcriptomic-based biological and immunological phenotypes in GBM. We propose that imaging genomics provides a technique for localizing biological processes and tumor immune microenvironments across space and time in GBM.
NIMG-45. 3D SINGLE-SCAN FOR MULTI-CONTRAST-WEIGHTED MRI FOR LESION DETECTION IN PATIENTS WITH GLIOMAS
Authors: Liu Jing , Jakary Angela , Lafontaine Marisa , Wang Yan , Xu Duan , Saloner David , Butowski Nicholas , Hess Christopher , Villanueva-Meyer Javier , Chang Susan , Lupo Janine
Published: November 2019

INTRODUCTION

Multi-contrast-weighted (MCW) MRI allows derivation of T1-weighted, T2-weighted, and T2-FLAIR images and their parametric maps. Under current practice, these high-resolution 3D MR images are acquired separately with a total scan time is approximately 30 minutes. The goal of this study was to develop a novel sequence and processing strategy for MCW MRI and lesion detection of gliomas with 1mm isotropic resolution in 6 minutes, which can significantly improve clinical imaging workflow. The proposed whole brain, single-scan method enables the generation of segmented tumor regions that correspond the hyperintense lesion on T2-weighted or T2-FLAIR images (T2L).

METHODS

Our strategy involves using a highly accelerated 3D MRI sequence to achieve whole brain, MCW images that can be jointly segmented with modified k-means clustering. Six patients with enhancing gliomas were scanned with this sequence before the injection of gadolinium, 4 of which also received a repeat scan post-gadolinium. Our automatic segmentation of the T2L and manual definition of the contrast-enhancing lesion (CEL) was compared against manually segmented lesions drawn from conventional anatomical imaging.

RESULTS

Whole-brain MCW MRI was achieved with 1mm isotropic resolution in 6 mins. Grey-matter, white-matter, CSF, and the T2L could be automatically segmented with our clustering method. The resulting automatically-segmented T2L volume was not significantly different between our new sequence and clinically defined regions (average Dice Coefficient=0.81(+/-0.05); p=0.95).

CONCLUSIONS

Our novel, 6-minute scan and processing strategy was able to generate MCW anatomical images and automatically segment grey-matter, white-matter, and T2L volumes that were similar to manual segmentation of conventional anatomical imaging. We are currently extending the automatic segmentation to the CEL. This approach has the potential to improve clinical workflow by allowing time for therapy-specific advanced imaging and providing a noninvasive tool for monitoring tumor evolution. Validation is currently being performed in a larger cohort.
NIMG-54. DIFFUSION MRI PHENOTYPES PREDICT OVERALL SURVIVAL BENEFIT FROM BEVACIZUMAB IN RECURRENT GLIOBLASTOMA WITH A LARGE TUMOR BURDEN: EVIDENCE FROM CLINICAL PRACTICE AND A MULTICENTER PHASE 3 TRIAL
Authors: Patel Kunal , Raymond Catalina , Yao Jingwen , Tsung Joseph , Goldman Jodi , Schlossman Jacob , Tran Caleb , Brenner Andrew , Butowski Nicholas , Wen Patrick , Pope Whitney , Ji Matthew , Lai Albert , Leia Nghiemphu P , Rachmilewitz Minei Tamar , Cohen Yael , Harats Dror , Cloughesy Timothy , Ellingson Benjamin
Published: November 2019

We have previously shown that diffusion MR characteristics are a predictive imaging biomarker for survival benefit in recurrent glioblastoma treated with anti-VEGF therapy; however, contemporary clinical use of bevacizumab is often limited to patients with very large tumors and/or after multiple recurrences. We hypothesize that diffusion MR characteristics can be used to predict long-term survival benefit in these patients, which may be beneficial for clinical decision-making. The current study identified 83 recurrent glioblastoma patients from our institution who were treated with bevacizumab over the past 5 years with high quality anatomic and diffusion MRI data. Of these 83 patients, 35 had large contrast enhancing tumors (>20cc or >3.4cm diameter, group average). Additionally, we identified 37 recurrent glioblastoma patients from the bevacizumab treated control arm of a recent multicenter phase III trial (NCT02511405) with high quality data and large enhancing tumors for validation. Pre-treatment tumor volume was quantified using T1 subtraction maps and apparent diffusion coefficient (ADC) histogram analysis was used to phenotype patients as having high (> 1.24 um2/ms) or low (< 1.24 um2/ms) ADCL, the mean value of the lower peak using a double Gaussian mixed model. Median overall survival in patients with large volume recurrent glioblastoma was ~5.7 months. High ADCL was associated with significantly longer overall survival (OS) compared with low ADCL in both single center (P=0.0271, HR=0.486, mOS=5.5 vs. 2.8mo) and multicenter phase III data (P=0.0457, HR=0.507, mOS=7.9 vs. 5.7mo). Accounting for absolute tumor volume and age, both cohorts showed that ADCL was an independent prognostic factor for OS (Cox, P< 0.01). In summary, pre-treatment diffusion MR imaging is an independent predictive biomarker for OS in recurrent glioblastoma with a large tumor burden.