bluuebunny/crossref_metadata_2025 huggingface dataset:
IMMU-32. RNA-NANOPARTICLE VACCINES MEDIATE T CELL TRAFFICKING NECESSARY FOR BBB PASSAGE AND ANTI-GLIOMA IMMUNE RESPONSE
Authors: Mendez-Gomez Hector , Wummer Brandon , Grippin Adam , Weidert Frances , Huang Jianping , Deleyrolle Loic , Mitchell Duane , Sayour Elias
Published: November 2019

BACKGROUND

The blood-brain barrier (BBB) remains a potent obstacle for development of new therapies against glioblastoma (GBM). While activated T cells can cross the BBB, immunotherapy has yet to be fully unlocked for malignant brain tumors due their heterogeneity and immunosuppressive microenvironments. To overcome these challenges, our group has developed a novel treatment platform, which leverages the use of a clinically translatable nanoparticles (NPs) combined with personalized tumor derived mRNA to peripherally activate T cells against a heterogenous source of tumor antigens and reprogram the intratumoral milieu into an immune activated state.

OBJECTIVE

We sought to assess if RNA-NPs could activate systemic/intratumoral dendritic cells (DCs) and mediate a peripheral T cell response that could penetrate the GBM microenvironment.

RESULTS

We uncovered that RNA-NPs elicit potent innate immunomodulating effects through release of interferon-α (IFN-α) from plasmacytoid DCs (pDCs). After only a single RNA-NP vaccine, the bulk of systemic and intratumoral DCs in mice display an activated phenotype; DCs, harvested from intracranial tumors, elicit expansion of antigen specific T cell immunity. Tumor-specific RNA-NPs elicited enhanced survival outcomes in immunocompetent animals bearing NF-1/p53 mutant gliomas with increased intratumoral memory CD8+T-cells. Unlike immune checkpoint blockade (anti-PD-L1 mAbs), we found that RNA-NPs increase LFA-1 on peripheral CD8 splenocytes, which is necessary for activated T cell passage across the BBB. RNA-NPs also increased CCR2 on peripheral CD8 cells, which was dependent on IFN-α/β, as the percentage of CCR2+CD8+ splenocytes and anti-tumor activity (mediated by RNA-NPs) was abrogated in animals receiving concomitant type I IFN receptor (IFNAR1) mAbs.

CONCLUSION

Since LFA-1 is important for T cell trafficking across the BBB and CCR2 may promote chemotaxis to the brain (as GBMs are known to secrete CCL2), RNA-NPs may offer a new treatment modality and immunologic mechanism for unlocking peripheral T cell immunity against malignant gliomas.
IMMU-51. PROFILING THE IMMUNE SYSTEM IN PRIMARY AND RECURRENT GLIOBLASTOMA
Authors: Maddison Kelsey , Graves Moira , Bowden Nikola , Vilain Ricardo , Fay Michael , Tooney Paul
Published: November 2019

Immunotherapy has been shown to have benefit in some solid tumours including melanoma where immune infiltration can be pronounced. Until recently the central nervous system was thought to be immune privileged. Whilst research has shown that immune cells are capable of infiltrating tumours from glioblastoma patients, to date immunotherapy trials have not consistently shown a benefit in these patients. The aim of this study was to profile the immune system in primary and recurrent tumours from glioblastoma patients. Formalin-fixed paraffin-embedded sections of primary and matched recurrent tumours from 13 patients with glioblastoma were processed for immunohistochemical labelling of a range of immune cell markers. Immune infiltration was scored on digitally scanned immunolabelled sections using a categorical system of 0 (absent), 1 (present), 2 (moderate) and 3 (marked). CD3+ cells were observed in three topographical locations within primary and recurrent glioblastoma tumours namely the tumour proper, perivascular spaces and associated with haemorrhages within the tumour. CD3+ cell infiltration into the tumour proper was present (Score = 1) in 7 of 13 primary and recurrent tumours. Only one case (case #9) had CD3+ infiltration scores > 1 for both primary (score = 3) and recurrent tumour (score = 2). CD3+ cells were observed in perivascular spaces in 10 of the 13 cases of primary and recurrent glioblastoma. Only case #9 had CD3+ cells in perivascular spaces that was scored >1 for both primary and recurrent tumours. In conclusion, whilst CD3+ infiltration was observed in the tumour proper and perivascular spaces within both primary and recurrent glioblastomas, the level of infiltration was quite low in this small cohort and as such requires further investigation in a larger cohort.
INNV-06. TREATMENT RESPONSE TO BEVACIZUMAB OVER TWO YEARS IN A PATIENT WITH GENETICALLY PROVEN SOMATIC NEUROFIBROMATOSIS TYPE 2 MOSAICISM
Authors: Basenach Elena , Förster Alisa , Raab Peter , Alzein Samer , Schmidt Gunnar , Krauss Joachim , Heidenreich Fedor , Hartmann Christian , Auber Bernd , Wiese Bettina , Weber Ruthild
Published: November 2019

Neurofibromatosis type 2 (NF2) is a tumor predisposition syndrome characterized by the development of schwannomas, especially bilateral vestibular schwannomas (VS), and meningiomas. Heterozygous pathogenic variants in the NF2 gene are known to cause NF2, whereby somatic mosaicism is present in ~25% of simplex patients. In schwannomatosis, a disorder phenotypically similar to NF2, heterozygous SMARCB1 or LZTR1 variants may be causative. Recently, bevacizumab has shown efficiency as therapy for VS in some NF2 patients. We report on a thirty-three-year-old patient with bilateral VS, fourteen additional schwannomas and one intracranial meningioma. Next generation sequencing using a cancer gene panel and Sanger sequencing of LZTR1 on blood and oral mucosa DNA revealed no pathogenic variants in NF2, SMARCB1 or LZTR1. Sanger sequencing on DNA from three schwannomas identified the known NF2 nonsense variant c.784C >T;p.(R262*) (NM_000268.3, GRCh37/hg19) in all tumors, leading to the diagnosis of somatic NF2 mosaicism. Because of hearing impairment and tumor progression the patient underwent an off-label therapy with 5mg/kg bevacizumab. To determine treatment response, we evaluated MRI scans from five pre-therapeutic and two therapeutic years as well as pure-tone audiometry. After 25 months of treatment, (i) the pure-tone average improved by 11.2 dB indicating a hearing benefit, (ii) four of seven non-vestibular schwannomas showed a volume reduction of ≥ 20%, (iii) the volume of three of seven schwannomas stabilized, and (iv) the growth rate of the meningioma decreased. In conclusion, in a patient with somatic NF2 mosaicism, an off-label therapy with bevacizumab was efficient with respect to hearing improvement and tumor shrinkage in over half of non-vestibular schwannomas over a period of two years.
INNV-13. A NOVEL TELEGRAM CHAT APPLICATION BASED BOT (FLORENCEBOT) FOR BRAIN TUMOUR AFFECTED PATIENTS
Authors: Puri Abhishek , Sandeman Kyle
Published: November 2019

The discoverability of reliable information online is difficult. As the network grows exponentially, unregulated content has the potential to cause harm. Telegram is a popular mainstream chat application. It allows automated software called bots that interact passively with an individual. Florence bot is unique in this space for the patient support; for those affected by brain tumours. It has been developed in PHP and hosted privately by the developer. Florence links to physician generated content (hosted externally on a blogging website) such as introduction, signs and symptoms of brain tumours and various treatment options along with their side effects. The content generates “web view” in Telegram itself, preserving written and multimedia formats. It ensures minimal overheads on the bot, making it responsive. It links to brain tumour channel (automated streamed information working as a public broadcast) and physician-administered support group. A physician designed bot is preferable to a third party mobile application to ensure the accurateness of information. No user-related information is available to bot developers as it does not have tracking and advertising elements; hence safeguards users privacy. It is more accessible and cheaper to deploy than a mobile application as it uses an instant messaging app as its container, which works across computing platforms. Florence bot is expected to bridge the gap for reliable information and real-time support independent of geographical limitations.
INNV-22. TO TREAT OR NOT TO TREAT – TREATMENT OUTCOMES OF VERY ELDERLY GLIOBLASTOMA PATIENTS
Authors: Baumgarten Peter , Prange Georg , Harter Patrick , Forster Marie-Therese , Wagner Marlies , Steinbach Joachim , Seifert Volker , Senft Christian
Published: November 2019

OBJECTIVE

The prognosis especially of older patients with glioblastoma is poor. Novel therapies are usually reserved for patients ≤65 years. As the population is growing older, the challenge remains as to how very elderly patients ≥75 years should be treated. Only limited outcome data exist for this patient subgroup.

METHODS

Between 2010 and 2018 we treated a total of 977 patients with glioblastoma at our institution. Of these, 144 patients were ≥75 years at diagnosis. The primary procedure was surgery or biopsy followed by adjuvant treatment, if possible. We retrospectively investigated progression-free and overall survival (OS) and looked at potential prognostic factors influencing survival, including Karnofsky performance score (KPS), surgical therapy, adjuvant therapy as well as MGMT promoter methylation status.

RESULTS

In our very elderly cohort, the median age was 79 years (range: 75–110). Biopsy only was performed in 108 patients, resection was performed in 36 patients. Median OS for the entire cohort was 5.9 months. Patients without adjuvant treatment fared worse than patients receiving either radiotherapy and/or chemotherapy (1.2 vs. 8.4 months, p< 0.001). Multivariate analysis showed that KPS at presentation (≥70 vs. ≤60), surgery vs. biopsy, and MGMT status (methylated vs. non-methylated) were significantly associated with OS (6.3 vs. 3.9 months, p=0.002; 12.6 vs. 4.9 months, p=0.003; and 10.5 vs. 5.0 months, p=0.009, respectively).

CONCLUSION

For patients with glioblastoma ≥75 years, the natural course of the disease is devastating, and there is a negative treatment bias in these patients. Very elderly patients, too, benefit from multimodal treatment including microsurgical tumor removal. Treatment options and outcomes should be thoughtfully discussed with patients before treatment decisions are made.
INNV-38. RATE OF EEG IN GLIOMA PATIENTS: SHOULD THIS BE PART OF STANDARD OF CARE FOR NEW BRAIN TUMOR PATIENTS?
Authors: Sherman Wendy
Published: November 2019

Current guidelines recommend antiepileptic drug (AED) therapy for glioma patients only in patients who have experienced a seizure. There is no current recommendation in regards to performing EEG monitoring in glioma patients. Thus, typically only clinical seizures have prompted AED therapy in glioma patients. Our purpose was to investigate the rate of EEG monitoring in glioma patients entered into our glioma registry, along with seizure and AED rates. Using our glioma registry to date, of 167 glioma patients, 119 patients had EEGs performed during their clinical course. Of those 119 patients, 104 glioma patients had either clinical or electrographic seizure activity and all 104 were on AEDs. This observation indicates that baseline eeg monitoring might be considered in all newly diagnosed glioma patients to reduce seizure incidence, potentially, starting AED prophylaxis if epileptiform activity is seen on EEG prior to clinical seizure activity to potentially reduce morbidity and healthcare costs related to clinical seizure activity. This warrants further prospective study.
INNV-40. TARGETED NEXT GENERATION SEQUENCING OF PEDIATRIC HIGH-GRADE GLIOMA AND ITS THERAPEUTIC IMPLICATIONS, MD ANDERSON EXPERIENCE
Authors: McCall David , Eterovic Agda , Moss Tyler , Baig Muhammed , Fuller Greg , Huse Jason , Sandberg David I , Rytting Michael , Gill Jonathan , Chandra Joya , Khatua Soumen , Shaw Kenna , Meric-Bernstam Funda , Zaky Wafik
Published: November 2019

INTRODUCTION

The new understanding of molecular pathways in cancer is paving the way towards personalized cancer medicine, especially in refractory disease. High-grade gliomas (HGG) are common pediatric brain tumors that tend to recur, with no available standard therapy upon recurrence. HGG are challenging tumors with illusive biology and poor outcome. We report here the molecular testing of 27 pediatric HGG patients.

MATERIALS AND METHODS

An analysis of pediatric patients with HGG treated at UT MD Anderson Cancer Center (MDACC) who underwent molecular genetic profiling using next generation sequencing with different genomic panels (AmpliSeq™Cancer Hotspot and Oncomine Panels – by Thermo Fisher Scientific).

RESULTS

27 patients with HGG (median age 14 years, range 3–18 years old) underwent genomic profiling. Primary diagnoses were glioblastoma multiforme (n=22), anaplastic astrocytoma (n = 2), gliosarcoma (n= 1), anaplastic pleomorphic xanthoastrocytoma (n= 1) and anaplastic oligoastrocytoma (n= 1). There are 46 genes common to the panels used. The most common mutation was in TP53 (73%). Other mutations included PIK3CA (19%), IDH1 (11.5%), 7.7% for ATM, EGFR and PTEN, and 3.8% for BRAF, FGFR1 and FGFR2. 24 out of 27 patients were tested at initial diagnosis and 3 upon relapse/progression. Patients at initial diagnosis received standard of care therapy of radiation and temozolomide. Only 5 patients received targeted therapy upon progression/recurrence. Some challenges of genomically-matched therapy included lack of clinical trials accepting pediatric patients, unavailability of a liquid form of a drug, and insurance disapproval for off-label use.

CONCLUSION

The next generation of therapy for childhood cancers will be based upon in-depth molecular phenotyping that may facilitate the development of rational risk-adapted and target-based therapies. This cohort, though limited by sample size, highlights the opportunity to perform molecular testing and identification of alterations in actionable genes.
MNGI-04. PATTERNS OF FAILURE AND FACTORS INFLUENCING LOCAL RECURRENCE OF MENINGIOMA TREATED WITH POSTOPERATIVE RADIATION THERAPY
Authors: Susko Matthew , Vasudevan Harish , Magill Stephen , Calixto-Hope Lucas , Villanueva-Meyer Javier , Nakamura Jean , Ann Oberheim-Bush Nancy , Theodosopoulos Philip , Solomon David , Braunstein Steve , Sneed Patricia , McDermott Michael , Raleigh David
Published: November 2019

BACKGROUND

Factors associated with meningioma recurrence after postoperative radiotherapy are poorly understood, and the optimal postoperative radiotherapy target delineation for meningioma is unknown. The objective of this study was to identify factors influencing meningioma recurrence after postoperative radiotherapy to inform patient selection and treatment design.

METHODS

Medical records were retrospectively reviewed for patients who underwent meningioma resection at a single institution between 1991 and 2015. Patients with sufficient tumor tissue for histologic classification and who received postoperative radiation therapy with external beam radiotherapy (EBRT), stereotactic radiosurgery (SRS) or brachytherapy, were included. Local freedom from recurrence (LFFR) was analyzed according to tumor and treatment characteristics using the Kaplan Meier method.

RESULTS

We identified 86 patients with 96 meningiomas who met inclusion criteria. Nineteen meningiomas (20%) were WHO grade I, 56 (58%) were grade II and 21 (22%) were grade III. Forty-one meningiomas (43%) were recurrent, and 55 (57%) were de novo. The postoperative radiotherapy modality was EBRT for 58 patients (60%), SRS for 20 (21%) patients and brachytherapy for 18 (19%) patients. With a median follow up of 4.3 years (IQR 2.1–8.8 years), there were 48 (50%) local failures that occurred a median of 17 months after immediate prior resection (IQR 9–33 months). WHO grade II/III and recurrent meningiomas had worse LFFR (p< 0.001). The 5-year LFFR was 53% after EBRT (95% CI 41–69%), 53% after SRS (95% CI 34–84%) and 15% after brachytherapy (95% CI 3–74%), although meningiomas that were treated with brachytherapy were significantly more likely to have received prior EBRT or SRS (86% versus 29%, p< 0.001).

CONCLUSIONS

These data provide a foundation for understanding patterns of meningioma recurrence after postoperative radiotherapy. Ongoing analyses aim to quantify the relationships between postoperative radiotherapy dose, target delineation and local control of meningioma.
MNGI-12. PLEIOTROPIC MLLT10 VARIATION CONFERS RISK OF MENINGIOMA, BREAST, AND OVARIAN CANCERS
Authors: Walsh Kyle , Zhang Chenan , Calvocoressi Lisa , Hansen Helen , Berchuck Andrew , Schildkraut Joellen , Bondy Melissa , Wiemels Joseph , Claus Elizabeth
Published: November 2019

BACKGROUND

Women ages 35–44 have three-fold higher risk of meningioma compared to men. Epidemiologic studies have implicated exogenous hormone use, but endogenous hormonal factors are inconsistently associated. Elevated body mass index (BMI) is consistently associated with meningioma risk in both men and women, and personal history of breast cancer has also been associated with meningioma risk. Recent genome-wide association studies (GWAS) have identified a meningioma risk locus on chromosome 10p12 near previous GWAS hits for breast and ovarian cancers.

METHODS

To elucidate the pleiotropic role of 10p12 variation in predisposition to diverse tumors - possibly via a common mediating factor - we performed imputation‐based fine‐mapping in three case-control datasets of meningioma (927 cases, 790 controls), female breast cancer (28108 cases, 22209 controls), and ovarian cancer (25509 cases, 40941 controls). Analyses were stratified by sex (meningioma), estrogen receptor status (breast), and histotype (ovarian), then combined using ASSET meta-analysis. Lead variants were queried for association with >700 additional traits to identify potential effect-mediators.

RESULTS

Two-sided ASSET meta-analysis identified a lead variant near the MLLT10 promoter (P=1.4x10-13) associated with significantly increased risk of meningioma in women (OR=1.42, 95% CI: 1.20–1.69) and non-significantly increased risk in men (OR=1.19, 95% CI: 0.91–1.57). The meningioma risk allele was also associated with ovarian cancer risk (OR=1.09, 95% CI: 1.06–1.12) and ER+ breast cancer risk (OR=1.05, 95% CI: 1.02–1.08), but protected against ER- breast cancer (OR=0.91, 95% CI: 0.86–0.96). The risk allele was associated with higher body fat percentage, waist circumference and BMI at genome-wide levels (P< 5.0x10-8), but mediation analysis adjusting for BMI did not attenuate its association with meningioma risk.

CONCLUSION

We identify a MLLT10 eQTL that confers risk of female meningioma, ER+ breast cancer, ovarian cancer, and obesity, but which protects against ER- breast cancer. Our results implicate a possible estrogenic mechanism underlying meningioma tumorigenesis.
PATH-18. CSF-DERIVED CIRCULATING TUMOR DNA REFLECTS DISEASE COURSE AND CLONAL EVOLUTION IN MEDULLOBLASTOMA
Authors: Liu Anthony P Y , Kumar Rahul , Smith Kyle , Robinson Giles , Gajjar Amar , Northcott Paul
Published: November 2019

Medulloblastoma (MB) is the most common malignant brain tumor in young children. A multi-modal approach comprises standard of care, and recent advances in molecular studies have identified clinically relevant subgroups. Nonetheless, 30% of MB patients relapse or progress, conferring dismal prognosis. Such suboptimal outcome is partly due to a lack of sensitive biomarkers for response-adapted personalization of treatment and relapse prediction. Circulating tumor DNA has been shown to correlate with disease status in a variety of adult cancers, but studies in pediatric brain tumors, including medulloblastoma, are scarce. Here, we aim to evaluate the utility of profiling cell-free DNA (cfDNA) derived from longitudinally-banked cerebrospinal fluid (CSF) samples collected from children with MB enrolled in two prospective, multi-center trials (SJMB03 and SJMB12, estimated sample size of 100 patients, including 50 with subsequent progression). cfDNA was extracted, quantified, and analyzed for size distribution from pre-centrifuged CSF serially banked during the course of treatment and follow-up. Low-pass whole genome sequencing (LP-WGS) enabled detection of chromosomal and focal copy number alterations (CNAs). CNAs detected in cfDNA were compared against known somatic changes in corresponding primary tumors. Detectability of tumor-specific CNAs in cfDNA was then correlated with tumor burden and patient outcome. Pilot analysis showed presence of arm level and/or focal CNAs in cfDNA from 80% of CSF samples in 20 children with metastatic MB, and longitudinal assessment revealed correlation with clinical course throughout treatment with radiotherapy and chemotherapy. Further comparison of tumor and longitudinal cfDNA derived CNAs revealed divergent genomic alterations implicating potential oncogenic mechanisms underlying treatment failure and recurrence. Our study performed on a large prospective series of MB trial patients substantiates the utility of CSF derived cfDNA as an actionable biomarker in high-risk MB patients while also facilitating understanding of tumor evolution and heterogeneity.
PATH-26. CHARACTERIZING GENETIC DIFFERENCE IN CYSTIC GLIOBLASTOMA
Authors: Chen Zhihua , Long Xidai , Miao Yifeng , Zhou Xuan , Rockne Russell
Published: November 2019

Glioblastoma (GBM) is characterized by widespread genetic and transcriptional heterogeneity. Cystic GBM (cGBM) as a rare type, yet the cause of cyst formation and their bioinformatics about the role of the epigenome in disease progression are still unknown. We believe that there are certain factors that cause the entity of tumor to dissolve, leading to the formation of cavities inside the tumor. Exploring the is mechanism and key gene targets may become important strategies for future treatment. Here, we present genome-scale maps of DNA methylation, WES and whole transcriptome sequence in matched cGBM and noncGBM, as well as MRI image digital analysis and immunology scales to investigate the difference between these two groups. Firstly, we find that they are totally two different groups by transcription start site (TSS) Upstream and downstream methylation distribution. When Cgbm VS NONCgbm, There are 220 sites are up-regulation and 6273 sites are down-regulation. Next, whole transcriptome Sequence result showed that 2934 differential mRNA are down-regulation and 4524 differential mRNA are up-regulation in cGBM group, compare with noncGBM. At the same time, 896 differential genes are down-regulation and 1044 differential genes are up-regulation in cGBM group; 1744 differential IncRNA are down and 1643 differential IncRNA are up. Finally, we didn’t find different novel gene on whole transcriptome sequence. This is the first time we detect the varieties between cGBM and noncGBM based on the realm of DNA methylation, WES and whole transcriptome sequence. The further analyses deserve to do to explain the formation of cyst in tumor and vital gene target, which could be benefit to new treatment decision.
PATH-42. IDH-MUTANT LOWER-GRADE ASTROCYTOMAS CAN BE STRATIFIED FOR RISK BY CDKN2A, CDK4 AND PDGFRA COPY NUMBER ALTERATIONS
Authors: Rui Yang Ryan , Ka-Wai Li Kay , Ng Ho-Keung
Published: November 2019

In the 2016 WHO classification of tumors of the CNS, isocitrate dehydrogenase (IDH) mutation is a main classifier for lower-grade astrocytomas and IDH mutated astrocytomas is now regarded as a single group with good prognosis. However, the molecular and clinical heterogeneity among IDH-mutant lower-grade astrocytomas have only rarely been investigated. In this study, we recruited 161 IDH-mutant lower-grade astrocytomas, and examined PDGFRA amplification, CDKN2A deletion, and CDK4 amplification by FISH analysis, TERT promoter mutation by Sanger sequencing, and ATRX loss and p53 expression by immunohistochemistry. We identified PDGFRA amplification, CDKN2A deletion, and CDK4 amplification in 18.6%, 14.9%, and 18.0% of our cohort respectively, and these alterations occurred in a mutually exclusive fashion. PDGFRA amplification was associated with shorter PFS (p< 0.0001) and OS (p< 0.0001). In tumors without PDGFRA amplification, CDKN2A deletion was associated with a shorter PFS (p=0.0332). Tumors were then divided into three risk groups based on the presence of molecular alterations: high-risk (PDGFRA amplification), intermediate-risk (CDKN2A deletion or CDK4 amplification) and low-risk (neither CDKN2A deletion, CDK4 amplification nor PDGFRA amplification). These three risk groups were significantly different in overall survival with mean survivals of 40.2, 62.9, and 71.8 months. The high-risk group also demonstrated a shorter PFS compared to intermediate- (p=0.036) and low-risk (p< 0.0001) groups. Our data illustrate that IDH-mutant lower-grade astrocytomas is not a homogeneous group and should be molecularly stratified for risk.
PATH-47. TTF MAY APPLY SELECTIVE PRESSURE TO GLIOBLASTOMA CLONES WITH ANEUPLOIDY: A CASE REPORT
Authors: Ruff Michael , Clarke Nathan , Kizilbash Sani , Carabenciov Ivan , Uhm Joon , Jenkins Robert
Published: November 2019

BACKGROUND

The Tumor Treating Fields (TTF) mechanism of action is hypothesized act upon mitosis by disrupting the cell spindle apparatus. However, biomarkers and human tissue correlation of the effect of the TTF device are lacking. CASE: A 41 year-old previously healthy woman was found to have a right frontoparietal glioblastoma after she developed subacute onset of left hemiparesis and headache. The tumor was IDH wild type MGMT promoter unmethylated and TERT mutated. Chromosomal Microarray (CMA) was performed and demonstrated genome wide aneuploidy primarily characterized by hyperdiploidy. She underwent a gross total resection of the enhancing portion of the tumor and subsequent standard chemoradiotherapy (60 Gy IMRT with concomitant temozolomide) followed by initiation of the TTF device and adjuvant temozolomide. Six months after diagnosis, after 72 days of using the TTF device with 75% compliance and completion of the third cycle of temozolomide the patient had radiographic recurrence. She underwent a repeat resection. Pathology demonstrated recurrent tumor. Genetic analysis no longer demonstrated chromosomal losses or gains: the tumor was diploid.

DISCUSSION

This case may be a demonstration of effect of the TTF device applying a selective pressure to cells with multiple chromosomal gains and losses as the efficiency of mitosis in these cells may already be severely compromised. We are currently performing CMA on all patients with available tissue treated with the TTF device at our institution, with a planned retrospective analysis to explore this hypothesis further.

CONCLUSION

Repeat resection with detailed genetic analysis of GBM recurrence after therapies may help generate hypotheses regarding mechanisms of resistance, and in this case, mechanisms of action of the TTF.
PATH-52. ANAPLASTIC PILOMYXOID ASTROCYTOMA HARBORING BRAF FUSION, PTEN AND TERT MUTATIONS
Authors: Kissoon Trisha , Gururangan Sridharan , Kresak Jesse , Governale Lance
Published: November 2019

Pilomyxoid astrocytomas (PMA) are focal neoplasms that are often cured with total resection. We present a case of a progressive PMA with histologic and molecular features suggestive of malignant transformation. A 13-year old boy presented with headaches, diplopia, and seizures. He had previously been followed for 7 years by serial imaging for a cystic/solid enhancing mass in the right temporal lobe without biopsy that had remained stable up to 6 months prior to his current illness. MRI of brain demonstrated significant progression of the solid component with extension into the subependymal portions of the lateral ventricles, leptomeningeal spread in brain and spine, and hydrocephalus. Patient underwent a partial resection of tumor and VP shunt placement. Pathology demonstrated a prominent myxoid matrix with angiocentric arrangement of monomorphous bipolar cells. PHH3 and Ki-67 stains confirmed multiple mitoses and elevated proliferation rate. Next Generation sequencing of tumor confirmed the presence of a KIAA1549-BRAF duplication/fusion, CDKN2A deletion, along with PTEN and TERT promoter mutations without BRAF V600E or ATRX mutations. The histology and molecular features was suggestive of a pilomyxoid astrocytoma (PMA) with anaplastic transformation. Patient is currently receiving carboplatin + vincristine plus a MEK inhibitor (TrametinibTM, Novartis Corporation, Cambridge, MA) for tumor control. We believe that the tumor was initiated by the oncogenic BRAF fusion and the dramatic progression and spread of disease after a long period of stability was probably related to recent acquisition of additional deleterious mutations that have been previously reported in anaplastic pilocytic astrocytoma.
PATH-55. MUTATIONS OF H3.3 AND H3.1 IN A LARGE COHORT OF GLIOMAS
Authors: Sumrall Ashley , Mittal Sandeep , Phuphanich Surasak , Heimberger Amy , Eschbacher Jenny , Korn Michael , Gatalica Zoran , Pandey Manjari , Xiu Joanne
Published: November 2019

Mutations in the histone genes H3.3 and H3.1 are driver events in pediatric and adult gliomas and carry diagnostic and prognostic importance for tumors originating from midline structures. Patients with tumors affected by these mutations are difficult to treat. We surveyed a large cohort of gliomas for H3-mutations, including H3K27m. Consecutive gliomas submitted for tumor profiling at Caris Life Sciences from 2015- 2019 were analyzed. NextGen sequencing was done on 592 genes; MGMT promoter methylation was tested by pyrosequencing; and EGFRvIII and gene fusions were tested by RNA-sequencing. Of nearly 1800 tumors analyzed, 41 harbored H3F3A alterations, including 33 with the K27M mutation (4 arose from the spinal cord, 1 from cerebellum, 1 from brain stem, 4 from thalamus, and 23 from brain, NOS). Eight G34R mutations were identified. A HIST1H3B-K27M was detected in a tumor from the brain stem. H3 mutations were more prevalent in pediatric tumors, and all H3 mutations seen in pediatric tumors were from grade IV tumors. Among the H3-mutated adult tumors, histology differed. There were 2 grade II tumors, 1 low grade glioma, 1 anaplastic ganglioglioma, and 2 anaplastic astrocytomas. In the investigated cohort, H3-mutations were mutually exclusive of IDH1/2 mutations and EGFR alterations. Significantly higher mutation rates were seen in H3-mutated tumors for TP53, ATRX, NF1, PDGFRA, FGFR1, FBXW7, BLM, and TSC2 compared with H3-WT. The H3-WT tumors were more enriched for MGMT-methylation and PTEN mutation. In H3-mutated tumors that were MGMT-methylated, most H3-mutations seen were G34R while K27M was largely exclusive. There was a heterogeneous distribution of H3 mutations, and the co-occurring molecular alterations seen in H3-mutated tumors further support the hypothesis that these tumors are a distinct molecular entity. By better characterizing these associations, we can develop insight into novel treatment strategies for a class of tumors with historically dismal prognosis.
PATH-58. REAPPRAISAL OF HISTOLOGICAL FEATURES AND MOLECULAR ANALYSIS OF LOWER GRADE GLIOMAS AND ASSOCIATION WITH OVERALL SURVIVALS
Authors: Pareira Eriel , Ohara Kentaro , Shibuya Makoto , Nakagawa Yu , Yoshida Kazunari , Sasaki Hikaru
Published: November 2019

INTRODUCTION

Based on WHO 2016 classification of grade II and III glioma (lower grade glioma/LrGG), the pathological diagnosis of oligodendroglioma is associated with IDH mutation status and 1p/19q codeletion. It was reported that the classical oligodendroglioma features closely related to the presence of 1p/19q codeletion. In this study, we compared histology of oligodendroglial features with molecular prognostic factors such as ATRX, TERT, IDH1/2 and copy number aberrations and their relations with patients’ prognoses.

METHODS

In this study, we analyzed 94 cases of primary LrGG resected in 1990 to 2016 in Keio University Hospital, Japan. Using WHO 2007 classification of LrGG, we re-diagnosed the tumors based on their histological features and compared them to their initial diagnoses (made by the pathologists on the time of resections). The presence of classic for oligodendroglioma (CFO) features were closely documented. ATRX mutation was analyzed by immunohistochemistry. IDH1/2 and TERT mutation status were analyzed using Sanger sequence. Copy number aberrations analyzed using comparative genomic hybridization (CGH). In addition, we analyzed IDH-mut/codeleted tumors with cancer genetic panel.

RESULTS

Re-diagnosis shown there is a shift of trend toward oligodendroglioma diagnoses from astrocytoma and a trend of change from grade II to grade III. IDH-mut/codel tumors shown no correlation between CFO and molecular prognostic factors nor CNAs but there was correlation between overall survival and molecular factors such as CIC (p= 0.046) and FUBP1(p= 0.03). IDH-mut/non-codel tumors shown no correlation between CFO and overall survival but ATRX and gain of 8q were found to be correlated with pathological diagnosis.

CONCLUSION

There is a lot of change in histological diagnosis of oligodendroglioma from each eras. IDH-mut/codel tumors shown there is correlation between FUBP1 and CIC with overall survivals. IDH-mut/noncodel tumors shown there is correlation between gain of 8q with overall survivals.
PATH-60. PRIMARY CNS LYMPHOMA PRECEDED BY ACUTE DEMYELINATION
Authors: Low Justin , Buckley Anne , Randazzo Dina
Published: November 2019

Primary CNS lymphoma commonly presents with nonspecific encephalopathy or focal neurologic deficits. Magnetic resonance imaging typically shows a homogeneously enhancing mass with surrounding edema. The imaging differential diagnosis is broad, and includes high grade glioma and neuroinflammatory conditions. Definitive diagnosis therefore requires biopsy. Here we present a case of primary CNS lymphoma that was diagnosed as an acute demyelinating process on initial biopsy. A 68 year old female presented with gait instability and vertigo. MRI showed right cerebellar and right trigonal enhancing lesions. Biopsy revealed an acute demyelinating inflammatory process and she was diagnosed with acute disseminated encephalomyelitis. She was treated with intravenous methylprednisolone followed by oral prednisone with resulting clinical and radiographic improvement. She was re-admitted to hospital 4 months later with encephalopathy. Imaging showed a new enhancing mass in the pericallosal frontal lobes. Repeat brain biopsy showed diffuse large B-cell lymphoma. This case illustrates a highly unusual situation of biopsy-proven central demyelination preceding a primary CNS lymphoma diagnosis. It raises a number of etiopathological questions concerning the coexistence and potential causal relationships between demyelination and lymphoma. Additionally, it highlights the need for repeat biopsy if clinical and radiographic suspicion for lymphoma persists despite an alternative initial biopsy result.
PATH-61. IMMUNOHISTOCHEMICAL PHENOTYPING AND SURVIVAL ANALYSIS OF WHO GRADE II-IV GLIOMAS
Authors: Poulos Nora , Sattiraju Srikar , Opalak Charles , Dozmorov Mikhail , Harrison Jason , Richard Hope , Broaddus William
Published: November 2019

INTRODUCTION

Specific genetic mutations are linked to clinical prognosis in gliomas. There has been increasing demand to understand the association between tissue biomarker expression and survival. Using patient-derived samples, WHO grade II-IV gliomas were evaluated by the protein-staining pattern of molecular markers of interest across tumor grade, and the association between their expression and survival was investigated.

METHODS

Tissue microarrays (TMA) containing duplicate 1 mm cores were generated from 78 gliomas (WHO grade II-IV) using an automated TMA system. Immunohistochemistry was performed per the manufactures recommendation to evaluate expression of: Wilms tumor 1 (WT1), platelet endothelial cell adhesion molecule (CD31), adhesion G protein-coupled receptor E5 (CD97), complement decay-accelerating factor (CD55), hypoxia inducible factor 1 subunit alpha (HIF1α), EGF-like module-containing mucin-like hormone receptor-like 3 (EMR3), integrin, and isocitrate dehydrogenase 1 (IDH1). Samples with moderate (+1) or intense (+2) staining to WT1, CD31, CD97, CD55, or HIF1α, or any staining to EMR3 or IDH1 mutation, were considered positive.

RESULTS

Of the 78 tumor samples, there were 11 (14%) WHO grade II, 22 (28%) grade III, and 45 (59%) grade IV gliomas. Across grade III gliomas, anaplastic astrocytomas had significantly higher positive WT1 (p=0.04), CD31 (p=0.002) and IDH1 wild-type (p< 0.0001) staining. High-grade (III & IV) gliomas had significantly higher positive staining for WT1 (p=0.013), CD31 (0.024), integrin (p=0.021), and IDH1 wild type (p=0.044). In all gliomas, positive staining for WT1 (p< 0.0001), CD31 (p=0.009), CD97 (p=0.024), EMR3 (p=0.036), and IDH1 wild type (p=0.0006) were associated with worse overall survival. After adjusting for patient age, positive staining for WT1 (p=0.003) was associated with worse overall survival.

CONCLUSION

Using immunohistochemistry, unique biomarker staining patterns were identified for WHO grade III anaplastic astrocytomas and for high-grade gliomas. Irrespective of grade, staining for WT1, CD97, CD31, EMR3, and IDH1 wild-type were associated with worse overall survival.
PATH-63. TRANSCRIPTIONAL SIGNATURES IN HISTOLOGIC STRUCTURES WITHIN GLIOBLASTOMA TUMORS MAY PREDICT PERSONALIZED TREATMENT SENSITIVITY AND SURVIVAL
Authors: Kersch Cymon , Claunch Cheryl , Ambady Prakash , Bucher Elmar , Schwartz Daniel , Barajas Ramon , Iliff Jeffrey , Heiser Laura , Muldoon Leslie , Neuwelt Edward
Published: November 2019

OBJECTIVE

Personalized treatment strategies in Glioblastoma multiforme (GBM) has been hampered by intra-tumoral heterogeneity. The goals of this study were to (1) determine the impact of intra-tumoral heterogeneity on established predictive and prognostic transcriptional signatures in human GBM, and (2) develop methods to mitigate the impact of tissue heterogeneity on transcriptomic-based patient stratification.

METHODS

We analyzed transcriptional profiles of GBM histological structures from the open-source Ivy Glioblastoma Atlas Project. To generate these data, infiltrative tumor, leading edge, cellular tumor [CT], perinecrotic zones, pseudopalisading cells, hyperplastic blood vessels and microvascular proliferation were microdissected from 34 newly diagnosed GBM and underwent RNA sequencing. Data from The Cancer Genome Atlas were used for validation. Principle component analysis, network analysis and gene set enrichment analysis were used to probe gene expression patterns.

RESULTS

Distinct biological networks were enriched in each tumor histological structure. Classification of patients into GBM molecular subtypes varied based on the structure assessed, with many patients classified as every subtype depending on the structure analyzed. Using only CT to classify subtypes, we identified biologically unique patterns suggesting that proneural and mesenchymal tumors may be more sensitive to chemoradiotherapy and immunotherapy, respectively. Survival outcome predicted by an established multigene panel was confounded by histologic structure. Utilizing CT transcriptomics we developed a novel survival prediction gene signature that identified the highest-risk GBM patients in both CT and bulk tissue gene expression profiles.

CONCLUSIONS

Histologic structures contribute to intra-tumoral heterogeneity in GBM. Using mixed-structure biopsy samples could incorrectly subtype tumors and produce invalid patient stratification. Limiting transcriptomic analysis to the CT allowed us to develop a new survival prediction gene signature that appears accurate even in mixed tissue samples. The biological patterns uncovered in the subtypes and risk-stratified groups have important implications for guiding the development of precision medicine in GBM.
PATH-64. PROSPECTIVE, BLINDED PLASMA BASED ANALYSIS FOR DIAGNOSIS OF NEWLY DIAGNOSED GLIOMA
Authors: Lee Ian , Scarpace Lisa , Hunt Rachel , Nelson Kevin , Patil Darshana , Datta Vineet , Akolkar Dadasaheb , Apurva Sachin , Fulmali Pooja , Puranik Sneha , Snyder James , Noushmehr Houtan , Devhare Pradeep , deCarvalho Ana , Datar Rajan , Walbert Tobias , Kalkanis Steven
Published: November 2019

INTRODUCTION

In patients with newly diagnosed intracerebral lesions, gliomas are often suspected. However, other conditions such as multiple sclerosis, abscess or lymphoma are possible, as well. Furthermore, biopsy can be challenging due to eloquent and/or deep location within the brain. In this prospective, blinded study, analysis of plasma isolated cell-free DNA and exosome mRNA and miRNA from newly diagnosed glioma patients and from cancer-free volunteers was used to predict disease.

METHODS

Plasma was drawn from 52 patients with newly diagnosed gliomas (28 high grade glioma (HGG), 10 low grade (LGG)) and 14 patients without documented history of cancer and recent MRI brain which was negative for brain tumor. High quality DNA and RNA was isolated and sequenced using Next Generation Sequencing and Digital Droplet PCR was used for detection and verification of trace molecular artifacts. Multianalyte processing yielded data that was harmonized and interpreted through an Artificial Intelligence based algorithm to assess for possible glioma and to assign grade in a blinded fashion. EGFRvIII, TP53 and IDH1 mutations were also analyzed and compared to molecular testing from tumor specimens.

RESULTS

66% (25 of 38) of glioma patients were correctly diagnosed as having a malignancy. 43% of HGG and 60% of LGG patients were correctly graded. Of the 14 normal controls, 6 were concluded to be cancer-free. IDH1, EGFRvIII, and TP53 mutation had concordance of 64% (21/33), 82% (14/17) and 36% (5/14), respectively.

CONCLUSIONS

Analysis of plasma cell free tumor derived DNA and RNA was relatively sensitive for detecting glioma in treatment naïve patients. In contrast, this analysis was not specific in ruling out malignancy in the normal control patients. Given this profile, in patients with newly diagnosed intracerebral lesions suspicious for glioma, this may be a useful screening test to determine the need for more invasive testing, i.e. biopsy/resection.
NIMG-07. LACUNARITY AND FRACTAL DIMENSION ACT AS PRETREATMENT IMAGING BIOMARKERS FOR SURVIVAL IN GLIOBLASTOMA PATIENTS
Authors: Curtin Lee , Whitmire Paula , White Haylye , Mrugala Maciej , Hu Leland , Swanson Kristin
Published: November 2019

Glioblastoma (GBM) is the most aggressive primary brain tumor with a median survival of only 15 months with standard of care treatment. Lacunarity, a quantitative morphological measure of how shapes fill space, and fractal dimension, another morphological measure of the complexity of pixel arrangement, of segmented necrotic regions on gadolinium-enhanced T1 weighted (T1gd) MRI have previously been shown to distinguish both overall survival (OS) and progression free survival (PFS) in GBM (n = 95). In our larger patient cohort (n = 389), we sought to validate or refute previously published results connecting morphological metrics and patient survival. We identified pretreatment necrotic regions of our retrospective first-diagnosis GBM patient cohort using segmented T1gd MRI enhancing regions. We calculated lacunarity and fractal dimension across all T1gd MRI slices with enhancing tumor, and used the median lacunarity and fractal dimension values for our analysis. We find that a lacunarity threshold can significantly distinguish OS (14 months vs 19 months median, log-rank p = 0.015, n = 389) and a fractal dimension threshold can significantly distinguish PFS (8 months vs 11 months median, log-rank p = 0.015, n = 123). We believe that morphological metrics such as lacunarity and fractal dimension could play a role in standard-of-care prognostic considerations at tumor presentation. This link between morphological and survival metrics could be driven by underlying biological phenomena or microenvironmental factors that should be further explored.
NIMG-10. BRAIN TUMOR MRI STRUCTURED REPORTING ALLOWS CALCULATION OF INTERRATER AGREEMENT OF PATIENTS REVIEWED AT TUMOR BOARD
Authors: Cooper Maxwell , Hoch Michael , Abidi Syed , Hu Ranliang , Shim Hyunsuk , Weinberg Brent
Published: November 2019

INTRODUCTION

Longitudinal imaging evaluation of brain tumor patients with MRI is a challenging endeavor, as there is considerable overlap between imaging findings of tumor progression and treatment related changes. There is felt to be a high degree of variation between individual interpreters, particularly in complex cases. Structured reporting systems, such as the recently described brain tumor reporting and data system (BT-RADS), attempt to maximize consistency between reading radiologists, although how successful they are at achieving this is unknown.

METHODS

Patients with a diagnosis of a primary brain tumor with imaging presented at adult brain tumor board between October 2017 and March 2019 were reviewed. The most recent follow-up MRI was scored on an 8-point scale as described by BT-RADS, ranging from 0 to 4 with increasing suspicion for worsening disease, as described in the original radiologist report. Secondary review of MRI was performed by one of three neuroradiologists routinely participating in brain tumor conference. Interrater agreement between primary and secondary review were calculated using rates of exact agreement and linear weighted kappa.

RESULTS

Of studies reviewed, 270 out of 275 had imaging and reports suitable for repeat structured scoring. Grade 4 astrocytoma (glioblastoma) was the most common diagnosis, followed by grade 2 oligodendroglioma and grade 2 astrocytoma. The overall agreement rate between initial and secondary review was 83.0% with kappa of 0.89 +/- .05. There was perfect agreement on studies with improvement (1a or 1b) with lower levels of agreement (63.6–82.4%) for studies with worsening imaging findings (3a-4).

CONCLUSIONS

Using a structured reporting system to categorize MRIs in brain tumor patients allows for precise characterization of variation between report conclusions on primary and secondary review. Overall agreement is good, but variation rates increase with worsening findings which may be harder to correctly interpret.
NIMG-18. EFFECT OF BEVACIZUMAB AGAINST CYSTIC PART OF BRAIN TUMOR
Authors: Yamasaki Fumiyuki , Takano Motoki , Yonezawa Ushio , Taguchi Akira , Onishi Shumpei , Sugiyama Kazuhiko , Kurisu Kaoru
Published: November 2019

BACKGROUND

Bevacizumab improves the symptom via reducing the peritumoral edema and/or normalizing BBB, and occasionally via reducing the tumor size. However, the effect against active cystic portion has not been documented yet. We focused on the effect of bevacizumab on cystic component of brain tumors.

MATERIALS AND METHODS

Between 2008 and 2018, 139 patients with primary or metastatic brain tumor were treated with bevacizumab in our institution. We defined cystic lesions as high intense lesion of size ≥1 cm on T2-weighted imaging, and excluded necrotizing cysts and cystic changes in surgical resection cavity. The images before and after administration of bevacizumab were examined, and changes in cyst size was evaluated as follows: CR, PR, MR (reduction by ≥25%), SD, PD. The effect of bevacizumab on tumor itself was determined according to RANO criteria.

RESULTS

Of the 139 patients, 212 (15.1%) had cystic component. Among these 21 tumors, 14 had progressively increasing cysts prior to bevacizumab administration. On the first imaging following administration of bevacizumab, the response of cysts were as follows: CR 2, PR 7, MR 7, SD 5. The best response of cyst to bevacizumab treatment were as follows: CR 6, PR 7, MR 4, SD 4. The group of patients with progressively increasing cysts prior to bevacizumab treatment had significant cyst size reduction compared to stable cyst size groups, at initial image after bevacizumab (mean 62.6% vs. 22.5%, P=0.0055) and at best response timing (mean 76.3% vs. 32.8%, P=0.0050). The effect on the tumor itself was not associated with cyst responses, and the response rate as per RANO was as follows: CR 1, PR 11, SD 9.

CONCLUSION

Bevacizumab is effective against progressively increasing cysts. Although cyst reduction effect and tumor response are independent, bevacizumab may be effective for patients who are symptomatic due to cystic enlargement.