bluuebunny/crossref_metadata_2025 huggingface dataset:
GENE-21. ROLE OF POT1 MUTATION IN GLIOMA PROLIFERATION AND SEXUAL DIVERGENCE OF SURVIVAL
Authors: Jalali Ali , Yu Kwanha , Beechar Vivek , Mehra Deepika , Lozzi Brittney , Bondy Melissa , Deneen Benjamin
Published: November 2019

Germline POT1 mutations are associated with risk of several cancers including glioma. In The Cancer Genome Atlas, we found that the level of POT1 gene expression in tumors is associated with overall survival in IDH wild-type glioma independent of age and tumor grade (P=0.036). To assess if POT1 expression in a native mouse model of IDH wild-type glioma (referred to as C3 tumors) affects survival, we targeted both mouse POT1 orthologs (Pot1a/Pot1b) in C3 tumors using CRISPR/Cas9, generating C5 tumors. Interestingly, we noted a sexual divergence of survival, with female C5 mice dying faster than males (P=0.0034), whereas C3 mice show no sexual divergence in survival. To assess the genes and pathways underlying this divergence, we performed RNAseq profiling on C3 and C5 tumors and normalized the sex differences in the C5 profile for baseline sex differences in the C3 profile. Compared to males, female C5 tumors had lower enrichment of numerous gene sets related to immune surveillance. To specifically assess the effects of glioma-associated human POT1 variants, we expressed these variants in a mouse tumor sphere culture. We noted that expression of POT1-G95C variant increased the rate of sphere formation in vitro. In vivo expression of this variant in embryonic mouse brain during the gliogenic period increased the proliferative rate as assessed by BrdU uptake (P=0.008). These findings suggest a potential role for human POT1 variants in growth and proliferation of glial progenitor cells as well as glioma tumor cells. Additionally, the sexual divergence of survival in C5 tumors points to a differential interaction between POT1 loss and sex in regulation of immune response to these tumors.
GENE-24. DNA METHYLATION SIGNATURES DETECTED IN A SERUM-BASED LIQUID BIOPSY DISTINGUISH FUNCTIONAL AND INVASIVENESS FEATURES IN PITUITARY ADENOMAS
Authors: Wells Michael , Sarraf Sabedot Thais , Asmaro Karam , Mosella Maritza , Malta Tathiane , Nelson Kevin , Snyder James , deCarvalho Ana , Mukherjee Abir , Bahn Arti , Robin Adam , Rosenblum Mark , Mikkelsen Tom , Poisson Laila , Lee Ian , Walbert Tobias , Kalkanis Steven , Rock Jack , Noushmehr Houtan , Chitale Dhananjay , Castro Anavaleria
Published: November 2019

Pituitary tumors are the second most common CNS neoplasia (~15%). Despite mostly benign and slow-growing, they may be nonfunctioning and invade surrounding structures resulting in significant comorbidities. Currently, classification of PT according to their risk for aggressiveness is mainly based on invasiveness detected by imaging methods and histopathological features which requires surgically resected tumor. Being able to detect molecular markers associated with tumor subtypes and behavior pre-surgically using minimally invasive approaches (blood draw) is desirable in these tumors and may help to address current diagnostic and therapeutic challenges. In tissue specimens, distinct DNA methylation patterns distinguish PT according to their functional status but their role in invasiveness is still unclear. We hypothesized that profiling cell-free DNA (cfDNA) released by PT into the bloodstream allow the identification of epigenetic markers associated with relevant clinicopathological features. Genome-wide methylome profile of paired serum cfDNA (EPIC array) and tissue from 13 patients with pituitary macroadenomas (9 males; median age: 62; 9 Nonfunctioning/4 functioning, 6 invasive/7 noninvasive) and 3 controls serum (patients with epilepsy). Unsupervised analysis of the serum methylome from patients harboring PT was distinct from controls and other diseases (hypopituitarism, glioma and colorectal cancer) and supervised analysis (Wilcoxon Rank-sum Test) identified significant differentially methylated probes (DMP) that segregated PT from control serum specimens. Nonfunctioning and invasive-specific DMPs identified in the serum also defined functional, and less prominently invasive status, in the tissue of an independent cohort of PT. This is the first study to show the feasibility to profile the serum methylome from patients with PT using cfDNA. In addition, we identified unique methylation signatures that distinguished PT according to functional and invasiveness subtypes. These results underpin the potential role of methylation profile and liquid biopsy as a noninvasive approach to assess clinically relevant molecular features in the serum of patients harboring PT.
GENE-28. LONGITUDINAL MOLECULAR TRAJECTORIES OF DIFFUSE GLIOMA IN ADULTS
Authors: Barthel Floris , Johnson Kevin C , Varn Frederick , Moskalik Anzhela , Tanner Georgette , Kocakavuk Emre , Anderson Kevin , Abiola Olajide ,   GLASS Consortium, Huse Jason , DeGroot John , Stead Lucy F , Verhaak Roel
Published: November 2019

Treatment options for adult patients with glioma has remained largely unchanged over the past three decades. Targeted inhibitors and immunotherapies have improved outcomes for many cancer types but their relevance in glioma is unclear. The inevitability of glioma disease recurrence demands an understanding of mechanisms driving therapy resistance. The Glioma Longitudinal Analysis (GLASS) Consortium was initiated to establish a definitive portrait of the recurrence process and to discover vulnerabilities that render the tumor sensitive to therapeutic intervention. GLASS is a community-driven effort that seeks to overcome the logistical challenges in constructing adequately powered longitudinal genomic glioma datasets by pooling data from patients treated at institutions worldwide. Currently, the GLASS Data Resource comprises DNA sequencing data (exome and/or whole-genome) from 288 patients of whom high-quality data in at least two time points are present from 222 patients (n = 134 IDHwt, n = 63 IDHmutant-noncodel, n = 25 IDHmutant-codel). We inferred longitudinal mutation, copy number, clonal frequency, and neoantigen profiles and demonstrated that driver genes found at initial disease persisted into recurrence. Treatment with alkylating-agents resulted in a hypermutator phenotype at different rates across glioma subtypes, most frequently among IDHmutant-noncodels, and hypermutation was not associated with differences in overall survival. Acquired aneuploidy was frequently detected in recurrent IDHmutant-noncodel gliomas and further converged with acquired cell cycle pathway alterations and poor outcomes. We showed that the clonal architecture of each tumor remains largely intact over time and that genetic drift was associated with increased survival. Finally, we found that neoantigens were exposed to stable selective pressures throughout a tumor’s progression. Our results collectively suggest that the strongest selective pressures occur early during glioma development and that current therapies shape this evolution in a largely stochastic manner. The GLASS Data Resource provides a genomic reference to study the patterns of glioma evolution.
GENE-31. IDENTIFICATION OF CORE AND CONTEXT-SPECIFIC FITNESS GENES IN GLIOBLASTOMA STEM CELLS VIA GENOME-WIDE CRISPR-Cas9 SCREENS
Authors: MacLeod Graham , Angers Stephane , Dirks Peter , Rajakulendran Nishani , Ahmadi Moloud , Bozek Danielle , Luchman Artee , Weiss Sam
Published: November 2019

Advances in the characterization of the genetic, epigenetic and transcriptomic landscapes of glioblastoma (GBM) tumor samples and primary cell lines have yielded considerable insight into tumor initiation and progression. A major finding from these studies is the high degree of inter- and intra-tumoral variability displayed in GBM, which has increased interest in the identification of clinically relevant disease subtypes for precision targeting. While multiple groups have identified subtypes of GBM tumors and GBM stem cell lines, efforts to identify specific actionable targets have yet to bear fruit. To address this gap, we performed genome-wide TKO CRISPR-Cas9 fitness screens to functionally interrogate the genomes of a panel of 16 genetically/epigenetically characterized GBM stem cell lines. Our screens identify over 1,500 fitness genes per GBM stem cell line which collectively provide a functional landscape of genetic vulnerabilities in GBM. The size and heterogeneity of our screen panel provided us with the capability to identify both core (i.e. SOX9, Protein Ufmylation, JUN) and context specific fitness genes. Specifically, we have identified genes preferentially required for the proliferation of GBM stem cells based on transcriptionally defined subtypes (i.e. SOX2, OLIG2 in Proneural GSCs), genetic alterations (i.e. CDK6 in CDKN2A/B deleted GBM) and disease stage (i.e. ATP6AP2 in recurrent GBM). Experimental validation of key subtype-specific fitness genes is currently underway using genetic knockout and drug/inhibitor treatment. Our data provides biological insight and novel mechanistic understanding of heterogeneity in GBM and points to opportunities for precision targeting of defined GBM subtypes.
GENE-35. MGMT PROMOTER METHYLATION IN NEWLY DIAGNOSED LGG AS A POTENTIAL BIOMARKER FOR TMZ-ASSOCIATED HYPERMUTATION AT RECURRENCE
Authors: Mathur Radhika , Zhang Yalan , Grimmer Matthew , Hong Chibo , Berger Mitchel , Molinaro Annette , Ann Oberheim-Bush Nancy , Chang Susan , Costello Joseph
Published: November 2019

Low-grade gliomas (LGGs), which include grade II astrocytoma and grade II oligodendroglioma, inevitably recur despite aggressive treatment with surgery, and sometimes, with radiation and the chemotherapeutic agent temozolomide (TMZ). The clinical benefit of TMZ in LGG is unclear, and a subset of TMZ-treated LGGs recur with hypermutation in association with malignant progression to high-grade tumors. It is currently unknown why some TMZ-treated LGGs recur with hypermutation while others do not. O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair protein that reverses mutagenic lesions induced by TMZ. The amount of MGMT protein in a cell is regulated at the epigenetic level by promoter methylation. Here, we hypothesize that epigenetic silencing of MGMT by promoter methylation facilitates TMZ-induced mutagenesis and contributes to the development of hypermutation. We demonstrate in a cohort of 37 TMZ-treated patients with an initial diagnosis of IDH-mutant LGG that methylation level of the MGMT promoter in initial untreated tumors is significantly associated with hypermutation at recurrence. We also confirm our previous finding that methylation level of the MGMT promoter in recurrent hypermutated tumors is higher than in recurrent tumors that are not hypermutated. These results provide a plausible mechanistic basis for observed differences in propensity of TMZ-treated LGG patients to develop hypermutation at recurrence. Furthermore, they establish the potential of MGMT promoter methylation level to inform treatment decisions in the clinic for patients with newly diagnosed LGG.
GENE-42. EXOME SEQUENCING ANALYSIS TO IDENTIFY POSSIBLE GENOMIC DRIVERS OF METASTATIC INVASION INTO THE SPINE
Authors: Calinescu Alexandra , Sultan Zain , Rocco Sabrina , Gates Chris , Clines Gregory , Szerlip Nicholas
Published: November 2019

The spine is a common site of metastatic spread of many cancers, causing debilitating pain and suffering. Treatment of spinal metastases is limited by resistance to radiation, chemotherapy, and proximity to the spinal cord. It is currently not known what causes the high incidence of spinal metastases, yet theories have been proposed, like the venous metastatic spread theory (Batson, 1940) and the “seed and soil” hypothesis (Paget, 1889), postulating that factors intrinsic to the tumor cells or to the microenvironment determine the location of cancer dissemination. Recent advances in high throughput sequencing allow for in depth analyses of the molecular signatures of tumors. To identify if there are intrinsic genetic alterations common to cancer cells that disseminate into the spine, we sequenced the exome of metastatic tumor cells harvested from the vertebrae of 9 patients with different primary tumors: carcinomas and sarcomas. Exome sequencing was performed using the HiSeq 4000 (Illumina) platform on DNA from tumor cell lines and control blood or bone marrow. Data was analyzed at the University of Michigan Bioinformatics Core and variants were called using the VarScan method (http://varscan.sourceforge.net/) in somatic mode. This analysis identified a total of 2366 genes with high impact mutations (888–1026 per sample); of these, 232 genes are common to all patients analyzed. Ninety-six of the identified genes (4%) are included in the Catalogue of Somatic Mutations in Cancer, and of these, seven: ACSL6, ACVR1, ALK, FGFR2, HSP90AA1, PTPN6 and PTPRB, have high impact mutations in all 9 patients with spinal metastatic disease. Pathway analysis of genes mutated in 5 or more patients shows significant overrepresentation of 41 KEGG pathways including TGFb, HIF1-a, VEGF, Wnt and Estrogen signaling pathways. Ongoing experiments are performed to validate the sequencing analysis and characterize functional consequences of the common mutations identified.
GENE-43. TARGETING GABPb1L INHIBITS IN VIVO GROWTH OF TERT PROMOTER MUTANT GLIOBLASTOMA
Authors: Amen Alexandra , Lew Rachel , Ren Shawn , McKinney Andrew , Mancini Andrew , Doudna Jennifer , Fellmann Christof , Costello Joseph
Published: November 2019

Understanding cancer cell immortality in primary glioblastoma (GBM) is essential for the development of more informed treatments. Multiple cancer types, including >80% of GBMs, undergo immortalization by reactivating Telomerase Reverse Transcriptase (TERT) through acquired mutations in the TERT promoter. TERT, the catalytically active and rate-limiting subunit of telomerase, functions to maintain telomeres, which cap and protect the ends of chromosomes. Our past work has demonstrated that the transcription factor GABP - and specifically its tetramer-forming isoform GABPb1L - binds and activates the mutant TERT promoter. The generation of CRISPR-induced indels in GABPb1L results in a gradual loss of cell viability in TERT promoter mutant but not TERT promoter wild type tumor cells in vitro, but the extent to which GABPb1L function is compromised in this setting is unclear. Thus, the potential for use of GABPb1L as an effective therapeutic target for TERT promoter mutant GBM requires further investigation. Here, we use CRISPR-based strategies to demonstrate that full knockout of GABPb1L is rapidly lethal in TERT promoter mutant cells in vitro, in association with a decrease in both TERT mRNA and telomerase activity. Heterozygous deletion of GABPb1L in the context of TERT promoter mutations leads to slowed growth of orthotopic xenograft tumors in mice, and prolonged survival. Additionally, inducible RNAi-mediated inhibition of GABPb1L in growing tumors is also capable of decreasing tumor burden and increasing survival, further strongly suggesting that targeting GABPb1L in patient tumors could be a viable treatment strategy. Finally, reduced GABPb1L synergizes with temozolomide (TMZ) therapy such that TMZ treatment in the context of low GABPb1L and low TERT leads to a complete ablation of orthotopic GBM xenografts. These results highlight the potential to improve disease outcomes by targeting TERT through inhibition of GABPb1L, particularly in conjunction with TMZ treatment.
GENE-49. RNA PROCESSING GENES CHARACTERIZE RNA SPLICING AND FURTHER STRATIFY LOWER-GRADE GLIOMA
Authors: Chai Rui-Chao , jiang tao , Wang Yong-Zhi
Published: November 2019

Aberrant expression of RNA processing genes may drive the alterative RNA profile in lower-grade gliomas (LGGs). Thus, we aimed to further stratify LGGs based on the expression of RNA processing genes. This study included 446 LGGs from The Cancer Genome Atlas (TCGA, training set) and 171 LGGs from the Chinese Glioma Genome Atlas (CGGA, validation set). The least absolute shrinkage and selection operator (LASSO) Cox regression algorithm was conducted to develop a risk-signature. The ROC curves and Kaplan–Meier curves were used to study the prognosis value of the risk-signature. Among the tested 784 RNA processing genes, 276 were significantly correlated with the OS of LGGs. Further LASSO Cox regression identified a 19-gene risk-signature, whose risk score was also an independently prognosis factor (P< 0.0001, multiplex Cox regression) in the validation dataset. The signature had better prognostic value than the traditional factors “age”, “grade” and “WHO 2016 classification” for 3‐ and 5‐year survival both two datasets (AUCs > 85%). Importantly, the risk-signature could further stratify the survival of LGGs in specific subgroups of WHO 2016 classification. Furthermore, alternative splicing events for genes such as EGFR and FGFR were found to be associated with the risk score. RNA expression levels for genes, which participated in cell proliferation and other processes, were significantly correlated to the risk score. Our results highlight the role of RNA processing genes for further stratifying the survival of patients with LGGs and provide insight into the alternative splicing events underlying this role.
GENE-61. METHYLATION-BASED LIQUID BIOPSY OF MENINGIOMA PRIMARY AND RECURRENT SAMPLES
Authors: Sarraf Sabedot Thais , Malta Tathiane , Snyder James , Walbert Tobias , Lee Ian , Kalkanis Steven , Castro Anavaleria , Noushmehr Houtan
Published: November 2019

Meningiomas are mostly benign CNS tumors, however a subset of these tumors may become atypical or malignant. The standard of care to monitor patients after diagnosis requires serial MRI assessments, which have limited value in distinguishing malignant tumors from benign disease. Therefore the discovery of non-invasive methodologies that reflect meningioma tumor burden and its dynamic evolution in real-time is highly desirable. Liquid biopsy (LB) could be used to fine-tune surveillance and treatment with minimal risk to patients. Evidence of circulating tumor cells and cell-free (cf) tumor DNA in the blood has been shown in several tumor types, however limited progress has been made for brain tumors with known biomarkers; possibly due to the unlikelihood of capturing point mutations in circulating DNA fragments. On the other hand, DNA methylation signatures are maintained even in small DNA fragments, which suggests that DNA methylation is an attractive marker to be studied in liquid biopsy of brain cancers. In order to identify DNA methylation-based biomarkers using archival serum and tissue specimens, we analyzed the epigenome (Illumina Human EPIC array) of patients with primary (n=10) and recurrent (n=4) meningiomas and epileptic patients (n=5) as control. cfDNA fragment size distribution revealed peaks with 150~200bp on average. We identified 482 CpGs (p-value< 0.001) differentially methylated between primary meningiomas and controls, which 294 (61%) show a DNA methylation profile similar to the matched tumor tissue. Overall, we observed that recurrent samples are hypermethylated (56%) compared to primary. From this pilot data, we were able to investigate the LB methylome of meningioma patients and identify potential markers to detect tumor cells in the serum of these patients, which could eventually allow clinicians to monitor impending disease progression and recurrence.
GENE-62. IDENTIFICATION OF FGFR4 p.G388R VARIANT IN CEREBELLAR HEMANGIOBLASTOMAS
Authors: Snuderl Matija , Kannan Kasthuri , Gagner Jean-Pierre , Mashiach Elad , Karajannis Matthias , Heguy Adriana , Zagzag David
Published: November 2019

BACKGROUND

While most hemangioblastomas (~70%) are sporadic and occur predominantly in the cerebellum, they may present as well as familial form associated with von Hippel-Lindau (VHL) syndrome, an autosomal dominant disorder caused by germline mutations of the VHL gene that trigger nuclear translocation of hypoxia-inducible factor (HIF)-1α and angiogenesis. Although inactivation of VHL, a tumor suppressor gene, has been observed in hemangioblastomas, the underlying pathogenic mechanisms responsible for familial and sporadic hemangioblastomas remain incompletely understood.

METHODS

Whole exome sequencing of cerebellar hemangioblastoma tumors and matched blood leukocytes from 24 patients, age 24–63, was performed. After preparation and amplification of barcoded libraries, exomes were captured using Kapa Biosystems methodology and paired-end sequenced on Illumina HiSeq 2500 to an average 100-fold coverage. Following read alignment to hg19 genome, tumor and germline (leukocyte) sequences were compared, and pathogenic single nucleotide variants (SNVs) identified and validated by re-sequencing followed by pathway analysis. Additionally, tumor RNA isolated using Maxwell Promega was sequenced on Illumina instrument and the expression counts determined and normalized.

RESULTS

We found 314 pathogenic and/or highly deleterious mutations (both germline and somatic) with a median of 13 mutations per patient. Five patients had VHL syndrome (germline VHL mutation) and 4 carried somatic VHL mutations. Among the VHL tumors, 82 mutations were identified, including HNF1B, NOTCH1 and TCF7L1, suggesting a potential contribution of altered RNA metabolism based upon pathway analysis. Among all hemangioblastomas, germline growth factor receptor variants (FGFR4 p.G388R (14/23 (61%) patients), IGF1R, PDGFRA and TYK2) known to activate STAT3 signaling and induce HIF-1α and angiogenesis, were identified. Non-hierarchical clustering of RNA sequencing data revealed two transcriptionally-distinct subtypes of hemangioblastomas.

CONCLUSIONS

Our findings indicate that hemangioblastomas can also occur by germline mutations known to activate STAT3 signaling, which may have significant implication in genetic testing and counseling of patients with hemangioblastomas.
HOUT-01. ALOPECIA SYMPTOM IMPACT SCALE (ASIS): MEASURING THE SYMPTOMS OF ALOPECIA AND THEIR IMPACT IN PATIENTS WITH PRIMARY BRAIN TUMORS
Authors: Mendoza Tito , Rowe Lindsay , Vera Elizabeth , Acquaye Alvina , Gilbert Mark , Armstrong Terri
Published: November 2019

INTRODUCTION

Alopecia manifests in many cancer patients receiving therapy. These patients may experience similar physical symptoms and impairment as patients with autoimmune alopecia areata. The Alopecia Areata Symptom Impact Scale (AASIS) was originally validated for patients with autoimmune disorder. However, the validity and reliability of the AASIS among primary brain tumor (PBT) patients has not been evaluated.

METHODS

A cross sectional survey of 100 PBT patients was conducted as part of an IRB approved prospective protocol using structured questionnaires and open-ended responses. Participants completed the AASIS to measure symptoms of alopecia areata and their impact on daily functioning along with the Body Image Scale (BIS) to assess the prevalence of body image disturbance. Analyses included factor analysis to determine the number and nature of underlying constructs, Cronbach’s alphas to assess reliability, and correlational analysis to establish concurrent validity.

RESULTS

Patients’ median age was 48(range 23– 74), and 56% were male. Glioblastoma was most common (32%); low grade tumors (I and II) were 30% of diagnoses. The median time from initial diagnosis was 5 years (range 0–22), and 64% of patients had a KPS of 90–100. An item from the AASIS, ‘body hair or eyelashes loss’, was deemed to be irrelevant, rated low by PBT patients and was removed. Factor analysis revealed 3 underlying constructs: physical (e.g. itchy skin, scalp hair loss), affective (e.g. feeling anxious, feeling sad) symptoms, and impact of alopecia (e.g. work, quality of life) with Cronbach’s alphas of 0.78, 0.89 and 0.96, respectively. The BIS had the highest correlation with the affective symptom subscale (0.58, p< .001).

CONCLUSION

Our results demonstrate the desired reliability and validity for use in studies examining alopecia and its impact in PBT patients. Dropping the term ‘areata’, the modified tool is now ASIS, and can be implemented in future studies.
HOUT-04. ASSOCIATION OF COMMON PATIENT-REPORTED IMMUNOTHERAPY SYMPTOMATIC SIDE EFFECTS AND PSEUDOPROGRESSION IN PATIENTS WITH PRIMARY CENTRAL NERVOUS SYSTEM (CNS) TUMORS
Authors: Vyas Yamini , Vera Elizabeth , Bryla Christine , Crandon Sonja , Wu Jing , Wall Kathleen , Theeler Brett , Siegel Christine , Reyes Jennifer , Penas-Prado Marta , Leggiero Nicole , Cordova Christine , Burton Eric , Antony Ramya , Boris Lisa , Aboud Orwa , Gilbert Mark , Armstrong Terri
Published: November 2019

BACKGROUND

Immunotherapy agents have unique symptomatic side effects; patient-reported outcomes (PROs) can help to characterize the benefits and burdens associated with therapy. Common immunotherapy-associated symptoms include pain, fatigue, shortness of breath, and irregular bowel patterns. The purpose of this study was to assess the severity of symptoms and their association with imaging changes in CNS tumor patients undergoing single agent or combination treatment with immune checkpoint inhibitors (ICIs).

METHODS

Patients completed the MDASI-BT or MDASI-SP at baseline and longitudinally (every 8 weeks), and results through cycle 4 are reported. Neuro-imaging was categorized as stable, possible ICI-related pseudoprogression, or progression by clinical team review.

RESULTS

29 Brain Tumor (BT) and 6 Spinal Tumor patients participated; the majority of which were male (62%) and white (91%), ranging 24-74yo (mean = 46). Glioblastoma was the most common diagnosis (31%) followed by medulloblastoma (16%), with 56% of patients having greater than 2 recurrences prior to the study. At baseline, both brain and spine tumor patients reported moderate to severe fatigue (Brain=4, Spine=6) and pain (Spine=5) with shortness of breath and pain worsening over time. BT patients with pseudoprogression were more likely to report increased fatigue (87%) and pain (63%) compared to those with stable (29%) or true progressive (17%) disease on imaging. BT patients with pseudoprogression also reported worsening of cognitive (43%) and neurologic (57%) symptom burden.

CONCLUSIONS

In contrast to the common pseudoprogression after chemoradiation, treatment-specific symptoms were worse with ICI-related pseudoprogression by MRI where an immunologic reaction was the likely cause of the imaging worsening. These results suggest that commonly used symptom and functional assessments to distinguish true progression from pseudoprogression may not be helpful with immunotherapy. Additional studies including those with pathologic confirmation of progression or pseudoprogression combined with outcomes measures are needed to develop more accurate determinations of disease status.
HOUT-09. DEVELOPING OMMAYA CLINICS FOR LEPTOMENINGEAL CARCINOMATOSIS (LMC): STANDARDIZED TREATMENT, IMPACT ON SURVIVAL/NEUROLOGIC DISABILITY AND ROLE FOR ADVANCED PRACTITIONERS
Authors: Leese Erika , Manikowski Jesse , Mahadevan Anand , Conger Andrew , Mongelluzzo Gino , Tosha Gatson Na
Published: November 2019

Leptomeningeal carcinomatosis (LMC), first described in 1870, involves leptomeningeal and CSF invasion by neoplastic cells and portends poor survival. Among solid tumor LMC, breast cancer is the most common followed by lung and melanoma. With an estimated 100,000+ new cases yearly, the dual-edged sword of systemic treatment drives the increasing incidence as cancer patients live longer and on non-CNS penetrating therapies. Addition of immuno-oncotherapies has impacted LMC survival. At time of diagnosis, most patients have multiple neurologic disabilities. Multiple reports on the topic have not yielded consistent treatment standards to extend patient survival. Most agree that local CNS control coupled with systemic therapy offers the best survival. Still, there are few established Ommaya clinics (OC). Importantly, LMC is a common exclusionary criterion for clinical trials. A single institutional evaluation of 147 patients (2012–2019) with a diagnosis of LMC was completed. 69 of 147 were excluded, leaving 48 pre-OC and 30 OC patients. The mOS (weeks) of those treated with intrathecal chemotherapy (ITC) versus no ITC was compared between cohorts: pre-OC and OC (3.36, 15.29****). Average KPS at time of diagnosis in pre-OC and OC was 70–80 (ECOG 2–3). The mOS was compared between breast (5, 28*), lung (3, 3) and melanoma (5,10*) in the pre-OC and OC respectively. The treatment standardized for the OC includes whole-brain radiation, Ommaya reservoir placement, systemic treatment, treatment with ITC (2x weekly – q other month) and MR imaging every 3 months. Breast cancer patients fared the best followed by melanoma and lung patients in the OC. With use of advanced practitioners (APs), standardization of treatment and surveillance is achievable. Patients treated according to a standardized OC regimen experienced longer overall survival along with a 10% improvement in KPS after two months of treatment. Development of institutional OCs reduces treatment variability and increases clinical surveillance.
HOUT-10. TREATMENT OUTCOME IN ADOLESCENTS AND YOUNG ADULTS (AYAS) WITH GLIOBLASTOMA
Authors: An Josiah , Chennamadhavuni Adithya , Mott Sarah , Garje Rohan
Published: November 2019

BACKGROUND

Glioblastoma is one of the most aggressive and commonly encountered brain tumors. Standard of care includes surgical resection with adjuvant or concurrent chemoradiation which is predominantly based on adult clinical trials. Our study objective was to assess whether survival differed in AYA compared to older adults.

METHODS

The National Cancer Database was used to identify patients with at least surgically resected glioblastoma from 2004 to 2016. Cox regression models were utilized to estimate the effect of treatment on overall survival (OS) while accounting for immortal time bias (3-months) and clustering within facility.

RESULTS

Among 51,718 patients with glioblastoma identified, 2,930 patients were AYA. Multivariable analysis (MVA) shows OS was significantly higher in AYA, female, non-white, high income, unilateral cancer patients with private insurance receiving treatments in high volume facilities. OS among AYA patients was significantly lower in surgery + (radiation or chemotherapy: S+(RT or CT) group compared to surgery only (S) (HR=1.33, 95% CI 1.06–1.65), but no significant survival difference between surgery + chemoradiation (S+C+RT) groups and surgery only (HR=0.97, 95% CI 0.83–1.14). Median survival is ~28 months in AYA among S and S+C+RT groups whereas significantly lower survival (median OS ~18 months) is seen in S+RT or CT. Non-AYA patients were at 2 times increased risk of death compared to AYA patients who received the same type of treatment.

CONCLUSIONS

In conclusion, AYA population has more than twice the median OS in comparison to non-AYA patients. Worse overall survival was seen among S+RT or CT in comparison to S and S+RT+CT in AYA group. For patients needing either chemotherapy or radiation with surgery, possibly a trimodal approach might provide better survival advantage. Prospective studies are needed to further explore optimal treatment modalities in this unique population.
HOUT-11. EXTENSIVE BRAINSTEM INFILTRATION, NOT MASS EFFECT, IS A COMMON FEATURE OF END-STAGE CEREBRAL GLIOBLASTOMAS
Authors: Drumm Michael , Dixit Karan , Grimm Sean , Kumthekar Priya , Lukas Rimas , Raizer Jeffrey , Kam Kwok-Ling , McCord Matthew , Sachdev Sean , Kruser Timothy , Steffens Alicia , Javier Rodrigo , McCortney Kathleen , Horbinski Craig
Published: November 2019

BACKGROUND

Progress in extending the survival of glioblastoma (GBM) patients has been slow, suggesting that preclinical and clinical trial approaches may not fully take into account the nature of this cancer. A better understanding of why GBM patient survival remains poor is critical to developing new strategies. Postmortem studies on GBM can shed light on how GBM spreads and how GBM patients are dying.

METHODS

The brains of 25 GBM patients were autopsied and examined for gross and microscopic abnormalities. Clinical-pathologic correlations were accomplished through detailed chart reviews. Data were compared with older published autopsy GBM studies that predated the use of concurrent radiation and temozolomide (RT/TMZ).

RESULTS

In pre-RT/TMZ GBM autopsy series, mass effect was observed in 72% of brains, with herniation in 50% of cases. Extensive infiltration of tumor into the brainstem occurred in only 21% of those older cases. In the current series, only 7 of 25 (28%) GBMs showed mass effect (P=0.0004), and none (0%) showed herniation (P< 0.0001). However, extensive GBM infiltration through the cerebral peduncles, into the brainstem, was present in 17 cases (68%, P< 0.0001), with accompanying destruction of the brainstem and white matter tracts. There was a direct correlation between longer patient survival and the presence of brainstem infiltration (P=0.001).

CONCLUSIONS

With improving care, severe mass effect is less common in GBM patients today, whereas life-threatening brainstem invasion is now more frequent. This has major implications regarding preclinical GBM models, as well as the design of clinical trials aimed at further improving patient survival.
HOUT-12. RETURN TO WORK FOLLOWING AWAKE SURGERY FOR GLIOMAS IN SPEECH-ELOQUENT AREAS
Authors: Forster Marie-Therese , Lortz Irina , Seifert Volker , Senft Christian
Published: November 2019

OBJECTIVE

Pursuing a profession is an indispensable component of human happiness. The aim of this study was to analyze patients′ professional, socio-economic and psychological outcomes besides their neuro-oncological and functional evaluation after awake surgery for gliomas in eloquent areas.

METHODS

The neuro-oncological and functional outcomes of patients with gliomas other than glioblastoma undergoing awake surgery during a period of 5 years were prospectively assessed within our routine oncological follow-up. Repercussions of the disease on their professional status, socio-economic situation, and neurocognitive function were evaluated retrospectively with structured interviews.

RESULTS

We analyzed data of 37 patients with gliomas (3 WHO Grade I, 6 WHO grade II, 28 WHO grade III). Gross total and subtotal tumor resections were performed in 20 (54.1%) and 11 (29.7%) patients, respectively, whereas in 7 patients (16.2%) resection had to remain partial. Median follow up was 24.1 months (range: 5–61 months). 31 patients (83.8%) had stable disease, 2 (5.4%) patients suffered from tumor progression and 4 (10.8%) patients died. Prior to surgery, all but one patient were employed. At the time of analysis, 24 (72.7%) of 33 alive patients had resumed their profession. 5 patients (15.2%) were on incapacity pension, 2 patients were on sick leave, and 2 had retired. The median time until return to work following surgery was 5.9 ±4.6 months. Young age (< 40 years) was the only factor statistically significantly associated with the ability to return to work (p< 0.001).

CONCLUSION

Despite brain tumor surgery in eloquent regions, the majority of patients with WHO grade II or III gliomas are able to return to work. Employing awake techniques in order to preserve neurological function is of utmost relevance for individual patients′ quality of life and may also decrease the economic burden due to work loss frequently encountered in glioma patients.
HOUT-23. ADULT MEDULLOBLASTOMA TREATMENT IMPACT SINCE 2006: A CANADIAN UNIVERSITY CENTER EXPERIENCE
Authors: Camila Quinones Ninos Maria , Belanger Karl , Lemieux Blanchard Emilie , Lemieux Bernard , Bahary Jean-Paul , G Masucci Laura , Roberge David , Menard Cynthia , Lambert Carole , Moumdjian Robert , Berthelet France , Florescu Marie
Published: November 2019

INTRODUCTION

Medulloblastoma (MB) is an aggressive primary brain tumor rare in adults. Prospective studies in adults are limited by the small number of patients.

METHODS

We retrospectively reviewed all MB patients treated at the CHUM between 2006 and 2017 in our clinical database adult SARDO. We don’t have the children follow up. We divided our cohort in 2 groups, those diagnosed between 2006–2013 and those diagnosed between 2014–2017.

RESULTS

49 patients were treated, 23 (47%) were children referred for radiation only from a pediatric center and 26 (53%) were adults. Median follow up of adults was 26 months. At 5 years, the entire cohort OS was 58%, but specifically for adults, the 5yOS was 80%. First line therapy had a 5y PFS 77% for adults, negatively influenced by the absence of adjuvant radiotherapy (83% vs 0%; p < 0.001) and the absence of adjuvant chemotherapy (80% vs 39%; p < 0.008). 96% of adult patients received radiotherapy and 52% of them received concomitant radiosensitizing chemotherapy with no impact on survival. Complete surgical resection was performed on 88% of patients, but the extent of resection did not have an impact on survival and did not change with time. From 2006–2013, the most common chemotherapy treatment (80%) in adults was Vincristine, Cisplatin and Lomustine. From 2014–2017, the chemotherapy was replaced by Cisplatin, Etoposide and Cyclophosphamide in 82% with no impact on survival (specific mortality for this chemo 3yOS 100% for both, 3y PFS 100%). Non Cisplatin based chemotherapy regimens were associated with decrease in PFS (67% at 3y). 78% of the progressive patients received second line chemo.

CONCLUSION

In our adult MB population, the demographic and tumor factors did’nt have an impact on prognosis but adjuvant radiotherapy and chemotherapy had a favorable impact on survival especially with Cisplatin, Etoposide and Cyclophosphamide regimen.
HOUT-24. CHALLENGES AND SUCCESSES IN THE GLOBAL REIMBURSEMENT OF A BREAKTHROUGH MEDICAL TECHNOLOGY FOR TREATMENT OF GLIOBLASTOMA MULTIFORME
Authors: Kelly Justin , Proescholdt Christina
Published: November 2019

OBJECTIVE

To highlight the challenges and differences regarding the reimbursement of breakthrough medical device technologies, by example of a novel cancer treatment using Tumor Treating Fields (TTFields).

BACKGROUND

TTFields is a breakthrough cancer treatment modality. The treatment is delivered through a medical device with the brand name Optune. Its efficacy was first established in glioblastoma multiforme. Reimbursement challenges for medical devices vary by. Common issues for novel device technologies like Optune however, are the difficulties to classify the treatment in the respective country’s health care system with the ability to develop a value-based reimbursement pathway.

MATERIALS/METHODS

We reviewed reimbursement decisions of payers for Optune from a total of 6 countries. We assessed their classification of the device, the flexibility of their health care framework and how Optune was implemented.

RESULTS

All 6 countries implemented Optune in their respective health care systems. 3 countries consider Optune to be an outpatient treatment delivered by durable medical equipment, one country classifies Optune as a hospital dispensed medical device, one country classifies Optune as an extended medical service and the last country as rehab services.The differential fitting of Optune in the respective country’s health care system allows each of the countries to take a positive, value-based reimbursement decision for this breakthrough technology. Generally, the speed of payer adoption for Optune varied based on the ability to assess the clinical data, rather than the more technical aspects of how the device is delivered to patients.

CONCLUSIONS

Classification of a breakthrough technology like Optune in the traditional framework of health care systems is challenging and handled differently by each country. Countries with a flexible approach regarding this novel oncological treatment modality however, were able to reach positive reimbursement decisions by classifying Optune in the category most suitable in the respective country’s health care system.
IMMU-14. ONCOLYTIC VIRUS EXPRESSING A POSITIVE IMMUNE CHECKPOINT MODULATOR AS A THERAPEUTIC APPROACH FOR DIPG
Authors: Laspidea Virginia , Puigdelloses Montse , Iñigo-Marco Ignacio , Garcia-Moure Marc , Ausejo Iker , Gallego Jaime , Fueyo Juan , Gomez-Manzano Candelaria , Alonso Marta M
Published: November 2019

Diffuse intrinsic pontine glioma (DIPG) is an aggressive brain tumor, being the leading cause of pediatric death caused by cancer. We previously showed that administration of the oncolytic virus Delta-24-RGD to DIPG murine models was safe and led to an increase in the median survival of these animals. However, not all the animals responded, underscoring the need to improve this therapy. In order to increase the antitumoral effect of the virus, we have engineered Delta-24-RGD with the costimulatory ligand 4-1BBL (Delta24-ACT). 4-1BB is a costimulatory receptor that promotes the survival and expansion of activated T cells, and the generation and maintenance of memory CD8+ T cells. In this project, we evaluated the oncolytic effect of Delta24-ACT and the antitumor immune response in DIPG murine models. In vitro, Delta24-ACT was able to infect and induce cell death in a dose-dependent manner in murine DIPG cell lines. In addition, Delta24-ACT was able to replicate in these tumor cells and to express viral proteins. Moreover, infected cells expressed 41BBL in their membranes. Delta24-ACT could induce immunogenic cell death due to an increased secretion of ATP and calreticulin translocation to the membrane of infected cells (in no-infected cells it located in the ER), DAMPs that can trigger the immune response activation. In vivo, Delta24-ACT demonstrated to be safe in all the tested doses and was able to induce a significant increase in the median survival of the treated animals. Moreover, long-term survivors display immunological memory. Delta24-ACT treatment led to antitumoral effect in DIPG murine cell lines in vitro. Of significance, we have demonstrated that in vivo administration of Delta24-ACT is safe and results in an enhanced antitumor effect. Future in vivo studies will explore the underlying immune mechanism of the virus.
IMMU-19. QUINOLINATE-INDUCED IMMUNE SUPPRESSION IN GLIOBLASTOMA
Authors: Kesarwani Pravin , Kant Shiva , Prabhu Antony , Chinnaiyan Prakash
Published: November 2019

Glioblastoma continues to be an invariably fatal malignancy with limited treatment options. We performed integrative cross-platform analyses coupling global metabolomic profiling with genomics in patient-derived tumors to provide insight into metabolic programs that may be driving the aggressive phenotype of this malignancy. A persistent theme that emerged was the interplay between metabolic remodeling and immune response. Most notable was a 64-fold accumulation of quinolinate, which represents a downstream intermediary of tryptophan metabolism, in glioblastoma, when compared to low-grade astrocytoma. We discovered a dynamic interaction between cells within the tumor microenvironment that contributes to the generation of quinolinate. Specifically, neither tumor cells nor immune cells demonstrated the capacity to completely metabolize tryptophan. Tumor cells were required to metabolize tryptophan to kynurenine, while only cells of monocyte lineage, including M1/M2 macrophages and microglial cells, demonstrated the capacity to generate quinolinate from tumor-generated kynurenine. We next sought to determine if the observed accumulation of quinolinate in glioblastoma had immune consequences. We discovered a novel role quinolinate plays in increasing (~50%) immunosuppressive M2 macrophage (CD45+CD11b+F4/80+ and CD206+) polarization and promoting a suppressive molecular phenotype (IL4Rα +). These findings were functionally recapitulated, with quinolinate-induced M2 macrophages demonstrating potent inhibition of CD8+T-cell proliferation. Intriguingly, quinolinate also skewed M1 polarization towards an “M2-like” phenotype both molecularly (CD45+CD11b+F4/80+CD206+) and functionally, by inhibiting CD8+T-cell proliferation and decreasing phagocytosis efficiency. Targeting quinolinate’s upstream enzyme kynurenine-3-monooxygenase (KMO) inhibited M2 polarization in vitro and deceased M2 macrophage levels in vivo by 60%. This was unique to KMO, as targeting tryptophan metabolism by inhibiting the more established, upstream target IDO1 did not influence M2 macrophage levels. As emerging studies suggest M2 macrophages play a central role in contributing towards the potent immunosuppressive microenvironment in glioblastoma, therapeutic strategies designed to target quinolinate metabolism may serve as a novel immuno-metabolic checkpoint with direct clinical implications in this malignancy.
IMMU-30. UTILIZING A NOVEL MASS CYTOMETRY-BASED IMMUNOMONITORING PLATFORM FOR THE CHARACTERIZATION OF VACCINE-REACTIVE, EPITOPE-SPECIFIC CD8+ T-CELLS IN HLA-A*0201+ PATIENTS WITH K27M+ DIFFUSE MIDLINE GLIOMAS
Authors: Taitt Jared , Watchmaker Payal , Nejo Takahide , Almeida Neil , Okada Kaori , Shahin Maryam , Gilbert Ryan , Mueller Sabine , Okada Hideho
Published: November 2019

Diffuse midline glioma (DMG), including diffuse intrinsic pontine glioma (DIPG) constitutes up to 20% of pediatric brain cancer and has a median survival of less than one year. We have identified a novel HLA-A*02:01-restricted neoantigen epitope encompassing the H3.3K27M mutation and implemented a pilot clinical trial through the Pacific Pediatric Neuro-Oncology Consortium (PNOC007). Newly diagnosed DIPG patients who are HLA-A2+ and H3.3K27M+ underwent radiation therapy, and then received the H3.3K27M peptide vaccine and tetanus toxoid (TT) peptide emulsified in Montanide in combination with poly-ICLC every 3 weeks for a total of 24 weeks. Our objective is to characterize vaccine-induced H3.3K27M-specific T-cell subpopulations in peripheral blood mononuclear cells through the evaluation of surface markers correlated with activation, memory, and exhaustion phenotypes utilizing a novel H3.3K27M-specific dextramer-based mass cytometry method. Through this approach, the temporal expansion of vaccine-reactive CD8+ T-cells was observed in all of patients (n = 4) who completed a minimum of 18 weeks on the study. These T-cells were subsequently stratified into discrete clusters on a tSNE plot using canonical CD8+ T-cell markers. Resultant clusters were further classified by their expression profiles, revealing distinct effector memory and exhausted subpopulations. Chronological monitoring of these groups indicates the time course-dependent development and persistence of vaccine-reactive exhausted and effector memory CD8+ T-cells in 75% of patients analyzed. Furthermore, a comparative analysis of myeloid subpopulations revealed an inverse correlation between the expansion of monocytic myeloid-derived suppressor cells (M-MDSCs) and length of enrollment in the trial. Future plans include the analysis of regulatory T-cells (Tregs) and MDSCs of all enrolled patients to solidify the relationship between the length of stay on the study and prevalence of immunosuppressive populations. This methodology offers insight into the progression of vaccine-induced patient immune responses and exhibits promise as a platform that may be extrapolated to other immunotherapies.