bluuebunny/crossref_metadata_2025 huggingface dataset:
PATH-04. THE BLOOD-BRAIN BARRIER IN DIFFUSE MIDLINE GLIOMA AND ITS IMPLICATIONS FOR DRUG DELIVERY
Authors: Haumann Rianne , El-Khouly Fatma , Breur Marjolein , van Zanten Sophie Veldhuijzen , Kaspers Gertjan , Hendrikse Harry , Hulleman Esther , van Vuurden Dannis , Bugiani Marianna
Published: December 2020

INTRODUCTION

Chemotherapy has been unsuccessful for pediatric diffuse midline glioma (DMG) most likely due to an intact blood-brain barrier (BBB). However, the BBB has not been characterized in DMG and therefore its implications for drug delivery are unknown. In this study we characterized the BBB in DMG patients and compared this to healthy controls.

METHODS

End-stage DMG pontine samples (n=5) were obtained from the VUmc diffuse intrinsic pontine glioma (DIPG) autopsy study and age-matched healthy pontine samples (n=22) were obtained from the NIH NeuroBioBank. Tissues were stained for BBB markers claudin-5, zonula occludens-1, laminin, and PDGFRβ. Claudin-5 stains were used to determine vascular density and diameter.

RESULTS

In DMG, expression of claudin-5 was reduced and dislocated to the abluminal side of endothelial cells. In addition, the expression of zonula occludens-1 was reduced. The basement membrane protein laminin expression was reduced at the glia limitans in both pre-existent vessels and neovascular proliferation. PDGFRβ expression was not observed in DMG but was present in healthy pons. Furthermore, the number of blood vessels in DMG was significantly (P< 0.01) reduced (13.9 ± 11.8/mm2) compared to healthy pons (26.3 ± 14.2/mm2). Markedly, the number of small blood vessels (< 10µm) was significantly lower (P< 0.01) while larger blood vessels (> 10µm) were not significantly different (P= 0.223). The mean vascular diameter was larger for DMG 9.3 ± 9.9µm compared to 7.7 ± 9.0µm for healthy pons (P= 0.016).

CONCLUSION

Both the BBB and the vasculature are altered at end-stage DMG. The reduced vascular density might have implications for several drug delivery methods such as focused ultrasound and convection enhanced delivery that are being explored for the treatment of DMG. The functional effects of the structurally altered BBB remain unknown and further research is needed to evaluate the BBB integrity at end-stage DMG
PATH-05. A RETROSPECTIVE STUDY OF TREATMENT STRATEGIES AND OUTCOMES IN WHO GRADE II AND III ISOCITRATE DEHYDROGENASE (IDH) WILD-TYPE ASTROCYTOMA
Authors: Aaroe Ashley , Dono Antonio , Youssef Michael , Alfaro-Munoz Kristin , Weathers Shiao-Pei , O’Brien Barbara , Majd Nazanin , Harrison Rebecca , Loghin Monica , Soomro Zaid , Williford Garret , Fuller Gregory , Yung W K Alfred , Yeboa Debra , Esquenazi Yoshua , Ballester Leomar Y , de Groot John , Kamiya-Matsuoka Carlos
Published: December 2020

BACKGROUND

WHO grade II and III IDH wild-type astrocytomas behave more aggressively than their IDH mutated counterparts. A subpopulation shares molecular features with the novel entity proposed in cIMPACT-NOW Update 3 “Diffuse astrocytic glioma, IDH wild-type, with molecular features of glioblastoma (GBM), WHO IV”.

METHODS

We performed a retrospective analysis of clinical and molecular features, management and survival of 134 adult patients treated for grade II and III IDH wild-type astrocytoma between 06/2012 and 12/2018 at MD Anderson Cancer Center (MDACC - 112) and UT Health Science Center at Houston (UTHSC - 22). All patients had IDH1 sequenced, all but 2 had IDH2 sequenced, and 73 had further next generation sequencing.

RESULTS

Median age at diagnosis was 53 (interquartile range 18-83). 82 patients (61%) were male. 31 patients were histologically diagnosed with grade II astrocytoma, 102 with grade III astrocytoma, and one with diffuse glioma (insufficient tissue to render histologic grade or perform sequencing). EGFR alterations were found in 31 patients and TERT promoter mutations in 22. 84 (63%) received concurrent chemoradiation and adjuvant temozolomide (grade II, n=9; grade III, n=74; NOS, n=1). PFS overall was 12.0 months (grade II = 17.9; grade III = 10.7). OS in patients treated with concurrent chemoradiation and adjuvant temozolomide was 17.1 months versus 17.7 in patients treated with sequential radiation and temozolomide (p = NS), and 10.6 in patients treated with RT alone or surveillance (p< 0.016). The highest 2-year OS was seen in grade II patients treated with concurrent chemoradiation and adjuvant temozolomide (60%).

CONCLUSIONS

WHO grade II and III IDHwt astrocytoma survival is similar to historical GBM cohorts. The proportion meeting molecular criteria for GBM is yet undefined. Groups who received chemotherapy may perform better than those who do not. Further analysis of MGMT methylation and other molecular factors is ongoing.
PATH-07. SIGNIFICANCE OF H3K4me3 IN PEDIATRIC HIGH-GRADE GLIOMAS
Authors: Lewis Rebecca , Wadhwani Nitin , Mania-Farnell Barbara , Tomita Tadanori , James Charles , Xi Guifa
Published: December 2020

Pediatric high-grade gliomas (pHGGs) account for ~20% of childhood brain tumors, are incurable in nearly all instances, and have an average patient survival of less than 15 months. Histone posttranslational modifications (PTMs) are deregulated in pHGGs. There are many gaps in our knowledge regarding the mechanisms by which “normal” PTM is subverted during pHGG development. Preliminary results from our lab show pHGGs are enriched in H3K4me3 and that the extent of this specific PTM is predictive of patient survival length. H3K4me3 levels are controlled by methyltransferase and demethylase activity. Gene expression analysis indicates SETD1A and WDR82, enzymatic subunits of human SETD1A containing methyltransferase complex (referred to as hSETD1A-COMPASS), are responsible for H3K4 methylation. SETD1A and WDR82 are significantly elevated in pHGGs, relative to pediatric low-grade gliomas (pLGGs), and both show a direct association with glioma malignancy. Interestingly, these associations do not exist in adult gliomas. The results suggest that hSETD1A-COMPASS specifically impacts pHGG development and is a potential therapeutic target for these tumors.
PATH-09. NEXT-GENERATION SEQUENCING OF GLIOBLASTOMA MULTIFORME ‘EXTREME RESPONDERS’
Authors: Zameer Mohammed , Fives Cassie , Peters Niamh , Birmingham Niamh , Collins Dearbhaile , O’Reilly Seamus , Bambury Richard
Published: December 2020

BACKGROUND

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

METHODS

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

RESULTS

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

CONCLUSION

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

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

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

BACKGROUND

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

METHODS

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

RESULTS

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

CONCLUSIONS

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

BACKGROUND

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

DESIGN

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

RESULTS

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

CONCLUSIONS

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

BACKGROUND

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

METHODS

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

RESULTS

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

CONCLUSION

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

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

BACKGROUND

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

METHODS

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

RESULTS

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

CONCLUSIONS

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

INTRODUCTION

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

METHODS

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

RESULTS

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

CONCLUSIONS

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

BACKGROUND

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

METHODS

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

RESULTS

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

CONCLUSION

In the era of precision oncology, targeted gene sequencing of adult primary brain tumors may aid in diagnosis beyond histopathology by identifying the genetic landscape of tumors and molecular targets for individualized therapies.
QOLP-08. UTILIZING STAKEHOLDER ENGAGEMENT TO DEVELOP A MINDFULNESS-BASED INTERVENTION FOR PATIENTS WITH GLIOBLASTOMA (GBM) AND THEIR CAREGIVERS
Authors: Donovan Laura , Driver Aurelia , Wilkie Martha , Morris Jessica , Hillyer Grace
Published: December 2020

BACKGROUND

Patients with GBM and their caregivers report impaired quality of life (QOL). Distress, fatigue and anxiety are common. Mindfulness-based interventions (MBIs) can help reduce anxiety and depression and improve QOL in patients with chronic diseases and other types of cancer, but have not been well studied in patients with brain tumors and their caregivers. The feasibility and acceptability of an MBI in this population is unknown.

METHODS

Using the Consolidated Framework for Implementation Research (CFIR), we developed a 15-minute survey for patients with brain tumors and their caregivers to assess attitudes and beliefs toward a MBI. As this study is formative, we chose to assess select domains including intervention characteristics, characteristics of individuals (knowledge and beliefs), and the outer setting (patient needs and resources). Questions were adapted from the literature to reflect constructs from each domain or created by the authors. The survey was published using Qualtrics, an online survey platform. We partnered with OurBrainBank to distribute the survey to key stakeholders using social media platforms. OurBrainBank is a patient-led movement centered around a symptom-tracking app for patients and carers, participation in patient-driven research, improved access to clinical trials, and patient advocacy.

RESULTS

The survey was published on 5/29/20. In one week, we received 14 responses. 7/14 identified as having a brain tumor or being the primary caregiver for someone with a brain tumor. Of these, 5/7 indicated they would be possibly or definitely interested in participating in a research study testing a MBI. Over the next 5 months, we anticipate 200 people will complete the survey. We will analyze the results using descriptive statistics.

DISCUSSION

Technology can aid in stakeholder engagement which is critical to intervention development. Results from this survey will be used to develop a MBI tailored to patients with GBM and their caregivers.
QOLP-15. QUALITATIVE STUDY OF DIFFERENTIAL QUALITY OF LIFE (QOL) IN SUPRASELLAR MENINGIOMA PATIENTS TREATED VIA ENDOSCOPIC ENDONASAL APPROACH VERSUS OPEN CRANIOTOMY
Authors: Khalafallah Adham , Fung Shirley , Kozachik Sharon , Valappil Benita , Shaar Hussam Abou Al , Wang Eric , Zenonos Georgios , Snyderman Carl , Gardner Paul , Gallia Gary , Rowan Nicholas , Mukherjee Debraj
Published: December 2020

BACKGROUND

The optimal surgical treatment of suprasellar meningiomas remains controversial. While successful surgery has historically been measured by extent of tumor resection (EOR), surgeons must also balance tumor- and patient-specific characteristics with quality of life (QoL) outcomes when considering either an open craniotomy or endoscopic endonasal approach (EEA).

METHODS

We conducted 28 in-depth individual interviews with patients diagnosed with suprasellar meningioma and treated via EEA (n=14) or craniotomy (n=14). We used a structured interview script and the transcribed interviews were independently coded by two researchers. Consensus was used to identify themes and domains of interest.

RESULTS

The overall sample (80% between 40-69 years old, 70% female, and 82% white) was largely similar between craniotomy and EEA cohorts. Tumor volumes were not different between both cohorts (p=0.2), with a combined average of 4.4 cm3 (standard error ± 0.7). Suprasellar meningiomas caused a wide range of symptoms with 21 concepts elicited. The most frequently endorsed concepts were “Vision” (n=22), “Headaches” (n=11), “Fatigue” (n=11), “Cognitive Symptoms” (n=10), “Pituitary Dysfunction – including Trouble Sleeping and Frequent Urination” (n=9), “Sinus Problems” (n=7), and “Personality Changes” (5). Both surgical approaches demonstrated improvements in vision (69.2% EEA, 66.7% craniotomy) and headaches (100% EEA, 80% craniotomy). Compared to EEA, craniotomy yielded a longer list of complications (3 vs.14) and surgery-specific symptoms (9 vs.16). More craniotomy patients reported having negative emotions (5 vs.1), new depression and anxiety (6 vs.1), financial difficulties (3 vs.1), and reduced desire/ability to pursue fun activities (12 vs.7) after surgery relative to EEA counterparts.

CONCLUSION

Suprasellar meningiomas can be debilitating with significantly impact on patients’ health and QoL. Our findings demonstrate differential effects upon patients’ post-operative QoL associated with type of surgery. Our findings support the need for measuring patient-centered, disease-specific QoL outcomes in patients undergoing craniotomy versus EEA for suprasellar meningioma resection.
QOLP-18. A CALL TO ACTION: DEATH ANXIETY IN NEURO-ONCOLOGY
Authors: Loughan Ashlee , Husain Mariya , Willis Kelcie , Braun Sarah , Brechbiel Julia , Aslanzadeh Farah , Kovalchick Laurel
Published: December 2020

BACKGROUND

Patients with primary brain tumors (PBT) are at increased risk for psychological distress given the certainty of tumor progression, lack of curative treatments, and poor prognoses. A specific type of distress, death anxiety, was recently identified as an area of concern among neuro-oncology patients. However, researchers have yet to fully examine the prevalence or risk-factors of death anxiety in this population, and, importantly, what evidence-based treatments may be available to alleviate symptoms.

METHODS

Adult PBT patients (N=81) completed validated questionnaires on symptoms of death anxiety, generalized anxiety, and depression. Item-level frequencies were run to determine prevalence rates. Analyses were then conducted (t-tests, ANOVAs, Pearson correlations, regressions) to determine whether certain demographic, disease-related variables, and/or symptoms of psychological distress put patients at higher risk for death anxiety. Literature on evidence-based treatment options was also reviewed.

RESULTS

Over half (50-64%) of our sample endorsed items related to fear of death, distressing thoughts about death, and fear of the future, with 35% scoring above the cut-off for death anxiety. Predictors of death anxiety included generalized anxiety symptoms, bilateral or right hemisphere tumor, and female gender (r2=0.367; F(3,77)=16.488, p< .05). Younger age, lower grade tumors, and heightened depressive symptoms were associated with higher death anxiety (p< .05). While interventions to reduce distress in advanced cancer populations are available, most have purposely excluded neurological cancers, thus limiting their generalizability in neuro-oncology.

CONCLUSION

The proportion of PBT patients who endorsed death anxiety aligns with other advanced cancer populations. However, item-level analysis suggests heightened concern in neuro-oncology and a need for targeted intervention. Moreover, specific demographic, disease-related, and psychological distress variables put certain PBT patients at increased risk. These findings highlight the need for routine screenings and monitoring, as well as inclusion of neuro-oncology patients in evidenced-based treatment trials for reducing distress, specifically death anxiety.
QOLP-20. A FEASIBILITY STUDY UTILIZING MINDFULNESS MEDITATION DURING CONCOMITANT CHEMORADIATION IN MALIGNANT GLIOMA PATIENTS: HEALTH-REPORTED QUALITY OF LIFE (HRQOL) RESULTS
Authors: Randazzo Dina , Buckley Evan , Herndon James , Cort Nicole , Affronti Mary , Lipp Eric , Desjardins Annick , Johnson Margaret , Landi Daniel , Ashley David , Friedman Henry , Glass Oliver , Porter Laura , Peters Katherine
Published: December 2020

BACKGROUND

Primary brain tumor patients experience high levels of distress due to their diagnosis and treatment leading to changes in their health-related quality of life (HRQoL). Even with the standard treatment of 6 weeks of radiation with concurrent temozolomide for malignant gliomas, the prognosis remains poor. We sought to provide a new intervention and coping skill for our patients during chemoradiation to alleviate some of their stress and anxiety. Mindfulness meditation is a mind-body therapy used in many other cancer groups which can alleviate stress and improve fatigue, cognition, and sleep.

METHODS

15 newly diagnosed malignant glioma subjects started 1-hour weekly phone mindfulness sessions during the 6 weeks of chemoradiation. They completed an in-person mindfulness session and interview upon return to the clinic with a final follow up survey 2 months later. Patient reported outcomes questionnaires were collected at each time point.

RESULTS

0/15 subjects completed their post-chemo/in-person visit, and 9 completed their final follow-up surveys 2 months later. Scores for perceived cognition, fatigue, sleep, anxiety, spiritual-well being and mindfulness improved over these time points. Completed HRQoL patient-reported outcome questionnaires with positive trends noted from the mean (SD) post-chemo/in-person visit change from baseline and the follow-up change from baseline were: FACT-Cog perceived Cognitive Impairments subscale 4.11(13.55), 9.14(16.77); FACT-G total -5.48(16.02), 7.02(13.44); FACT-Br total -3.15(24.76), 13.17(23.37); FACIT-F -5(7.68), 0(7.92); and the FACIT-Sp12 -1.38(7.6), 2.17(4.88). Trail making Part A completion times from baseline to follow up decreased over time in 8/9 subjects and 7/9 subjects in Part B. Per the final follow up survey, 7/9 subjects continued their meditation practices after the training sessions and subjectively noted benefits with their stress and anxiety. Conclusion: Despite this small sample size, this mindfulness meditation intervention did positively impact patient-report outcomes of HRQoL in this patient population, thereby larger randomized studies are warranted.
QOLP-21. A PRELIMINARY REPORT ON QUALITY OF LIFE AND SEXUAL FUNCTION IN BRAIN CANCER PATIENTS
Authors: Boccia Maria , Anyanda Elizabeth , Fonkem Ekokobe
Published: December 2020

As cancer treatment has advanced, quality of life (QoL) has become a significant consideration in patient and survivor care. The 2005 Institute of Medicine Cancer Survivorship Care Planning guide requires the inclusion of information on the possible effects of cancer on marital/partner relationship and sexual functioning, among other factors related to QoL. The purpose of this study is to explore the rates and types of sexual dysfunction among brain cancer patients. Patients were recruited from a neuro-oncology practice and given a QoL questionnaire (FACT-Br). Women were given the Female Sexual Function Index (FSFI). Men were given scales to assess premature ejaculation (PE), erectile dysfunction (ED), and Peyronie’s disease. In addition, information about site and type of tumor and treatment (surgery, radiation, chemotherapy) was collected. Descriptive statistics as well as T-tests and ANOVAs were used to analyze the data. Data were collected from 50 patients. The most common form of brain tumor in this sample was glioblastoma. The frontal lobe was the most common location of tumors. There was significantly more sexual dysfunction than previously reported, with 66% of the sexually active women meeting criteria for total FSFI. Of the men who were sexually active, 60% reported some ED and 80% reported PE. QoL measures were correlated with sexual dysfunction. Our capacity to address sexual function concerns of patients is dependent on our understanding the types of difficulties encountered. This study provides preliminary information about the effect of brain cancer diagnosis and treatment on a major contributor to QoL in these patients.
QOLP-23. PHASE II RANDOMISED PLACEBO-CONTROLLED DOUBLE-BLIND STUDY OF ACETAZOLAMIDE VERSUS PLACEBO FOR CEREBRAL OEDEMA IN RECURRENT AND/OR PROGRESSIVE HIGH-GRADE GLIOMA REQUIRING TREATMENT WITH DEXAMETHASONE
Authors: Agar Meera , Nowak Anna , Hovey Elizabeth , Barnes Elizabeth , Simes John , Vardy Janette , Wheeler Helen , Leonard Robyn , Hall Merryn , Tim Evonne , Spyridopoulos Desma , Sim Hao-Wen , Lwin Zarnie , Dowling Anthony , Harrup Rosemary , Jennens Ross , Kichenadasse Ganessan , Dunlop Tracey , Gzell Cecelia , Koh Eng-Siew
Published: December 2020

INTRODUCTION

Symptoms of raised intracranial pressure (ICP) in recurrent or progressive high-grade glioma (HGG) generally require corticosteroid treatment, often causing toxicity with variable effects on reversing ICP symptoms. Acetazolamide reduces ICP in other clinical settings including case series in glioma.

AIM

To explore whether addition of oral acetazolamide enables safe dexamethasone dose reduction in management of raised ICP in recurrent and/or progressive HGG.

METHODS

Participants had recurrent, progressive and/or persistent residual HGG requiring recommencement of dexamethasone, dose increase or dexamethasone dependency; prior/current bevacizumab was an exclusion. Eligible participants were randomised 1:1 to acetazolamide 250mg twice daily or placebo for 8 weeks. Standardised protocols were used for dexamethasone dose changes in both arms, with planned dose decrease from day 5 once ICP symptoms were stable. The primary endpoint was a composite of dexamethasone dose reduction and stability of performance status. Secondary endpoints included toxicity and feasibility (accrual and compliance).

RESULTS

Thirty participants of a planned sample of 84 were enrolled (mean age 58 y (32-89)) from 7 Australian sites. The mean baseline dexamethasone dose was 6.2mg (4-16mg). Mean duration on treatment was 38 days (4-57) in placebo group and 31 days (3-60) in acetazolamide group, with 9 participants (30%) completing all study treatment (6 placebo, 3 acetazolamide). Study withdrawal was due to adverse events (n=6 (1 placebo, 5 acetazolamide)) and disease progression (n=6 (3 per arm)). Four participants (13%) (2 per arm) were stable responders meeting the primary endpoint criteria (≥50% corticosteroid dose reduction from baseline by 28 days maintained for 7 days, and no deterioration in performance status). Ten participants experienced a total of 13 serious adverse events (acetazolamide arm: 5 participants (33%), 6 events, 2 related).

DISCUSSION

The addition of acetazolamide did not facilitate dexamethasone reduction. The study closed early due to poor accrual and increasing availability of bevacizumab.
QOLP-25. BASELINE QUALITY OF LIFE BURDEN IN PATIENTS WITH CENTRAL NERVOUS SYSTEM (CNS) TUMOURS TREATED WITH PENCIL BEAM PROTON THERAPY AT INDIA’S FIRST PROTON THERAPY CENTRE
Authors: Jalali Rakesh , Chilukuri Srinivas , Kumar Roopesh , Nangia Sapna , Panda Pankaj Kumar
Published: December 2020

The aim of this study is to evaluate and assess the impact of baseline quality of life (QOL) in adult patients with central nervous system (CNS) tumours treated with pencil beam proton therapy (PT) seen consecutively at India’s first proton therapy centre. Data sets of 50 consecutive adult patients with histologically proven brain neoplasms (both primary and recurrent) who were planned for proton therapy at our centre were during one full calendar year were considered for this study. The study included detailed neurological assessment, evaluation of QOL using EORTC questionnaire (QLQ-C30) and specific Brain Cancer module (BN20). In the present analysis, QOL scores before starting adjuvant treatment were measured and impact of patient and tumour related factors were analysed. Baseline global QOL data of all patients (available in 50) was 58.3 which is relatively low including in all histological tumour types. Physical function, role function, emotion function, cognitive and social function scores were 77.9, 80, 78.5, 80.3, 69.3 (higher values better), respectively. Domains of visual disorder, motor deficit, communication deficit, headache, seizures and drowsiness scores were 21.5, 20.3, 32.3, 31, 20.4, 32.6 and 14.5 (lower values better), respectively. Elderly patients (> 50 years) had poorer global score (p < 0.05). Patients with lower performance status (KPS < 70) had a lower global QOL (KPS > or = 80 vs. < or= 70; 42 vs. 75; p < 0.05) including in all histological types of high-grade gliomas (HGG) (HGG vs. LGG; 67 vs. 59; p < 0.05). Patients undergoing re-irradiation had poorer global score as compared to ones who had not received any radiation previously (p < 0.05). Patients with malignant, recurrent tumours, poor performance status and patients who had previously been irradiated had significantly lower QOL scores even before starting adjuvant treatment.
QOLP-26. USE OF MEDICAL ASSISTANCE IN DYING (“DEATH WITH DIGNITY”) IN WASHINGTON STATE PATIENTS WITH BRAIN TUMORS.
Authors: Graber Jerome , Sofie Kaite , Taylor Lynne
Published: December 2020

Since 2009, Washington State has had a “Death with Dignity” (DWD) process whereby people with a terminal illness may legally obtain a prescription for medications that will end their life. Patients initiate a voluntary request from two physicians certifying they have a prognosis < 6 months, are aware of other palliative care options, and have capacity without the comorbidity of a psychiatric diagnosis. Since 2015, over 200 people annually have used the DWD process in Washington. Other papers have described the characteristics of people using DWD with a diagnosis of cancer or amyotrophic lateral sclerosis (ALS) but none have specifically looked at patients with brain tumors (BT) who used DWD. We describe 20 people with BT who accessed DWD since 2015 at our center. Median age at the time of death was 51 (range 38-79) and 75% were men. Glioblastoma was the diagnosis in 10 (50%), anaplastic glioma in 8 (40%), grade II astrocytoma in 1, and a presumed high-grade glioma by imaging in 1. Median Karnofsky Performance Status (KPS) was 90 at diagnosis (range 50-100) and 70 at DWD request (range 40-90). Standard radiation (RT) and chemotherapy was used by 17 (85%) prior to DWD request, while 3 patients (15%, ages 70-79, KPS 50-90) requested DWD immediately after diagnosis and did not undergo further treatment. Pain was present in 4 patients (20%), 2 using opioids (10%). Six patients (30%) continued tumor treatments after approval for DWD. Median OS was 22 months (range 2-285) and 24 months excluding patients who declined treatment (range 8-285). Most glioma patients in our cohort requested DWD after undergoing chemoradiation, pain was uncommon and rarely severe, and survival from diagnosis was comparable to standard therapy. As access to medical assistance in dying continues, further research is needed on its utilization for people with brain tumors.