bluuebunny/crossref_metadata_2025 huggingface dataset:
IMMU-51. SINGLE-CELL ANALYSIS OF TUMOR-ASSOCIATED MICROGLIA AND MACROPHAGES FROM HUMAN GLIOBLASTOMA
Authors: Anand Atul , Andersen Rikke Sick , Burton Mark , Harwood Dylan Scott Lykke , Poulsen Frantz Rom , Halle Bo , Pedersen Christian Bonde , Kruse Torben , Thomassen Mads , Kristensen Bjarne
Published: November 2021

Patients with glioblastoma, the most frequent and malignant primary brain tumor type, have a poor prognosis with a median survival of 14 months. A major therapeutic problem is chemoresistance. In surgically removed glioblastoma tissue, tumor-associated microglia and macrophages (TAMs) constitute up to 30 % of the total cells. TAMs are capable of secreting cytokines, chemokines and growth factors, thereby influencing the tumor microenvironment. However, the existence of different TAM subtypes and their role in glioblastoma is not fully comprehended and rarely considered therapeutically. This could explain why many glioblastoma clinical trials fail despite of promising preclinical results. This project aims to interrogate the existence and characteristics of different TAM subtypes in human glioblastoma biopsies in order to identify novel subpopulations and therapeutic targets. To study the heterogeneity in TAMs, CD11b+ cells were isolated from glioblastoma patient′s tissue, and single-cell RNA sequencing was performed using the 10X Genomics Chromium platform for single-cell generation and an Illumina NovaSeq6000 system for sequencing. We have sequenced TAMs from three glioblastomas and CD11b+ cells from brain tissue adjacent to two brain metastases samples. In the filtered data set of almost 71,000 CD11b+ cells, we were able to identify recently described TAM populations, such as an interferon-induced, a phagocytic, a hypoxic and a proliferating subset. Interestingly, we also discovered potential novel TAM subsets, such as a pro-angiogenic subset. We have detected a TAM population which is more complex than the established M1 and M2 phenotypes, constituting novel TAM subsets. We are currently investigating these findings to validate specific markers associated with these subpopulations, and for the identification of novel clinically relevant targets.
INNV-10. TUMOR TREATING FIELDS (TTF) AS MAINTENANCE THERAPY FOR AN OLIGODENDROGLIOMA CASE AND LONG-TERM FOLLOW-UP
Authors: Ko Uvin , Du Steven , Moldenhauer Matthew , Kong Xiao-Tang
Published: November 2021

INTRODUCTION

Recurrence of low- and high-grade gliomas is observed often after radiation and chemotherapy. Despite continued research on glioma management, there is limited knowledge regarding maintenance treatment after standard care. Tumor Treating Fields as maintenance therapy after radiation and chemotherapy may potentially help prevent recurrence.

CASE REPORT

In 2011, a 35-year-old male reported headaches to a local ED. A non-enhancing mass was detected on his brain MRI. Observation was advised by his local surgeon. The patient presented with seizures in early 2014, and his brain MRI found the mass developed new enhancement. In late 2014, the patient had multiple seizures, and significant progression of the tumor was discovered. The patient underwent craniotomy and biopsy in the middle cerebral artery distribution area in early 2015. Pathology reported grade II oligodendroglioma; however, the patient only underwent a biopsy, which might have missed the high-grade glioma region. His brain MRI showed a significant enhancing lesion with rapid growth, which was clinically more consistent with grade III oligodendroglioma. Radiation therapy was conducted followed by 6 cycles of PCV chemotherapy throughout 11 months. Post-radiation-chemotherapy brain MRI was stable with a moderate size residual tumor at the right insula region. Following patient wishes, NovoTTF-100A, or Optune, was administered 6 weeks after completion of chemotherapy as maintenance therapy for 2 years to prevent tumor progression. Now, after 3 years being off Optune, the patient is stable without new neurological symptoms or tumor progression. DISCUSSION: Our case highlights the potential effect of Tumor Treating Fields as maintenance therapy after initial radiation and chemotherapy for low- and high-grade oligodendrogliomas. The patient had rapid tumor progression prior to diagnosis and only underwent a biopsy without resection, yet uncommonly, has survived since initial image diagnosis 10 years ago and tissue diagnosis 6 years ago and is fully functional currently.
INNV-13. UNDERSTANDING FACTORS THAT INFLUENCE THE DECISION OF ACCEPTING TUMOR TREATING FIELDS (TTF) THERAPY
Authors: Kumthekar Priya , Lyleroehr Madison , Lacson Leilani , Stupp Roger , Lukas Rimas , Lezon Ray , Mora Kellie , Schmidt Karyn , Dixit Karan , Kaiser Karen
Published: November 2021

BACKGROUND

Tumor Treating Fields (TTF) Therapy is an FDA-approved therapy in the first line and recurrent setting for glioblastoma. Despite Phase 3 evidence showing improved survival, it is not uniformly utilized despite its availability. This qualitative prospective study interviewed glioblastoma patients to better understand key driving factors for decision making.

METHODS

Adult glioblastoma patients who were offered TTF and who signed IRB approved consent were included. Patients participated in a one-time recorded interview with the researchers from the Northwestern University Department of Medical Social Sciences and were asked about factors shaping their decision to use or not use TTF.

RESULTS

40 patients were enrolled with a mean age of 53 years, 92.5% were white and 60% were male. Of the 33 (82.5%) participants who accepted TTF, 23 (69.7%) reported their physician recommending TTF, 8 (24.2%) reported physician neutrality toward TTF, and 2 (6.1%) said their physician advised against TTF. Among the 7 (17.5%) participants who did not choose TTF, 4 (57.1%) reported physician neutrality, 2 (28.6%) reported that their physician advised against TTF, and 1 (14.3%) reported that their physician recommended TTF. Participants who decided against TTF stated that head shaving, appearing sick, and inconvenience of wearing/carrying the device most influenced their decision. For those choosing to use TTF, the most influential factors were extending life and following their doctor's opinion; other factors included level of familial support and the clinical evidence supporting TTF.

DISCUSSION

This clinical study was a collaboration with the Medical Social Sciences team to better understand the key factors that drive patient decision making with TTF. Findings suggest that physician support and positive Phase 3 results are among the key decision-making factors. Properly understanding the path to patients’ decision making is crucial in optimizing use of TTF and other therapeutic decisions for glioblastoma patients.
INNV-15. PROTEIN TYPING AND MRNA ANALYSIS OF CIRCULATING EXOSOMES FOR GLIOBLASTOMA THERAPY USING PLASMONIC-ENHANCED INTEGRATED MAGNETO-ELECTROCHEMICAL SENSOR
Authors: Lin Hsing-Ying , Huang Chen-Han , Hsu Peng-Wei , Lu Yu-Jen , Chou Peter C Y , Chen Hugo C H , Liu Vicky Y H
Published: November 2021

Monitoring of drug efficacy in glioblastoma multiforme (GBM) is a major clinical problem. Glioblastomas shed large quantities of exosomes into the circulation. Although these hold promise as potential biomarkers of therapeutic response, their identification and quantification remain challenging. Recently, we develop a highly sensitive and rapid analytical technique for profiling circulating exosomes directly from serum plasma of patients with glioblastoma. Exosomes are labeled with target-specific metal nanoparticles and detected by a miniaturized integrated magneto-electrochemical sensing system. Compared with current methods, this integrated system has a much higher detection sensitivity and can differentiate GBM exosomes from nontumor host cell–derived exosomes. We also show that circulating GBM exosomes can be used to analyze primary tumor mutations and as a predictive metric of treatment-induced changes. This platform could provide both an early indicator of drug efficacy and a potential molecular stratifier for human clinical trials.
INNV-16. CNS-TAP TOOL RECOMMENDATIONS OF TARGETED ANTI-CANCER AGENTS COMPARED TO THOSE SELECTED BY A MULTIDISCIPLINARY TUMOR BOARD IN A MOLECULARLY-DRIVEN DIPG CLINICAL TRIAL (PNOC003)
Authors: Roberts Holly , Ravi Karthik , Schepers Allison , Marini Bernard , Kline Cassie , Mueller Sabine , Koschmann Carl , Franson Andrea
Published: November 2021

Genetic sequencing of diffuse intrinsic pontine gliomas (DIPG) has revealed genomic heterogeneity, sparking an interest in individualized and targeted treatment options for this particularly devastating disease. A feasibility study, PNOC003: Molecular Profiling for Individualized Treatment Plan for DIPG (NCT02274987), was completed within the Pacific Pediatric Neuro-Oncology Consortium. In this study, a multidisciplinary tumor board reviewed detailed molecular and genomic profiling of each participant’s tumor and made molecularly-targeted treatment recommendations. Separately, our team developed the Central Nervous System Targeted Agent Prediction (CNS-TAP) tool, which combines pre-clinical, clinical, and CNS penetration data with patient-specific genomic information to derive numeric scores for targeted anticancer agents, aimed to objectively evaluate these therapies for use in patients with CNS tumors. We hypothesized that highly-scored agents within CNS-TAP would overlap with the agents recommended by the tumor board in PNOC003. For each study participant, we used the genomic profiling report to identify actionable alterations and incorporated these data into CNS-TAP to identify the highest-scoring agents. We compared high-scoring agents within CNS-TAP with recommendations from the tumor board for each of the enrolled 28 participants. Overall, 93% of patients (26/28) had at least one agent recommended by both the tumor board and CNS-TAP. Additionally, 38% of all agents (36/95) recommended by the tumor board were also selected by CNS-TAP. We identified factors that likely contributed to the differences in therapy recommendations between these two methods: CNS-TAP requires additional clinician input to account for drug-drug interactions, includes only classically-defined anticancer agents, and cannot easily be updated in real-time as new data emerge. However, CNS-TAP provides an objective evaluation of targeted therapies, whereas tumor boards are inherently subjective. A prospective study incorporating both CNS-TAP and a molecular tumor board for targeted therapy selection in high-grade glioma is currently ongoing to further compare and objectively evaluate these methods.
INNV-17. RESPONSE TO AVAPRITINIB IN A PEDIATRIC SPINAL CORD H3K27M-MUTANT GLIOMA PATIENT
Authors: Mayr Lisa , Madlener Sibylle , Verena Rosenmayr , Schmook Maria , Stepien Natalia , Baumgartner Alicia-Christina , Dorfer Christian , Haberler Christine , Müllauer Leonhard , Dieckmann Karin , Peyrl Andreas , Kim Sean , Hsieh Antony , Dimitrijevic Sasa , Gojo Johannes
Published: November 2021

H3K27M-mutated diffuse midline glioma (H3K27M-DMG) may arise in the pons, thalamus and spinal cord generally having a dismal prognosis. Notably, H3K27M-DMG are driven by oligodendrocyte precursor-like cells which are partly sustained by PDGFRA signaling. Co-mutations including TP53, ACVR1, PDGFRA, KIT and PI3K pathway alterations are present in a subset of cases, and molecular profiling may allow detection of additional targetable alterations. However, small-molecule inhibitors often have limited efficacy associated with low blood-brain-barrier (BBB) penetration. Here, we report on a patient with spinal, leptomeningeal disseminated H3K27M-DMG treated with avapritinib, an orally administered, BBB-penetrant and highly selective KIT and PDGFR inhibitor, provided through a compassionate-use program. Initial therapy consisted of subtotal resection, focal radiotherapy and temozolomide (TMZ) resulting in disease stabilization. Ten months after diagnosis, leptomeningeal metastases were detected, biopsied and treated with local irradiation and TMZ. The patient subsequently received systemic and intrathecal chemotherapy augmented with dasatinib. Molecular analyses of the biopsy revealed the H3F3A and TP53 mutations present in the primary tumor, as well as de novo PDGFRA and KIT amplifications with gene copy numbers of 25 and 21, respectively. Upon further disease progression, therapy with avapritinib was initiated. Assessment of treatment response according to RANO criteria after four months revealed stable disease of the target lesion in the cerebellum and partial response of all non-target lesions. Avapritinib was generally well tolerated with lower limb edema (Grade 2), small intratumoral bleeding (Grade 1) and unrelated hydrocephalus (Grade 3) as reported adverse events. As precaution, treatment was interrupted and re-initiated after one week as the bleeding was stable. A ventriculoperitoneal shunt was implanted resolving the hydrocephalus. Pharmacokinetic analyses revealed up to 65% avapritinib plasma exposure and clinically relevant levels in cerebrospinal fluid. In summary, we report on first effective therapy of treatment-resistant H3K27M-DMG with avapritinib as clinical proof of concept.
INNV-23. CASE REPORT OF CISPLATIN + ETOPOSIDE FOR THE TREATMENT OF METASTATIC MALIGNANT MENINGIOMA
Authors: Nguyen Minhdan , Truong Judy , Sharma Akanksha , Kesari Santosh , Carrillo Jose , Chow Jared , Landa Eve , Griffiths Chester , Kelly Daniel , Wagle Naveed
Published: November 2021

INTRODUCTION

Meningioma have an annual incidence of 5 per 100,000 and is the most frequent primary tumor of the central nervous system. Risk factors include radiotherapy and hormone intake. Most meningioma are grade I benign tumors, but up to 15% are atypical and 2% anaplastic according to the WHO 2016 histological criteria. Extra-CNS metastasis is exceedingly rare but carry a poor prognosis. Surgical resection and radiation therapy are the only approved therapies for the treatment of high grade or recurrent meningioma. Chemotherapy options have been limited and none have shown significant response rates.

METHODS

We report a case of a 33 year old male with an anaplastic meningioma (WHO Grade III) with metastasis to the lungs and rapid progression despite repeat resection. The subject was previously treated with resection and radiation therapy to a skull base/sinonasal lesion. Progression occurred at anterior cranial fossa, which required repeat resection. Within a month, the meningioma showed substantial progression with invasion into the orbit and nasopharynx as well as metastasis to the lung. The subject experienced significant clinical decline which included bilateral vision loss. The subject was treated with Cisplatin and Etoposide for 4 cycles.

RESULTS

The patient had immediate clinical improvement after the first cycle. Repeat MRI imaging of the brain showed partial response with approximately 40% tumor reduction, and CT of the chest showed complete response. The subject’s performance status also improved significantly with treatment including recovery of eyesight bilaterally.

CONCLUSION

This case showed that the use of Cisplatin + Etoposide for metastatic malignant meningioma can have significant objective and clinical response. The use of this regimen warrants further investigation. A clinical trial is currently being developed.
INNV-25. RITUXIMAB MONOTHERAPY FOR TREATMENT OF RARE LOW GRADE PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA; A CASE REPORT AND LITERATURE REVIEW
Authors: Tobin Grace , Neil Elizabeth
Published: November 2021

Primary central nervous system lymphoma (PCNSL) is a specific variant of non-Hodgkin's lymphoma confined to the brain, leptomeninges, spinal cord, and/or eyes. The majority of PCNSL is diffuse large B-cell lymphoma (DLBCL), however, a small percentage are categorized as low-grade lymphomas (LGL). Compared to high-grade and aggressive DLBCL, LGL are indolent; allowing for targeted and less neurotoxic first-line treatments. There is currently no consensus for LGL treatment. A patient at our institution was diagnosed with LGL without extra-CNS involvement 11/2018 and then, successfully treated with rituximab monotherapy. This 65 year-old, immunocompetent woman presented with one month of right leg weakness and numbness. Brain MRI demonstrated a subtly enhancing infiltrative left thalamic lesion extending into the left frontal lobe with surrounding edema. Flow cytometry on spinal fluid showed rare monotypic B-cells. Brain biopsy results showed an atypical predominantly perivascular lymphoid infiltrate. These atypical small lymphoid cells had mature-appearing nuclear chromatin, absent nucleoli, and uniformly expressed CD79a and CD20 with variable PAX-5 expression, lacked CD56 and CD117 expression, and had plasmacytic differentiation; thus consistent with marginal zone lymphoma, a type of indolent B-cell lymphoma. There was no evidence of extra-CNS involvement on PET scan, bone marrow biopsy, or ocular exam. She had normal cognitive functioning on neuropsychological testing. Interestingly, SPEP showed a monoclonal IgM immunoglobulin of kappa-light chain-type that became a monoclonal protein in the gamma fraction. Additionally, CT abdomen initially showed splenomegaly that resolved on repeat imaging a year later. Radiation therapy was deferred due to high risk. Weekly rituximab 500mg/m2 was initiated for 4 doses, then monthly for 4 doses. Therapy was well tolerated and she noted clinical improvement plus there was positive response on brain imaging. Repeat ophthalmology exam and CT body without any evidence of cancer. She is now 29 months progression-free since completing rituximab.
INNV-31. NEURO-ONCOLOGY OUTPATIENT SATISFACTION IS MAINTAINED IN THE ERA OF COVID-19 TELEMEDICINE
Authors: Petitt Zoey , Herndon James , Gottfried Oren , Cone Christina , Landi Daniel , Khasraw Mustafa , Friedman Henry , Ashley David M , Desjardins Annick , Peters Katherine , Johnson Margaret
Published: November 2021

INTRODUCTION

The use of telemedicine increased during the COVID-19 pandemic. However, the impact on patient satisfaction in the Neuro-oncology population is unknown. This quality improvement project compares outpatient satisfaction before and during the COVID-19 pandemic as well as in-person versus telemedicine platforms during the pandemic.

METHODS

We performed an IRB-exempt retrospective analysis of aggregate de-identified outpatient satisfaction scores among Neuro-oncology patients seen at The Preston Robert Tisch Brain Tumor Center (PRTBTC) at Duke University. The Clinician & Group Consumer Assessment of Healthcare Providers and Systems (CG-CAHPS) is a survey developed and distributed by Press Ganey Associates, and is the most widely used outpatient satisfaction survey in the United States. We compared pre-COVID-19 CG-CAHPS scores from patients who received in-person care at the PRBTC between April 2019 and March 2020 to COVID-19 pandemic CG-CAHPS scores (i.e. those who received either telemedicine or in-person care at the PRTBTC) from April 2020 to March 2021.

RESULTS

Approximately 1448 surveys were completed for both in-person and telemedicine visits. During the pandemic, 48.6% of surveys represented telemedicine, with monthly variations from 84.6% (April 2020) to 21.4% (March 2021). Patient satisfaction scores pre-COVID-19 were similar to those during the pandemic: overall provider rating from 0-10 (9.28 v 9.36), knowledge of medical history (96.9% v 95.4%), listens carefully (96.6% v 96.9%), shows respect (97.2% v 98.1%), and time spent (93.2% v 95.5%). During the COVID-19 pandemic, in-person and telemedicine demonstrate similar levels of satisfaction: overall provider rating from 0-10 (9.29 v 9.48), knowledge of medical history (94.9% v 96.1%), listens carefully (95.4% v 99.0%), shows respect (97.5% v 99.0%), and time spent (94.7% v 96.7%).

CONCLUSION

Outpatient satisfaction prior to and during the COVID-19 pandemic was similar. Patients reported similar satisfaction between in-person and telemedicine platforms. We support the ongoing use of telemedicine for outpatient Neuro-oncology.
INNV-35. A MULTI-DISCIPLINARY REVIEW OF NEWLY DIAGNOSED HIGH GRADE GLIOMA REFERRALS TO THERAPIES, AND IMPLEMENTATION OF A SCREENING TOOL TO IMPROVE ACCESS TO THERAPIES AT THE ROYAL MARSDEN HOSPITAL (RMH)
Authors: Jethwa Joanne , Jagger Charmaine , Williams Leanne , Jenkins Lizzy , Ashforth Kate
Published: November 2021

Brain tumours make up 3% of all cancers. The disease and treatment have significant impact on function and quality of life (QoL). Early outpatient rehabilitation can improve function. National Institute of Clinical Excellence recommends patients have access to rehabilitation across the pathway, but unmet need is prevalent in this population. We recognised late referrals in our Trust and poor patient awareness of Therapies, resulting in reduced access to rehabilitation. METHOD: A retrospective notes review of new neuro-oncology patients (n=56) referred to RMH from July - December 2018 was undertaken to identify therapy needs and timeliness of referrals. A therapy screening tool was devised and piloted from July – December 2019. Additionally, an MDT questionnaire was circulated to gain feedback regarding this service. RESULTS: Retrospective review revealed that of those patients with identified therapy needs, 16% of physiotherapy (PT), 10% of Occupational Therapy (OT) and 9% of Speech and Language Therapy (SLT) were referred late. Additionally, referrals were not received for 40% of patients with OT needs, 32% for PT and 30% for SLT. Following implementation of the screening tool, referrals occurred earlier in the pathway, and rates increased by 60% in SLT, 59% in PT, and 25% in OT. An MDT questionnaire revealed 100% consensus that screening was beneficial to patients and the MDT with improved access to therapies. CONCLUSION: Brain tumour patients require prompt therapy intervention to improve and maintain function and QoL. We identified high levels of unmet need which was eliminated by a screening tool and subsequently increased referral rates. Patients and the MDT had improved awareness of the role of Therapies, as well as earlier access. The neuro-oncology MDT benefitted from the effects of therapy intervention improving patient tolerance to oncological treatment. Therapists were able to identify and manage impairments earlier, improving QoL.
INNV-38. COVID-19 INDUCED TELEMEDICINE LESSONS FOR CLINICIANS CARING FOR PATIENTS WITH PRIMARY BRAIN TUMORS
Authors: Komlodi-Pasztor Edina , Brady Amy , Grossman Stuart
Published: November 2021

BACKGROUND

The COVID-19 pandemic triggered a rapid conversion from in-person to video-visits for new patient consultations and follow-up visits. Now with available vaccines and declining case rates efforts are underway to return to in-person visits as they provide more revenue and are viewed as best for patients and clinicians. This abstract reviews these assumptions.

METHODS

Electronic medical records from seven full-time faculty neuro-oncologists at Johns Hopkins Hospitals were retrospectively reviewed from 4/1/20 to 3/31/21 to examine the use of video visits over time and their patient demographics.

RESULTS

From 4/1/20 to 3/31/21, 279 new patients were seen (57% video-visits) with a median age of 52 years for both video and in-person visits. Patients came from 15 states for video and 17 states for in-person visits. There were also 2247 follow-up visits (85% video-visits) with a median age of 47 yrs for video and 50 yrs for in-person visits. Patients came from 28 states for video and 14 for in-person visits. No show visits were more frequent for in-person visits. During early months of the pandemic, few patients were seen in the clinics. Thereafter, video-visits rose sharply comprising 93% of follow-up visits in June 2020 and 62% of new patient consultations in September 2020. These rates have remained high (in March 2021, 72% of all follow-up visits and 59% of new patient consultations).

CONCLUSIONS

Despite reductions in COVID-19 infection rates, our neuro-oncologists continue to favor video-visits for new patient consultations and follow-up visits. Video-visits save patients and caregivers travel time, parking costs, and time away from work. They also allow an acceptable history and neurological exam, participation by many family members, easy sharing of MRI scans and laboratory data, and discussions unencumbered by face masks and shields. These advantages to video-visits remain significant even as the pandemic recedes.
INNV-41. MY STORI – A SYMPTOM TRACKING AND REPORTING INSTRUMENT MOBILE APPLICATION FOR BRAIN TUMOR PATIENTS
Authors: Celiku Orieta , Odom Kristin , Ramidi Mahendar , Armstrong Terri
Published: November 2021

INTRODUCTION

Managing symptom burden is an integral part of brain tumor patient care, but tools to facilitate tracking symptoms and self-management for this population are lacking. Reporting is often limited to self-report as part of clinical follow-up care, or episodic between visits if symptoms are severe. While general-purpose and cancer-specific mobile applications that track medical symptoms are becoming more prevalent, they may not cover the entire range of symptoms experienced by patients with brain tumors or allow tracking of self-management strategies.

METHODS

We developed an iOS operating system mobile application using Apple’s UIKit, Foundation, WebKit, and Core Graphics frameworks. Core Data and iCloud were used to implement local and cloud-based data storage for personal use. Findings from our Outcomes Surveys informed selection of core symptoms to track. A multidisciplinary team of neuro-oncology scientists, providers, and communication specialists developed self-care content from evidence-based sources.

RESULTS

We developed My STORI, a free mobile application to capture the experiences of brain tumor patients. Patients and their family members can track daily symptoms and their impact on function and record any actions that were taken to mitigate them. Evidence-based self-care information on how to recognize, manage, and report symptoms is provided. Graphical summaries of how these symptoms evolve over time, and how they are impacted by clinical appointments, treatment, and self-care activities can be displayed and compiled into reports that can be shared with their care team, family, or health care record.

CONCLUSIONS

Mobile applications have the potential to promote self-care, facilitate symptom management, and enable intuitive, frequent, and convenient reporting of clinically relevant data to the health-care team. The My STORI application is an innovation in patient care guided by evidence-based research and can be used to track symptom management, promote self-care, and enhance communication to improve clinical care and research.
PATH-03. FERROPTOSIS-RELATED LONG NON-CODING RNA SIGNATURES PREDICT PROGNOSIS IN PATIENTS WITH GLIOMA
Authors: Lai Donglin , Zuo Xiaojia , Yang Xintong , Zheng Yanjun , Duan Baoyu , Li Yanfei , Wan Guoqing , Lu Changlian , Gu Xuefeng
Published: November 2021

Ferroptosis, with iron-dependent and ROS-dependent, is a novel type of cell death in a variety of diseases and some studies confirmed that ferroptosis-related lncRNAs are involved in the occurrence and development of several cancers. However, the ferroptosis-related lncRNA in the role of gliomas is unclear. Here, we constructed a prognostic scoring model of ferroptosis-related lncRNAs in gliomas. Data were downloaded from the Chinese glioma genome atlas (CGGA), the cancer genome atlas, and FerrDb database. In this study, we found 1051 lncRNAs associated with ferroptosis by Spearman's rank correlation analysis in CGGA653, and 547 lncRNAs were related to prognosis in gliomas. Subsequently, we identified 9 ferroptosis-related signatures (AC010729.2, AC062021.1, FAM225B, FAM66C, HOXA-AS2, LINC00662, LINC00665, MIR497HG, and TMEM72-AS1) by least absolute shrinkage and selection operator and Cox proportional hazards model. Next, all glioma patients were divided into high- and low-risk groups based on the median risk score based on these signatures, and the low-risk group had better prognosis significantly than the high-risk group by Kaplan-Meier curve. Moreover, the risk score can predict survival status with high sensitivity and specificity by receiver operating characteristic curve (area under the curve at 1, 3, 5 years: 0.791, 0.84, 0.856, respectively). In addition, some pathways (cell cycle, p53 signaling pathway, apoptosis, and oxidative phosphorylation) significantly enriched in KEGG enrichment pathway, and a nomogram was constructed by integrating some independent prognostic clinicopathological features to predict the overall survival in gliomas (C-index: 0.786). In summary, these 9 ferroptosis-related signatures have potential prognostic value and could be crucial factors for treating malignant gliomas.
PATH-12. CLINICAL AND PATHOLOGICAL ANALYSIS OF 43 PATIENTS WITH EPITHELIOID GLIOBLASTOMA
Authors: Zhen Junjie , Lai Mingyao , Zhou Jiangfen , Li Shaoqun , Cai Linbo
Published: November 2021

BACKGROUND AND PURPOSE

Epithelioid glioblastoma (eGBM) is a rare and aggressive subtype of glioblastoma. The clinical characteristics, pathological features and radiological findingsare still not well characterized.

METHODS

The clinical data of 43 patients with eGBM confirmed pathologically after surgery in Guangdong Sanjiu Brain Hospital from June 2015 to January 2021 were reviewed, and to investigate the clinical, pathological and imaging characteristics of the eGBM.

RESULTS

The range of patients' age was from 5 to 70 years (median 39 years). There were 24 males and 19 females. The median karnofsky performance score (KPS）at diagnosis was 70 (40-90). The most common symptom were headache (81.4%), and other common symptoms included nausea or vomiting (44.1%), limb weakness (30.2%), disturbance of consciousness (20.9%) and seizures (9.3%). Most of the tumors (97.6%) were located in the cerebral hemisphere ,except for one case located in the cerebellum,and with an average diameter of 5.3 cm (2.5-9.4 cm). There were 2 cases of intracranial metastasis and 7 cases of spinal cord metastasis in MRI. In pathologic examination, immunohistochemistry showed all the patients were IDH1 wild-type (43/43) and H3K27M wild-type(34/34). 25 (58.1%) of cases harbored BRAF mutation and 19 (44.2%) cases of MGMT positive. Most of patients were positive for GFAP, P53, Olig-2 and ATRX.

CONCLUSION

Epithelioid glioblastoma is more common in adults, most of which are located on the supratentorial, intracranial and spinal cord dissemination may occur. Half of patients showed BRFA mutation and maybe benefit from targeted therapy.These findings may help clinicians understand and treat epithelioid glioblastoma better.
PATH-14. ALPHA CARDIAC ACTIN EXPRESSION IS OBSERVED IN AGGRESSIVE GLIOMA SUBTYPES AND GLIOBLASTOMA STEM CELLS
Authors: Suresh Rahul , Fiola Sophie , Beaulieu Jamie , Diaz Roberto
Published: November 2021

BACKGROUND

Alterations in actin subunit expression have previously been observed in multiple cancers. In glioblastoma (GBM), the expression of ACTC1 has been associated with a more invasive phenotype and with shorter survival. We sought to explore the diversity of actin subunit expression across glioma subtypes and patient derived glioblastoma stem cells (GSCs).

METHODS

Bioinformatic analysis of multiple glioma databases was performed to profile actin subunit (ACTA1, ACTA2, ACTC1, ACTG1, ACTG2, and ACTB) mRNA levels. Expression levels were also evaluated in normal brain in comparison to liver and heart tissue. Western blot was used to analyze protein expression in GSCs, surgical tissue and human fetal astrocytes.

RESULTS

The primary actin subunits expressed in normal brain are beta actin (ACTB) and gamma actin (ACTG1). RNA sequencing of tissue from multiple glioma subtypes or different brain regions reveals a global increase in ACTG1 and ACTB abundance in gliomas compared to normal brain. LGG-GCIMP high and LGG-co-deleted glioma subtypes have the lowest ACTC1 expression. LGG-GCIMP low (HR 9.75, P< 0.001), LGG-mesenchymal-like (HR11.1, P< 0.001), LGG-classic-like (HR10.96, P< 0.001) subtypes are associated with ACTC1 expression. ACTC1, ACTCB, and ACTG protein expression was observed in GSCs, freshly resected GBM tissue, and human fetal astrocytes.

CONCLUSIONS

Gliomas have a specific pattern of actin subunit expression that differs in actin subunit type and abundance when compared to normal adult brain. Expression of ACTC1 is found in aggressive glioma subtypes and is shared by GSCs and human fetal astrocytes. Investigation into the neurodevelopmental role of ACTC1 and its contribution to oncogenic transformation in GBM is warranted.
PATH-15. NON-CANONICAL IDH 1 AND IDH 2 MUTATIONS ARE ASSOCIATED WITH IMPROVED SURVIVAL IN PATIENTS WITH GLIOMAS: RESULTS OF A META-ANALYSIS
Authors: nunno Vincenzo Di , Franceschi Enrico , Tosoni Alicia , Gatto Lidia , Mura Antonella , Acquaviva Giorgia , De Biase Dario , Bartolini Stefania , Brandes Alba Ariela
Published: November 2021

BACKGROUND

Non-canonical isocitrate dehydrogenase (IDH) mutations are uncommon among patients with grade 2 and 3 gliomas and their clinical significance is still unclear.

METHOD

We carried out a systematic review and meta-analysis to evaluate the prognostic impact of IDH1 and IDH2 non-canonical mutations. We searched English-written articles published on PubMed/Medline, Cochrane library, and Scopus until the 1st May 2021. Keywords adopted for the research were: ‘’IDH’’ OR ‘’IDH1’’ OR ‘’IDH2’’ OR ‘’Isocitrate dehydrogenase’’ AND ‘’glioma’’.

RESULTS

We selected 13 of 3513 studies reporting data of 4007 patients with a diagnosis of grade 2 and grade 3 including 3091 patients with a molecular proven IDH 1 or IDH 2 mutations. Between patients with IDH mutated gliomas, 479 (15.5%) patients showed non-canonical IDH 1 or IDH 2 mutations. The presence of IDH 1 non-canonical mutation occurred in younger age and in non codeleted 1p19q as compared to canonical IDH 1 mutation. However, patients with IDH 2 mutations showed more frequently 1p19q codeletion as compared to those with canonical IDH 1 mutated glioma. Four studies reported complete data survival for patients with non-canonical (n= 160) and canonical mutations (n= 1019). The pooled HR of these studies was 0.47 (95% CI, 0.28-0.81) confirming a positive prognostic role for non-canonical IDH 1 and IDH 2 mutations.

CONCLUSION

The presence of non-canonical IDH 1 and IDH 2 mutations defines a specific subgroup of gliomas occurring at younger age with improved survival. Patients with a non-canonical IDH 1 mutation showed less frequently 1p19q codeletion as compared to those patients harboring a canonical or IDH 2 mutation.
PATH-19. TERT PROMOTER MUTATION, NOT H3K27M MUTATION IS A PROGNOSTIC FACTOR FOR ADULT THALAMIC GLIOMAS
Authors: Nitta Masayuki , Muragaki Yoshihiro , Komori Takashi , Masui kenta , Saito Taiichi , Tsuzuki Shunsuke , Fukui Atsushi , Koriyama Shunichi , Onitsuka Hiromi , Ikuta Soko , Kuwano Jun , Kawamata Takakazu
Published: November 2021

Purpose

Thalamic diffuse glioma is classified as WHO grade 4 as Diffuse midline glioma, H3K27M mutation if H3K27M mutation was found regardless of its histological findings, but the significance of H3K27M mutation is not clear compared with pediatric cases. We aimed to find genetic prognostic factors in adult thalamic diffuse gliomas.

METHODS

Pathological diagnosis, genetic abnormalities, and clinical course of adult newly diagnosed thalamic gliomas diagnosed and treated at our institution from July 2007 to March 2020 were retrospectively analyzed.

RESULTS

The number of cases was 41 (24 males, 17 females), median age was 47 years (20-75 years). Tumor localization was 20 cases on the left, 14 cases on the right, and 7 cases on both sides. The pathological diagnosis was GBM 15 cases, DMG 15 cases, AA-IDH WT 7 cases, DA-IDH WT 4 cases, all of which were IDH wild type, and none of them had IDH mutation and 1p/19q co-deletion. H3K27M mutations were found in 15 cases and TERT promoter mutations were found in 12 cases, both of which were completely mutually exclusive. Tumor resection and biopsy was performed in 33 and 8 cases, respectively, and the median removal rate was 95% for those who underwent tumor resection. The median PFS and OS of all cases were 14.3 months and 38 months, respectively, and the median OS by pathological diagnosis was GBM 12.4 months, DMG 47.4 months, AA-IDH WT 37.3 months, DA-IDH WT not reached. The median OS in the H3K27M mutant group (47.4 months) was significantly better (p=0.02) than that in the TERT promoter mutation group (13.5 months).

CONCLUSION

There was no IDH mutation in adult thalamic gliomas, the H3K27M mutation and the TERT promoter mutation were mutually exclusive. The H3K27M mutation was not a prognostic factor, but the TERT promoter mutation was the strongest prognostic factor.
PATH-20. SPATIAL MAPPING OF THERAPY-INDUCED, PATHOLOGICAL CHANGES IN GLIOBLASTOMA AT SINGLE-CELL RESOLUTION
Authors: Vanmechelen Maxime , Beckervordersandforth Jan , Pey Jon , Antoranz Asier , Nasari Pouya , Pantano daniele , Bevers Sien , Leunissen Daphne , Moors Wout , Messiaen Julie , Sebastian Ivey , Milli Giorgia , Van Herck Yannick , Geens Emma , Verduin Maikel , Hoosemans Linde , Claeys Annelies , Derweduwe Marleen , Zurhausen Axel , Bosisio francesca , Eekers Danielle , Weyns Frank , Daenekindt Thomas , Van Eyken Peter , Goovers Mark , Hovinga Koos , De Vleeschouwer Steven , Clement Paul , Broen Martijn , Vooijs Marc , Sciot Raf , Hoeben Ann , Speel Ernst Jan , De Smet Frederik
Published: November 2021

Glioblastoma (GBM) remains a highly malignant, intrinsically resistant and inevitably recurring brain tumor with dismal prognosis. The aggressiveness and lack of effective GBM treatments can be attributed to the highly heterogeneous and plastic nature of GBM tumor cells, which easily confer resistance to standard-of-care (SOC) therapy. While tumor progression has also been attributed to interactions with the tumor microenvironment, quantitative data describing these interactions are still largely missing. Here, we used high-dimensional, multiplexed immunohistochemistry to map evolutions in the spatial, single-cell tissue architecture of 120 paired adult GBM tumor samples derived from 60 patients at diagnosis (ND) and upon recurrence (REC) following SOC treatment. We mapped the spatial distribution of a multitude of GBM tumoral subtypes across this multicentric cohort, through which we identified a high level of heterogeneity defined by specific tumoral niches within and across patients and which evolved when subjected to SOC therapy. In addition, we describe the relationship of the various tumoral niches with their local immune-infiltrates, highlighting an even more immunosuppressive environment following SOC resistance. Finally, by aligning these findings to the observed genomic aberrations and the clinical data of the patients, we are now able to more precisely describe the heterogeneous landscape of glioblastoma and how it evolves under SOC treatment at spatial, single-cell resolution.
PATH-24. COPY NUMBER ALTERATIONS IN NOTCH PATHWAY GENES ARE PROGNOSTIC IN A SUBSET OF DIFFUSE ASTROCYTIC GLIOMAS
Authors: Nuechterlein Nicholas , Cimino Patrick
Published: November 2021

Inactivating mutations in NOTCH1 occur in many cancer types and are frequently observed in IDH-mutant, 1p/19q-codeleted oligodendroglioma. Although the role of NOTCH1 as a tumor suppressor in diffuse glioma has become appreciated in human tissue and small animal models, the spectrum of inactivating mutations in Notch pathway genes in diffuse astrocytic gliomas has not been well described. To address this, we queried the TCGA lower-grade glioma and glioblastoma datasets to establish the extent of inactivation of Notch pathway genes, specifically by cataloging single nucleotide variants and those with copy number loss or deletion. Key alteration frequencies were found to be similar in two-independent glioma cohorts (Col, MSK). Notch pathway genes with inactivating alterations (overwhelmingly copy number loss) were present in 77% of TCGA diffuse gliomas. Across all diffuse gliomas, DLL3 loss was the most common alteration (TCGA 31%). For IDH-mutant diffuse astrocytic gliomas, JAG2 loss was the most common alteration (TCGA 23.0%, Col 35%, MSK 27%). DLL1 loss and MAML1 loss were mutually exclusive (p< 0.001) in TCGA IDH-mutant astrocytomas with a combined frequency of 39% (Col 47%, MSK 56%). The presence of any alteration in the top 10 altered Notch pathway genes indicated a shorter progression-free survival (p = 0.028) for TCGA IDH-mutant diffuse astrocytomas. For IDH-wildtype diffuse astrocytic gliomas, EP300 loss was the most common inactivating alteration (TCGA 35.4%, Col 49%, MSK 38%). EP300 loss, DLL1 loss, DLL4 loss were mutually exclusive (p = 0.006) in TCGA IDH-wildtype diffuse astrocytic gliomas with a combined frequency of 61% (Col 72%, MSK 66%). The presence of alterations in any of these three genes indicated a decreased overall survival (p = 0.045) in TCGA IDH-wildtype diffuse astrocytic gliomas. Overall, loss of differential Notch pathway genes has prognostic implications in both IDH-wildtype and IDH-mutant diffuse astrocytic gliomas.
PATH-31. METHYLATION SUBCLASS RECEPTOR TYROSINE KINASE II AS A DRIVER FOR SEIZURES IN IDH-WILDTYPE GLIOBLASTOMA
Authors: Drexler Richard , Eckhardt Alicia , Westphal Manfred , Schüller Ulrich , Dührsen Lasse , Ricklefs Franz
Published: November 2021

BACKGROUND

Seizures are a common symptom of patients suffering from glioblastoma and there is evidence that these tumours are morphologically different. However, the relationship of DNA methylation and glioblastoma-related seizures has not been well characterized. Only one study described an amplification of genes encoding receptor tyrosine kinases (RTK) as a positive predictor for intraoperative seizures during craniotomy.

METHODS

59 patients who underwent surgery with confirmed IDH-wildtype glioblastoma, WHO grade 4, were included. Genome-wide DNA methylation profiling was performed using an 850k Illumina EPIC array and classified by the DKFZ brain tumor classifier. Methylation glioblastoma subclasses and gene alterations were correlated with clinical characteristics including preoperative and long-term seizures.

RESULTS

Overall, 18 of 59 patients (30.5%) presented with seizures of whom suffered 8 (44.4%) from a focal and 10 (55.6%) from a generalized seizure. Correlation of preoperative seizures with glioblastoma subclasses and DNA genes identified a higher incidence of preoperative seizures in patients with the glioblastoma subclass of receptor tyrosine kinase II (RTK; EGFR amplified) (p=0.031). In addition, these patients were more likely to present with generalized seizures (p=0.05). In multivariate analysis, temporal location (p=0.014, OR 5.785) but moreover RTK II (p=0.024, OR 7.052) was most predictive for preoperative seizures. Furthermore, recurrent seizures with an increased antiepileptic medication at last follow-up (mean: 9.2 months) occurred more often in RTK II-glioblastoma (p< 0.05). Kaplan-Meier curves showed no significant association between the presentation of seizures and overall or progression-free survival. In addition, further survival analyses did not reveal a correlation of methylation glioblastoma subgroups with the outcome.

CONCLUSION

Our study showed a strong correlation of the RTK II methylation subclass with preoperative and long-term seizures in patients suffering from glioblastoma.
PATH-34. MOLECULAR AND CLINICAL HETEROGENEITY WITHIN SPINAL EPENDYMOMAS
Authors: Al-Kershi Sina , Kresbach Catena , Pohl Lara , Dorostkar Mario M , Suwala Abigail K , Wefers Annika K , Schweizer Leonille , Engertsberger Lara , Mohme Theresa , Mynarek Martin , Lamszus Katrin , Kluwe Lan , von Deimling Andreas , Benesch Martin , Hagel Christian , Mautner Viktor , Rutkowski Stefan , Schüller Ulrich
Published: November 2021

Ependymomas encompass multiple clinically relevant tumor types based on localization, genetic alterations, as well as epigenetic and transcriptomic profiles. Distinct global DNA methylation signatures serve as the most powerful diagnostic tool to distinguish these types. The methylation class of spinal ependymomas (SP-EPN) comprises mostly WHO°II tumors with slow progression and incomplete surgical resection rate. Molecular data of SP-EPN are scarce and clear treatment recommendations are lacking although these neoplasms represent the most common intramedullary tumors in children and adults. The only known recurrent genetic events in SP-EPN are the loss of chromosome 22q and mutations of the NF2 gene. However, data on the frequency of NF2 mutations range from 16 % to 71 % and originate from small series that lack epigenetic or transcriptomic characterization. Furthermore, it remains unclear whether SP-EPN with germline or sporadic NF2 mutation or with NF2 wild type status display clinical and other molecular differences. Finally, the underlying genomic and transcriptomic changes of SP-EPN without NF2 mutations are fully unclear. To provide a comprehensive molecular profile of SP-EPN, we integrated genomic and epigenetic analyses and clinical data of 170 cases. Unsupervised hierarchical clustering and t-SNE analyses of methylation data revealed three distinct molecular SP-EPN subtypes. Of the three subtypes, only subtype 1 and subtype 2 contained tumors with NF2 mutations, either as previously known germline mutations or as sporadic mutations without evidence for a syndromic disease (p< 0.0001). Besides the lack of NF2 mutations, subtype 3 tumors showed a higher frequency of MGMT promoter methylation (p= 0.0015) and occurred in significantly older patients compared to tumors of subtypes 1 and 2 (p= 0.0038). Further investigations such as whole-exome sequencing, copy number variation profiling, gene expression analysis, and histological evaluation are ongoing and will add to the picture of molecular and clinical heterogeneity within SP-EPN.
PATH-42. PROGNOSTIC FACTORS OF CNS GERM CELL TUMORS; MOLECULAR AND HISTOPATHOLOGICAL ANALYSES ON 154 CASES FROM THE IGCT CONSORTIUM
Authors: Satomi Kaishi , Nishikawa Ryo , Matsutani Masao , Ichimura Koichi , Takami Hirokazu
Published: November 2021

BACKGROUND

Germ cell tumors (GCTs) preferentially occurs in pediatric and young adult age groups. Chemo- and radiation therapies cause long-term sequelae in their later lives. We searched for clinical and histopathological features to predict the prognosis and affect treatment response, with a future goal of treatment stratification.

METHODS

A total of 154 GCT cases were included in the analysis. Total of 114 germinoma cases underwent measurement of tumor cell content on H-E specimen, and 82 GCT cases underwent 450K methylation analysis. 12p gain was determined on methylation-based copy number computation and FISH. Association with progression-free and overall survival (PFS/OS) was investigated.

RESULTS

The tumor cell content was widely distributed from < 5% to 90% in the specimens, with a median value of 50%. Patients with a higher tumor cell content (≥50%) showed shorter PFS than those with a lower tumor cell content (< 50 %) (p=0.03). In multivariate analysis with tumor location, tumor cell content was the sole statistically significant prognostic factor (p=0.04). 12p gain was found in 25-out-of-82 cases (30%) and was more frequent in NGGCTs, particularly in cases with malignant components. The presence of 12p gain correlated with shorter PFS and OS, even with histology and tumor markers incorporated in the multivariate analysis. Among NGGCTs, 12p gain still had prognostic significance for PFS and OS. The 12p copy number status was shared among histological components in mixed GCTs. Whole-genome amplification was suggested by FISH.

CONCLUSIONS

We found that tumor cell content significantly affected the prognosis of germinomas. 12p gain predicts the presence of malignant components of NGGCTs, and poor prognosis of the patients. Furthermore, 12p is likely to be an early event in the tumorigenesis of GCT. These potentially open the possibility of leveraging these pathological and molecular factors in future clinical trials when stratifying the treatment intensity.