bluuebunny/crossref_metadata_2025 huggingface dataset:
IMMU-41. RNA-MODIFIED T CELLS AS PROFESSIONAL ANTIGEN PRESENTING CELLS
Authors: Pohl-Guimarães Fernanda , Mitchell Duane
Published: November 2019

INTRODUCTION

With the lack of antigen presenting cells (APCs) in the central nervous system (CNS), anti-tumor immune responses from intracranial tumors are believed to be initiated in the peripheral lymph nodes. Recently, studies have shown that intratumoral dendritic cells (DCs), a well-known professional APC, play a crucial role at inducing anti-tumor immunity. Although DCs have been tested in cancer immunotherapy clinical trials for two decades, DC delivery strategies have limited access to the CNS, mainly due to the blood brain barrier (BBB). To bypass the limitations of the lack of intracranial APCs, we investigate the HYPOTHESIS that RNA-modified T cells can express and cross-present single tumor antigens locally within the CNS tumor microenvironment. Since activated T cells have an inherent ability to cross the BBB and can be genetically modified, this strategy makes them an attractive professional antigen presenting cells for cancer cell therapy.

METHODS

Using electroporation to deliver messenger RNA (mRNA) encoding a model tumor antigen to T cells, we evaluated the expression and cross-presentation capability of RNA-modified T cells.

RESULTS

We demonstrated that activated T cells can be genetically modified to express tumor antigens in vitro while retaining their inherent effector functions. Compared to unmodified T cells, T cells modified with tumor antigen encoding RNA showed high expression of inflammatory cytokines, including IFN gamma and TNF alpha and enhanced cellular proliferation and IL-2 secretion. Tumor antigen RNA-modified T cells demonstrated potent antigen presentation in vitro and importantly were significantly superior to RNA-loaded DCs in antigen presenting capacity.

CONCLUSIONS

This study strongly supports the implementation of a non-invasive and efficacious strategy to deliver “APC-like” T cell locally to brain tumors, thereby bypassing the lack of APCs within CNS malignancies.
INNV-02. ARE WE AGGRESSIVE WITH OUR GLIOBLASTOMA PATIENTS: A PROPOSED TOOL TO EVALUATE CENTERS ATTITUDES IN TREATMENT OF GLIOBLASTOMA
Authors: Al Abdulsalam Hissah , Alhothali Wajda , Alkhalidi Hisham , Orz Yasser , Alobaid Abdullah , Bafaqeeh Mohammed , Shaffi Ahamed Shaik , Hussain Sajjad , Albader Fahad , AlSaeed Eyad , Ibrahim Ahmed , Abdel Warith Ahmed , Alomair Ameen , Altewaijri Ikhlas , Elwatidy Sherif , Al-Habib Amro , Ajlan Abdulrazag
Published: November 2019

INTRODUCTION

Glioblastoma is the most common malignant primary brain tumor in adults. Optimal treatment for glioblastoma requires a multidisciplinary approach and knowledge of complications from both the disease and its treatment. Despite modern advances in the standards of care, the outcome in patients with Glioblastoma remains poor. Thus, it is crucial to optimize treatment strategies to improve over-all survival in patients with Glioblastoma, with the therapeutic challenge of “how aggressive a physician should be?” OBJECTIVES: We herein propose a novel method to compare aggressiveness in the standard of care between multiple centers, using a novel tool, and provide a more precise cut-off definition of aggressiveness.

METHOD

Multiple centers were included. A novel case-based questionnaire was generated which included only certain parameters, and then sent and answered jointly by tumor board members from each center. We then stratified centers into more aggressive vs. less aggressive based on our proposed Aggressiveness (AS) score.

RESULTS

In our novel cases, center A scored an AS score of 44 (Mean ± SD; 3.67 ± 1.07), while center B scored 49 (Mean ± SD; 4.08 ± 0.90) In real cases, center A scored 40 (Mean ± SD; 3.25 ± 1.42), while center B scored 44 (Mean ± SD; 3.75 ± 1.29). Our results showed consistency between centers evaluated using our tool. Age and presence of comorbidities were the most influential parameters.

CONCLUSION

In the current study, we present a novel and a reliable tool that can be easily used and replicated to compare aggressiveness in the treatment of Glioblastoma between multiple centers. The methodology we used has never been previously proposed and can serve as a novel concept to compare aggressiveness in treatment of all incurable diseases that require a multidisciplinary approach.
INNV-03. A MICROFLUIDIC CULTURE PARADIGM FOR THE EX VIVO MAINTENANCE OF HUMAN GLIOBLASTOMA TISSUE - A NEW GBM MODEL?
Authors: Olubajo Farouk , Achawal Shailendra , Rajaraman Chittoor , O’Reilly Gerry , Greenman John
Published: November 2019

The genetic and molecular variations that exist within Glioblastoma (GBM) determine treatment responses. One way to improve patient outcomes is to optimise treatment(s) pre-clinically by studying each tumour on an individual basis. Presented here are the results of a pilot study on the maintenance of human GBM tissue on a microfluidic platform. The device, fabricated using a photolithographic process, was composed of two layers of glass bonded together to contain a tissue chamber and a network of microchannels. A thin mesh layer was inserted to separate the tissue chamber from the microchannels and prevented blockage of the chip. Over an 18-month period, 33 patients were recruited, and 128 tissue sections were maintained in microfluidic devices for an average of 72 hours (h). Tissue viability as measured by Annexin V and Propidium Iodide staining showed that viability was 61.1 % in tissue maintained on chip after 72 h, compared with 68.9 % for fresh tissue analysed at the commencement of the experiment (P < 0.05). Other biomarkers, including Lactate Dehydrogenase (LDH) release and Trypan Blue assay, supported the viability of the tissue maintained on chip. Histological appearances of the tissue remained unchanged during the maintenance period and immunohistochemical analysis of Ki67 and Caspase 3 also showed no statistically significant differences. Analysis has shown a trend with tumours associated with poorer prognoses (e.g. recurrent tumours and IDH wildtype) displaying higher viability on chip compared to tumours linked with better outcomes (Grade 1–3 gliomas, IDH mutants and primary tumours). This work has demonstrated for the first time that human GBM tissue can be maintained ex vivo within a microfluidic device with viability comparable to fresh tissue samples. The model has the potential to be developed as a new platform for studying the biology of brain tumours, with the aim of facilitating personalised treatments.
INNV-04. IDH MUTATION PREDICTION IN GLIOMA: A MULTIMODAL APPROACH
Authors: Juratli Tareq , Zolal Amir , Stasik Sebastian , Pietzsch Mirko , Eisenhofer Graeme , Linn Jennifer , Schackert Gabriele , Thiede Christian , Krex Dietmar , Werner Annett
Published: November 2019

OBJECTIVE

Non-invasive and accurate diagnostic techniques to detect isocitrate dehydrogenase (IDH) mutant glioma may have great potential in routine clinical practice. With this in mind, we performed a multimodal diagnostic approach to predict the IDH mutation status in newly diagnosed gliomas using: 2-Hydroxyglutarate (2HG) single-voxel spectroscopy (SVS), IDH-mutant cell-free tumor-derived DNA (tDNA) in the CSF, in addition to 2HG (D- and L- forms) concentration measurement in the CSF.

METHODS

2HG MR spectroscopy was obtained in 18 patients with a newly diagnosed IDH-mutant glioma. The IDH1/2 mutation status was determined using next generation sequencing in the glioma tissue and in the CSF-tDNA (n=55). In addition, in a subset of patients (n=15), 2HG concentrations were measured in the CSF using liquid chromatography-tandem mass spectrometry (LCMS). Ratios of D-and L-2HG were used to evaluate differences in 2HG accumulation in tumors.

RESULTS

IDH mutations were correctly predicted using the 2HG spectroscopy with 93.3% sensitivity (17/18, 95% CI, 85.3–100%) and 100% specificity (18/18, 95% CI, 88.6–100%). The IDH mutation in the CSF-tDNA was successfully detected with 100% specificity (95% CI, 87.6–100%) and 73.3% sensitivity (95% CI, 65.6–88.3%). The range of the IDH mutation variant allele frequency (VAF) in the CSF-tDNA was 1.53- 47.9%. 2HG detection in the CSF revealed higher sensitivity (100%) and specificity (100%) in a small subset of patients (n = 7). The D-2HG/L-2HG ratios in IDH-mutant cases varied between 1.2 – 13.8, compared with 0.1 – 0.5 in IDH wild-type gliomas.

CONCLUSION

Our findings suggest that 2HG spectroscopy and 2HG detection in the CSF are two reliable methods in IDH mutation prediction in gliomas. On the other hand, the sensitivity of genomic IDH mutation detection in the CSF-tDNA was lower when compared with 2HG detection. Further studies are needed to complement the findings of our exploratory analysis.
INNV-07. THE KOREAN SOCIETY FOR NEURO-ONCOLOGY (KSNO) GUIDELINE FOR GLIOMAS: VERSION 2019.01
Authors: Zoon Kim Young , Kim Chae-Yong , Hoon Lim Do , Chung Dong-Sup
Published: November 2019

BACKGROUND

There was no practical guideline for the management of patients with central nervous system (CNS) tumor in Korea for many years. Thus, the Korean Society for Neuro-Oncology (KSNO), a multidisciplinary academic society, started to prepare a guideline for CNS tumors from February 2018.

METHODS

The Working Group was composed of 35 multidisciplinary medical experts in Korea. References were identified through searches of PubMed, MEDLINE, EMBASE, and Cochrane CENTRAL using specific and sensitive keywords as well as combinations of keywords.

RESULTS

First, for the glioblastoma as WHO Grade IV Gliomas, the maximal safe resection if feasible is recommended. Patients aged ≤ 70 years with good performance should be treated by concurrent chemoradiotherapy with temozolomide followed by adjuvant temozolomide chemotherapy (Stupp’s protocol) or standard brain radiotherapy alone. However, those with poor performance should be treated by hypofractionated brain radiotherapy (preferred) ± concurrent or adjuvant temozolomide or temozolomide alone (Level III) or supportive treatment. Second, for the WHO Grade III Gliomas, patients with anaplastic astrocytoma, IDH-mutant should be treated by standard brain radiotherapy followed by adjuvant temozolomide chemotherapy, or Stupp’s protocol, or standard brain radiotherapy with neoadjuvant or adjuvant PCV chemotherapy, or Standard brain radiotherapy alone (Level III). However, those anaplastic astrocytoma, IDH-wildtype should be treated by the protocol for glioblastoma. Third, for the WHO Grade II Gliomas, patients with diffuse astrocytoma, IDH-wildtype without molecular feature of glioblastoma should be treated by standard brain radiotherapy and adjuvant temozolomide chemotherapy (Level III), or standard brain radiotherapy alone, or observation. And patients with diffuse astrocytoma IDH-mutant and oligodendroglioma (IDH-mutant and 1p/19q codeletion) should be treated according to the risk factors.

CONCLUSION

The recent KSNO’s guideline recommends that glioma should be treated according to the molecular as well as histological features. However, the practice can be limited by the National Insurance for Health in Korea.
INNV-18. THE AVAILABILITY AND ROLE OF CLINICAL PHARMACISTS IN THE AMBULATORY NEURO-ONCOLOGY SETTING: AN INTERNATIONAL SURVEY
Authors: Patel Mallika , Lipp Eric , Miller Patrick Healy Elizabeth , Herndon James , Peters Katherine
Published: November 2019

BACKGROUND

Outpatient clinics treating neuro-oncology patients are becoming more multidisciplinary. Utilization of all team members is critical for the holistic care of these complex patients. Specifically, the role of a clinical pharmacist in the ambulatory multidisciplinary clinic remains undefined and will likely evolve as more therapeutic options are developed to treat central nervous system malignancies. We queried the Society for Neuro-Oncology (SNO) membership about the availability of a clinical pharmacist in their ambulatory setting and, if present, the role of that clinical pharmacist.

METHODS

In an IRB exempt study, we surveyed the SNO community (targeting primarily clinicians) and analyzed responses to queries about clinical pharmacists in the ambulatory neuro-oncology setting.

RESULTS

Of the 65 SNO members who responded, 52 of these were clinical members. Of these 52 clinical members, the majority were physicians (88.5%, n=46). Of these 46 physicians, most were in academic practices (93.5%, n=43). Over half of the 52 clinical respondents (51.9%, n=27) reported that they saw ≥ 30 primary brain tumor patients a month, thus typifying busy clinical neuro-oncology ambulatory clinics. Despite having busy clinics, only 12 (28.6%) of the 42 providers with access to a clinical pharmacist reported that their clinical pharmacist was solely dedicated to neuro-oncology patients. For the respondents who had access to a clinical pharmacist, only 28 (66.7%) of those pharmacists had direct patient interaction in the clinic. The top three roles of the clinical pharmacist included medication review (81%, n=34), chemotherapy dosing and modifications (73.8%, n=31), and practice guideline development (61.9%, n=26), none of which are associated with direct patient interaction.

CONCLUSIONS

We found that while our surveyed population of SNO clinical members have demanding outpatient neuro-oncology practices, most do not have the support or expertise of dedicated neuro-oncology clinical pharmacists.
INNV-28. MOLECULAR TESTING IN NEURO-ONCOLOGY – ASSESSMENT OF UTILITY AND PRACTICE PATTERNS. A SOCIETY FOR NEURO-ONCOLOGY MEMBERSHIP SURVEY
Authors: Mrugala Maciej , Chang Susan
Published: November 2019

BACKGROUND

Molecular testing (MT) is utilized in neuro-oncology with increasing frequency. Multiple molecular panels are available providing a spectrum of information. We were interested in learning how this information is acquired, what are the practice patterns regarding this type of testing, how are the results utilized in patient care and how prepared neuro-oncologists are to interpret these results.

METHODS

We conducted a survey using the Society for Neuro-Oncology membership database. We developed a set of 13 questions and administered the survey to 2022 members using the online platform.

RESULTS

We received 153 responses (7.5% of membership). 89% percent of responders routinely order MT. Of those who do not order MT on all patients, 50% test younger patients and 57% midline tumors. 83% use MT in recurrent glioma. Other common indications for MT included: metastatic tumors, meningioma, medulloblastoma, ATRT. Majority (60%) use in-house panels, followed by Foundation One (35%), TEMPUS (13%), CARIS (10%) and other panels (23%). For 57% of respondents, the data from MT was somewhat useful and for 41% it was very useful. 78% used the results of MT for clinical decision-making. BRAF, EGFR/ALK, H3K27 mutations were most commonly used for treatment decisions. 50% of respondents have molecular tumor boards at their institutions and a majority of practitioners share the results of MT with their patients (95%). Respondents would like to see SNO-endorsed official guidelines on MT, organized lists of targeted agents available for specific mutations, a database of targetable mutations and clinical trials and more educational programs on the subject.

CONCLUSIONS

Molecular testing is neuro-oncology is commonly done. Many providers rely on the information for clinical decision making where appropriate. In-house and commercial genetic panels are equally used in practice. There continues to be a need for more education on the subject and development of neuro-oncology specific guidelines.
INNV-30. RESPONSE WITH COMBINED DABRAFENIB AND TRAMETINIB AFTER BRAF INHIBITOR FAILURE IN BRAF-MUTATED GLIOBLASTOMA: A CASE REPORT
Authors: Kushnirsky Marina , De la Fuente Macarena I , Feun Lynn
Published: November 2019

Glioblastoma (GBM) carries a poor prognosis despite aggressive multimodality therapy. Oncogenic BRAF mutations are present in < 2% of GBM, along with other glioma types (ganglioglioma, pleomorphic xanthoastrocytoma). Although oral inhibitors of the oncogenic BRAFv600 kinase have demonstrated some efficacy in GBM, several mechanisms mediating resistance to BRAF inhibitors through MAPK reactivation have been described. BRAF inhibitor monotherapy is also associated with an increased risk for hyperproliferative skin lesions. We present a case of a 44-year-old man who initially presented with headaches and seizures and was diagnosed with a left temporal, MGMT unmethylated, BRAF V600E mutant GBM. He underwent gross total resection followed by radiation therapy with concurrent temozolomide, followed by 9 cycles of adjuvant temozolomide. He presented with progression of disease (POD) and subsequently failed treatment with carboplatin after two cycles (first recurrence). He had a repeat resection, and was enrolled in a clinical trial of autologous dendritic cell vaccine and presented with POD after 10 months on this treatment (second recurrence). He was started on another clinical trial of BRAF inhibitor, achieving partial response but developed POD after 7 months on this therapy (third recurrence). He was started on BRAF inhibitor dabrafenib and MEK inhibitor trametinib (D+T), achieving complete response. At the time of this report, 8 months after initiating treatment, the patient remains clinically stable with MRI showing CR. To our knowledge, this is the first report of clinical and radiographic response to combined D+T after BRAF inhibitor failure in BRAF-mutated glioblastoma. Several ongoing trials (NCT01677741, NCT01748149, NCT02124772, NCT02684058, NCT02285439), will elucidate the precise role of these drugs as single agent and in combination in pediatric and adult brain tumors.
INNV-31. ACCELERATING NEURO-ONCOLOGY RESEARCH AND IMPROVING PATIENT CARE THROUGH A ROBUST DATA FOUNDATION
Authors: Alfaro-Munoz Kristin , Hallatt Gemma , ravi Vinod , Futreal Andrew , Sookprasong Jamie , Yu Emily , Lari Bryan , Jin Jeff , DeGroot John
Published: November 2019

BACKGROUND

MD Anderson (MDA) strives to maximize learning from the > 44,000 patients seen annually. This has historically been challenging due to the diverse, often unstructured, and siloed nature of patient data. In 2018, MDA partnered with Palantir Technologies to integrate disparate clinical and research data sources into a single cloud-based platform enabling both technical and non-technical users to directly access and analyze data.

METHODS

IT experts, Palantir engineers and end users collaborated to integrate 150 deidentified datasets from the existing data warehouse, Natural Language Processing pipelines, molecular reports, public data and manually curated data, representing data from > 1.5 million patients. Data integration was tested by answering 12 retrospective queries, of which 5 were specific to neuro-oncology cohorts.

RESULTS

All 12 queries were resolved and within the neuro-oncology department we found the cohort identification process to be accelerated with users able to create reports backed by live data, with clear visibility into inputs, analysis and history. In addition, templates were created of common statistical workflows, empowering non-technical users to perform analyses (e.g. KM curve; Volcano plot). Secure access controls enabled increased collaboration between neuro-oncology and other departments.

CONCLUSIONS

This work highlights the value of a data foundation and unlocks the potential for new studies, fueling scientific discovery within neuro-oncology and across the institution. To extend the impact we are piloting a combination of (1) Purposeful structured data capture at the time of care, (2) Use of logic to suggest commonly uncaptured but critical patient events such as progression, and (3) Auditing functionality to allow users to manually fill in gaps and correct data in a transparent manner. Upon completion, we anticipate the ability to increase our research throughput and scope.
INNV-43. IMPROVING POST OPERATIVE FOLLOW-UP AND TIME TO ADJUVANT TREATMENT FOR HIGH GRADE GLIOMA
Authors: Catalino Michael , Zeitouni Daniel , Henretty Sonja , Zhu Anqi , Khagi Simon
Published: November 2019

BACKGROUND

High grade glioma patients are prone to lapses in treatment due to the complexities related to coordination of care, the timing of adjuvant treatment, and insurance barriers. The purpose of this study was to determine the impact of an institutional multidisciplinary protocol on transitions of care after surgery for high grade gliomas between 2015 and 2018.

METHODS

A retrospective cohort study was conducted using CPT codes for enrolled glioma patients between 2015–2018 with unplanned surgery. Historical controls were compared to the intervention group which began enrollment in November 2016. We used time-to-event analysis to compare time to neuro-oncology follow up and time to adjuvant treatment (radiation and/or chemotherapy). The effect of discharge disposition and insurance status was also assessed. The study incorporated an ad hoc analysis of survival outcomes.

RESULTS

The intervention and control groups had similar baseline characteristics. The intervention was associated with more patients following up with neuro-oncology within 2 weeks (51.1% in intervention group compared to 30.0% in control group), more patients starting radiation within 30 days (43.6% and 25.0%, respectively) and more patients starting chemotherapy within 30 days (59.0% and 35.0%, respectively). Time-to-event analysis revealed that the intervention trended toward earlier initiation of chemotherapy (p=0.076). Only 16.7% of patients discharge to a skilled nursing facility were able to initiate chemotherapy at the 30-day mark. Time-to-event analysis revealed that insurance status was significantly associated with initiating chemotherapy at the 30-day mark (p=0.023). Survival analysis is planned and will be reported in a future manuscript.

CONCLUSION

A multidisciplinary approach to capturing patients after surgery decreases time to follow up with neuro-oncology and initiation of adjuvant treatment. Timely follow up is associated with insurance status, discharge disposition, and multidisciplinary discussions between the treatment team and ancillary staff. Survival outcomes are being assessed and will be reported.
MNGI-02. FEATURES OF TUMOR TEXTURE INFLUENCE SURGERY AND OUTCOME IN INTRACRANIAL MENINGIOMA
Authors: Sauvigny Thomas , Ricklefs Franz , Hoffmann Lena , Schwarz Raphael , Burkhardt Till , Westphal Manfred , Ole Schmidt Nils
Published: November 2019

OBJECTIVE

Texture-related factors such as consistency, vascularity and adherence vary considerably in meningioma and are thought to be linked with surgical resectability and morbidity. However, data analyzing the true impact of meningioma texture on the surgical management is sparse.

METHODS

Patients with intracranial meningioma treated between 08/2014-04/2018 were prospectively collected for demographics and surgical treatment with related morbidity and extend of resection (EOR). Tumor characteristics were reported by the surgeon using a standardized questionnaire including items such as tumor rigidity, homogeneity, vascularization and adherence to surrounding neurovascular structure and analyzed for their impact on EOR and neurological outcome using multivariate regression analyses.

RESULTS

296 patients (214 female (72.3%) with intracranial meningiomas were included with a mean age of 60.4 years. 23% of patients had a transient and 6.1% permanent neurological deficits and three patients (1.1%) died. The occurrence of a neurological deficit was associated with duration of surgery (p = 0.013) and tumor adherence to neurovascular structures (p = 0.014). Similar associations were observed in subgroup analyses of different tumor localizations (e.g. convexity and skull base). With regard to EOR, the tumor adherence (p < 0.001) and recurrent surgery (p = 0.001) were found as independent predictors for subtotal resection. Noteworthy, the tumor rigidity had no significant impact on the morbidity or EOR.

CONCLUSION

Our analysis supports the notion that tumor texture has an impact on the surgical management of meningioma and provides sound data that tumor adherence is a significant factor influencing neurological outcome and EOR. In contrast, the influence of tumor rigidity has less impact than previously thought. Preoperative prediction of tumor texture is therefore required for optimized risk assessment.
MNGI-13. DYNAMIC IMAGING OF MENINGIOMA WITH 3’-DEOXY-3’-[18F]-FLUOROTHYMIDINE USING POSITRON EMISSION TOMOGRAPHY: A POSSIBLE PREDICTOR OF TUMOR GROWTH
Authors: Bashir Asma , Bitsch Vestergaard Mark , Marner Lisbeth , Larsen Vibeke A , Ziebell Morten , Fugleholm Kåre , Law Ian
Published: November 2019

BACKGROUND

Positron emission tomography (PET) with 3’-deoxy-3’-[18F]-fluorothymidine (18F-FLT) provides a non-invasive assessment of in vivo tumor proliferation that could be useful for predicting growth potential in meningiomas. We aimed to study static and dynamic 18F-FLT PET metrics prospectively to assess metabolic activity of meningioma, and their associations to potential tumor growth on subsequent MRI scans.

METHODS

Between April 2017 and December 2018, 44 patients harboring MRI-suspected (n = 37) and histologically-verified residual meningiomas (n = 7) underwent a 60-minute dynamic 18F-FLT PET prior to imaging surveillance. Maximum and mean standardized uptake values (SUVmax, SUVmean) with/without normalisation to blood radioactivity obtained from a 40-60-minute static PET image and a 60-minute venous blood sampling were calculated. Total volume of distribution (VT) was estimated by kinetic modeling using a two-tissue reversible compartmental model with a fractional blood volume and metabolite-corrected image-derived input function. Tumor growth rate was calculated by volumetric analysis of subsequent MRI scans.

RESULTS

At the time of this writing, a total of 53 follow-up MRI scans from 33 patients were available for review, with a median follow-up time of 11 months (range, 4–22.5 months). Tumor growth/progression was observed in 12 cases with a monthly median growth rate of 0.10 cm3 (range, 0.03–3.41 cm3). All 18F-FLT metrics were significantly higher in patients with radiological progression compared to patients with stable findings with maximum tumor-to-blood-ratio (TBRmax) as the most promising imaging biomarker (4.9 ± 1.4 vs. 3.4 ± 1.0, P = .003; Mann-Whitney) and the strongest predictor for tumor progression (hazard ratio, 3.125; 95% confidence interval, 1.390–7.028; P = .006; univariate binary logistic regression). Age, gender, previous residual remnant(s) and initial tumor volume (median, 3.1 cm3; range, 0.2–55.3 cm3) had no influence.

CONCLUSION

18F-FLT PET imaging could be a valuable tool in designing a patient-tailored surveillance strategy for patients with asymptomatic meningiomas.
MNGI-14. PROGNOSTIC FEATURES OF MALIGNANT MENINGIOMA: EVALUATION OF AGGRESSIVE MENINGIOMAS WITHIN A LARGE RURAL HOSPITAL SYSTEM DATABASE AND FIRST REPORT OF A METASTATIC CHORDOID MENINGIOMA TO THE LUNG
Authors: Tosha Gatson Na , Manikowski Jesse , Bross Shane , Hinger Bradley , Mauer Tian , Garcia Tiffany , Lacroix Michel , Mahadevan Anand , Mongelluzzo Gino , Vadakara Joseph , Jaffar Kazmi Syed A
Published: November 2019

Meningiomas comprise 37% of primary brain tumors, arise extra-axially from the arachnoid cap cells, and are typically identified by classic imaging and histopathologic features. Blacks, females, and people age 65+ have higher incidence rate - partially correlated with hormonal states, high body mass index, and known genetic predispositions. Prognostication is otherwise based on histopathologic findings and 90% of meningiomas are classified as benign (WHO grade I). Despite use of these prognostic tools, clinicians often observe a more divergent post-operative clinical course. While several pre-clinical studies have identified putative oncogenic influencers, many have failed to show correlation in human trials. Here, we evaluate a single institutional meningioma database stratified by geodemographic and clinical data to identify novel integrated prognostic indicators for aggressive tumor natural history. Our database contains 3,528 image-confirmed meningiomas between 1992–2019. This report focused on 415 pathology-confirmed cases between 2006–2019: WHO grades I, II, III were 73% (n=303), 25% (n=103), and 2% (n=9) respectively, 71% female predominance (n=294), median age at diagnosis 57-years-old, and 97.5% were white race. Thus far, full exome sequencing has been completed on >50% of cases and >80% have available tumor tissue for future testing as part of this rural Pennsylvania database with high incident aggressive and/or multiply recurrent meningiomas. We selected four representative cases to compare post-operative prognostication to observed clinical outcomes and provide molecular/genetic, histopathologic, treatment modality, comorbid, and other clinical features associated with morbidity/mortality. Included in this patient review is the first reported case of a rare (< 1%) chordoid meningioma, multiply recurrent despite 8-years of aggressive treatment modalities, including surgery, radiation, chemotherapy and androgen-blockade, with eventual extracranial metastasis to the lung, a meningiocarcinoma, if you will. Thorough interrogation of the completed database could yield novel predictive indicators of clinically aggressive meningiomas and guide clinical decision-making for optimized surveillance in high-risk patients.
PATH-04. INFLUENCE OF INDIVIDUAL CpG METHYLATION STATUS OF THE MGMT PROMOTOR ON OUTCOME IN ADULT PATIENTS WITH GLIOBLASTOMA MULTIFORME RECEIVING ALKYLATING AGENT TREATMENT
Authors: Siller Sebastian , Lauseker Michael , Giese Armin , Tonn Joerg-Christian , Niyazi Karim-Maximilian , Thon Niklas , Suchorska Bogdana , Kreth Friedrich-Wilhelm
Published: November 2019

BACKGROUND

Methylation of O-6-methylguanine-DNA-methyltransferase (MGMT) promotor causes gene silencing and has been associated with a favourable prognosis in patients with glioblastoma multiforme (GBM) receiving alkylating chemotherapy. However, analysis of MGMT promotor methylation is usually reported as a cut-off depending on the results of the correspondent CpG-site testing. This approach disregards a possible heterogeneity concerning the methylation status within the individual CpG-sites and its possible association with prognosis in GBM patients. The current study aimed at elucidating the association between methylation of CpG-sites 74–98 within the MGMT promotor region and outcome in GBM patients receiving alkylating agents.

METHODS

Individual methylation status of 230 patients with histologically proven GBM following concomitant radio-chemotherapy with TMZ after stereotactic biopsy or open tumor resection was assessed by the Sanger-sequencing approach. Methylation of CpG-sites 74–98 within the MGMT promotor region was defined according to a ratio of cytosine/thymine peak > 50%. The total number of methylated CpG-sites was correlated with outcome using proportional hazards models. In a subset of 34 patients, a correlation between individual CpG-site methylation and MGMT mRNA-expression was performed.

RESULTS

Median progression-free (PFS) and overall survival (OS) were 7.8 and 14.6months, respectively. The cumulative total number of methylated loci within the CpG-sites 74–98 was strongly associated with both PFS and OS and retained its prognostic influence on outcome in multivariate models (p< 0.001). Furthermore, a linear coherence between the total number of methylated CpG-sites 74–98 and survival parameters could be observed. Moreover, low number of methylated CpG-sites was observed in tumor specimen with a high mRNA-expression and vice versa (Spearman-correlation-coefficient: -0.62).

CONCLUSION

Our data suggest a strong linear coherence between outcome and the total number of methylated CpG-sites 74–98, thus an up-front analysis of the individual GpC-site methylation status prior to initiation of alkylating chemotherapy might help improving treatment response in GBM patients.
PATH-05. RAPID SIMULTANEOUS IDH MUTATION AND MGMT METHYLATION STATUS ASSESSMENT IN GLIOMA PATIENTS USING CRISPR-Cas9-TARGETED NANOPORE SEQUENCING
Authors: Wongsurawat Thidathip , Jejaroenpun Piroon , DeLoose Annick , Ussery David , Alkam Duah , Day J D , Nookaew Intawat , Rodriguez Analiz
Published: November 2019

Molecular classification of diffuse glioma enables more-precise diagnosis, prognosis, and treatment decisions. Currently, combination of two molecular markers, isocitrate dehydrogenase 1 and 2 (IDH1/ IDH2) gene mutation information and O6-Methylguanine-DNA-methyltranferase (MGMT) methylation status, are the main prognostic biomarkers of newly diagnosed diffuse gliomas. Furthermore, an accurate interpretation of MGMT-promoter methylation status is essential to determining which patients benefit from temozolomide (TMZ) therapy. The presence of an IDH mutation can be easily tested by PCR or next generation sequencing. However, there remains controversy with the identification of MGMT-promoter methylation status since there exists variable degrees of methylation and no clear consensus on cutoff values for “methylated” or “unmethylated” have been defined. To be best suited for routine clinical setting and research use, the optimal test should be reproducible, readily available, and timely. Therefore, we explored the feasibility of single-molecule nanopore third generation sequencing technology to comprehensively assess both mutation and methylation status simultaneously. This technology allows methylation detection directly from the native DNA sequence without requiring bisulfite treatment which reduces processing time. To specifically study IDH1, IDH2, and MGMT-promoter loci, we combined the CRISPR-Cas9 system to cut desired DNA fragments in a non–amplification dependent fashion. In addition, a data analysis pipeline was developed to quantitatively detect methylation. We applied our approach on human DNA controls, glioma cell lines and 4 patient brain tumor samples and were enabled to assess mutation and methylation status of targeted loci within 1.5 days. The promise of CRISPR-Cas9-targeted nanopore sequencing in accelerating and improving the molecular diagnostics of diffuse glioma will be illustrated in this meeting. These efforts are in line with improving precision medicine and can be applied to all cancer types.
PATH-09. MGMT PROMOTER METHYLATION IS A STRONG PROGNOSTIC FACTOR FOR SURVIVAL AFTER PROGRESSION IN HIGH GRADE GLIOMAS
Authors: Liu Yanwei , Li Yanong , Qiu Xiaoguang
Published: November 2019

High grade gliomas (HGGs: anaplastic gliomas and GBM) are the most lethal type of primary brain tumor. Maximal resection and postoperative concurrent chemoradiotherapy, and followed with adjuvant chemotherapy is the standard treatment. But patients with HGGs have a relapse rapidly and short survival. Studies have identified many clinical characteristics and biomarkers were associated with progression free survival (PFS) and over survival (OS). However, there has not yet a comprehensive study on the effects of these factors to survival after the first progression (SAP). 319 patients with HGGs were conducted maximum resection followed by radiotherapy and/or temozolomide chemotherapy and have been confirmed the first progression. Clinical characteristics, biomarkers (IDH1/2 mutation, MGMT promoter methylation, LOH1p/19q, TP53 mutation, EGFR amplification, Ki-67 expression) and clinical interventions (extent of resection, chemoradiotherapy, operation after progression) were analyzed in accordance with SAP. The 1-year SAP was 14.2% (median SAP: 5.1 months). Significant prognostic factors of improved SAP were tumor grade, MGMT promoter methylation and Ki-67 expression in univariate analysis (p< 0.05). Further multivariate analysis showed that MGMT promoter methylation and Ki-67 expression were independently prognostic markers for SAP (p< 0.05). In our data, HGGs could be divided into low, intermediate and high risk groups for SAP by MGMT promoter methylation and Ki-67 expression. However, analysis of 308 patients with GBM from The Cancer Genome Atlas (TCGA) found that MGMT promoter methylation is the only prognostic marker for SAP in multivariate analysis (p< 0.05). Consequently, MGMT promoter methylation is independently prognostic marker for SAP in patients with HGGs. MGMT promoter methylation, combined with Ki-67 expression, might establish a risk model for SAP and this stratification may aid in treatment strategy selection and clinical prognosis evaluation in HGGs.
PATH-10. RELATIONSHIP BETWEEN CYTOGENETIC COMPLEXITY AND PERITUMORAL EDEMA IN HIGH-GRADE ASTROCYTOMA
Authors: Su Sung Kyoung , Song Young-Jin , Han Jin-Yeong , Kim Ki-Uk
Published: November 2019

The purpose of the study is to reveal the association of cytogenetic complexity and peritumoral edema volume (PTEV) and its prognostic significance in high-grade astrocytoma patients by culturing patient tumor cells. Twenty-seven high-grade astrocytoma patients were divided into three groups according to karyotype complexity: normal, non-complex karyotype (NCK), and complex karyotype (CK). Endothelial growth factor receptor (EGFR) amplification was detected by FISH, and its association with chromosome 7 abnormalities was analyzed. Mean PTEV of each group was compared by ANOVA to evaluate the relationship between PTEV and cytogenetic complexity. The PTEV of patients in normal (n=6), NCK (n=8), and CK (n=13) groups were 24.52±17.73, 34.26±35.04, and 86.31±48.7 cm3, respectively (P=0.005). Ten out of 11 patients with EGFR amplification showed abnormalities in chromosome 7. The mean PTEV of EGFR-amplified and non-amplified groups were 80.4±53.7 and 41.3±37.9 cm3, respectively (P=0.035). The average survival of patients with PTEV less than 90 cm3 was 30.52±26.11 months, while in patients with PTEVs over or equal to 90 cm3, it was 10.83±5.53 months (P=0.007). The results show an association of complex karyotype with the PTEV of high-grade astrocytoma. EGFR amplification plays a significant role in the formation of peritumoral edema, causing PTEV to increase, which is related with survival. This implies that cytogenetic karyotype can be applied as a prognostic factor.
PATH-16. HISTOPATHOLOGICAL EPENDYMOMA VARIANTS ARE ASSOCIATED WITH DISTINCT CLINICAL PARAMETERS AND DNA METHYLATION PATTERNS
Authors: Neumann Julia E , Spohn Michael , Obrecht Denise , Mynarek Martin , Thomas Christian , Hasselblatt Martin , Dorostkar Mario M , Wefers Annika K , Frank Stephan , Monoranu Camelia-Maria , Koch Arend , Witt Hendrik , Kool Marcel , Rutkowski Stefan , Glatzel Markus , Schüller Ulrich
Published: November 2019

According to the current WHO classification, ependymal tumors are classified as subependymomas, myxopapillary ependymomas, classic ependymomas, anaplastic ependymomas and RELA-fusion positive ependymoma (RELA-EPN). Among classic ependymomas, the WHO defines rare histological variants, i.e. the clear-cell, papillary, and tanycytic ependymoma. In parallel to this WHO classification scheme, DNA methylation patterns can distinguish nine distinct molecular ependymoma subgroups, some of which tightly overlap with certain histopathological subgroups, e.g. subependyomas or myxopapillary ependymomas. Since very little is known about the molecular background of histological classic ependymoma variants, we analyzed histomorphology, clinical parameters and global DNA methylation patterns of diagnosed tanycytic ependymomas (n=12), clear-cell ependymomas (n=14) and papillary ependymomas (n=19). Surprisingly, up to 42% of these variants did not match to ependymomas using a previously published DNA methylation-based classifier for brain tumors. Among the tumors with a match to one of the nine known ependymoma methylation classes, tanycytic ependymomas were predominantly located in the spine, but showed diverse molecular methylation patterns. Most clear-cell ependymomas showed a common histomorphology, were found supratentorially and fell into the methylation class of RELA-EPN. Papillary ependymomas showed a “papillary”, “trabecular” or “pseudo-papillary” growth pattern. Interestingly, a true papillary growth pattern was strongly associated with the molecular class B of posterior fossa ependymoma (PFB), but tumors displayed DNA methylation sites that were significantly different when compared to PFB ependymomas without papillary growth. Our results show that the diagnosis of classic histological ependymoma variants can be challenging. While clear-cell and papillary ependymomas harbor common molecular features, tanycytic ependymoma may not represent a molecularly distinct subgroup.
PATH-17. HYPERPROGRESSIVE DISEASE IN PATIENTS WITH RECURRENT HIGH GRADE GLIOMAS TREATED WITH IMMUNE CHECKPOINT INHIBITORS OR CYTOTOXIC THERAPIES
Authors: Donovan Laura , Gedailovich Samuel , Joanta-Gomez Adela , Lassman Andrew , Iwamoto Fabio
Published: November 2019

BACKGROUND

Hyperprogressive disease (HPD), defined as a ≥ 2-fold increase in tumor growth rate (TGR) compared to baseline following initiation of immune checkpoint inhibitors (ICI), has been described in solid tumors but is not well explored high grade gliomas (HGG). We investigated the rate of HPD in HGG patients receiving ICIs for first or second recurrence compared to those treated with non-immunotherapy agents.

METHODS

Patients with HGG receiving ICIs for 1st or 2nd recurrence compared to a controls receiving other therapies at first progression. Prior or concurrent bevacizumab or anti-VEGFR were exclusionary due to pseudoresponse and decreased enhancement with these drugs. HPD was calculated by comparing TGR immediately before and after treatment.

RESULTS

49 patients met inclusion criteria (27 ICI, 25 control). 25/27 patients receiving ICIs and 20/22 patients in the control group were evaluable in the analysis. The ICI group included 60% men (15/25) and 80% (20/25) had a diagnosis of primary GBM. 68% were treated at first progression (17/25). Controls were 80% male (16/20) and all had a diagnosis of primary GBM. 28% (7/25) of patients met criteria for HPD in the ICI group compared to 4/20 controls (20%). Median OS in patients with primary GBM was 26mo in the ICI group vs. 15.9mo in controls. Median survival past progression in patients with primary GBM receiving ICI for 1st recurrence (13/25) was 12mo vs. 10.6mo in controls. 40% of patients in both groups had next generation sequencing (5/7 with HPD in ICI and 2/4 in control). EGFR alterations and MDM2/4 amplifications were not associated with HPD whereas PTEN mutations were more common in HPD (71% vs. 33.3%).

CONCLUSION

HPD is observed in patients with HGG treated with ICI at comparable rates to those with other cancers, but was also observed in 20% of patients receiving other therapies.
PATH-21. CLINICAL UTILITY OF DNA METHYLATION PROFILING FOR DIAGNOSIS OF CHALLENGING CENTRAL NERVOUS SYSTEM TUMORS: THE TORONTO EXPERIENCE
Authors: Karimi Shirin , Zuccato Jeffrey , Mamatjan Yasin , Mansouri Sheila , Suppiah Suganth , Nassiri Farshad , Diamandis Phedias , Munoz David , Aldape Kenneth , Zadeh Gelareh
Published: November 2019

The update on the WHO classification of central nervous system (CNS) tumors incorporated molecular signatures for a more accurate diagnosis. Recently, DKFZ has demonstrated the utility of DNA methylation profiling(MP) for molecular classification of CNS tumors. We performed a prospective clinical study over the last three years to evaluate the clinical utility ofDNA MP on FFPE samples of 66 challenging CNS tumor cases using online DKFZ classifier. Eleven samples were excluded due to low tumor DNA content or low calibration(predictive) scores(CS)< 0.3.DNA MP confirmed the original pathology diagnoses in 15(27%)cases. The integrated molecular diagnoses were changed in 38/55(70%) including establishment of a new diagnostic entity, change in molecular signature and subtyping. TheWHO grades were changed in 16(27%) of the tumors; about two-thirds resulted in upgrading. We detected non-canonical IDH mutations in 9 diffuse gliomas and the CNV plots revealed false positive FISH results for 1p/19q co-deletion in two diffuse gliomas. The CNV plots contributed to the final diagnosis in 40(72%) patients. The molecular subtypes of medulloblastoma, ependymoma and glioblastoma subclasses were determined in 36(65%) cases. Seventy-five percent of cases with confirmation of initial diagnosis or change in molecular diagnosis had CS > 0.5, among which 51% had a CS >0.9. The median and range CS of cases with new diagnostic entity and confirmed cases were 0.86(0.37–0.99) and 0.98(0.42–0.99), respectably. Furthermore, we detected higher CS in IDH-mutant gliomas in comparison to glioblastoma IDH-wild type(P=0.04). We also observed lower CS in mesenchymal glioblastoma in comparison to other subclasses. The MGMT promoter methylation was determined in 17/20(85%) glioblastoma cases. While the DKFZ group established CS of 0.9 as a cut-off for matching to methylation classes, our findings suggest lower threshold values in challenging CNS tumor cases. Our experience indicates clinical utility of MP of challenging CNS tumors as a reliable ancillary diagnostic tool in routine neuropathology practice.
PATH-39. DNA MISMATCH REPAIR ENZYME IMMUNOHISTOCHEMISTRY IS A RAPID, EFFECTIVE SCREENING TEST FOR HYPERMUTATED GLIOMAS
Authors: McCord Matthew , Steffens Alicia , Kam Kwok-Ling , Javier Rodrigo , McCortney Kathleen , Horbinski Craig
Published: November 2019

BACKGROUND

While gliomas with hypermutated DNA are resistant to alkylating agents like temozolomide, they may be especially responsive to immunotherapy, since they express abundant neoantigens on their cell surfaces. Screening for hypermutated gliomas is currently being done through next-generation sequencing (NGS) panels that cover large portions of tumor DNA, although this is costly and access to such testing is not universal. Since hypermutated gliomas typically contain inactivating mutations in one of the main DNA mismatch repair (MMR) proteins, and cancers with an MMR mutation usually show loss of normal MMR protein, we sought to determine the feasibility of rapidly screening for hypermutated gliomas with an MMR immunohistochemistry (IHC) panel that is already in widespread use for colorectal adenocarcinomas.

METHODS

Tumor mutation burden (TMB) was determined via NGS for 101 gliomas, including 64 GBMs, 24 grade II-III astrocytomas, 9 grade II-III oligodendrogliomas, and 4 grade I gliomas. IHC for MSH2, MSH6, MLH1, and PMS2 was performed and analyzed on all gliomas while blinded to mutation profile and TMB.

RESULTS

Seven of 101 gliomas (7%) showed loss of an MMR protein by IHC. All 7 had matching MMR gene mutations and were hypermutated (100%), defined as TMB >20 per megabase of DNA. Of the remaining 94 with intact MMR IHC, only one was hypermutated. That case had an inactivating splice region mutation in another gene involved in DNA repair, ATM, although ATM is not part of the IHC panel originally developed for colorectal cancer. Overall sensitivity and specificity of the current MMR IHC panel for hypermutated gliomas was therefore 88% and 100%, respectively.

CONCLUSION

The colorectal MMR IHC panel, available in virtually all clinical IHC labs, is also a good screening test for hypermutated gliomas. Expansion of the panel to include even more DNA repair proteins, like ATM, would enhance its utility.