bluuebunny/crossref_metadata_2025_split huggingface dataset:
INNV-15. CLINICAL DATA THAT MATTERS: A DISTILLATION OF NEURO-ONCOLOGY CLINICAL TRIAL INCLUSION CRITERIA USING MACHINE LEARNING
Authors: Snyder James , Wells Michael , Poisson Laila , Kalkanis Steven , Noushmehr Houtan , Robin Adam 
Published: November 2019

Abstract

INTRODUCTION
Neuro-oncologic conditions have dismal outcomes, ineffective treatments, poor access to clinical trials, and variability in care. Clinical trials do not capture a patient’s complete journey and are restricted to select populations. ‘Real-world-evidence’ (RWE) attempts to inform point of care decisions through routine collection of data with a clinical-trial-like rigor. RWE complements existing knowledge through broad patient participation, collection throughout disease course, and creation of large multidimensional datasets “knowledge network of disease” 1,2. RWE implementation is hindered by unstructured data, uncertainty of relevant features, and semantic heterogeneity. Clinical attributes were selected from trial inclusion criteria and prioritized for structuring in clinic notes for abstraction.

METHOD
We queried Clinicaltrials.gov from 1/1/2018-12/31/2018, refined to North America, recruiting, interventional, and adult. Meningioma, pituitary, glioblastoma, astrocytoma, oligodendroglioma, and ependymoma were chosen based on incidence3. Lymphoma and nerve sheath tumors were omitted. “Brain tumor” and “glioma” were added. ‘K-nearest-neighbor’ tokenization parsed inclusion criteria4. Document term matrix (n-gram) converted text to vectors5. A generative probabilistic model using ‘Latent Dirichlet Allocation’ plotted words into 10 clusters6. Hierarchal clustering was used to compare histology with terms.

RESULTS
401 trials parsed into 3676 statements and 4008 keywords. 10 clusters of terms were similarly distributed amongst histologies, suggesting generalizability across tumor types. Cluster revealed 8 categories: 1) Time: enrollment; 2) Performance status: KPS; 3) Testing: mutations, upper limit of normal, routine hematologic laboratory assays; 4) Imaging: extent of surgery; 5) Pregnancy/childbearing; 6) Tumor grade; 7) Treatment history: recurrence, chemotherapy, radiation, time; 8) Informed consent

CONCLUSIONS
Dissecting the compendium of clinical trials using machine learning can identify general parameters for trial enrollment to guide RWE clinical collection. Using practical definitions of the most germane trial data, specific information can be sought after and defined to improve research quality, maximize research yields and improve patient care whilst minimizing wasted research and clinical endeavors.
INNV-16. COMPLETE RESPONSE OF THALAMIC IDH WILDTYPE GLIOBLASTOMA AFTER PROTON THERAPY FOLLOWED BY CHEMOTHERAPY TOGETHER WITH TUMOR TREATING FIELDS
Authors: Stein Marco , Dohmen Hildegard , Woelk Bernhard , Uhl Eberhard , Jensen Alexandra 
Published: November 2019

Abstract

BACKGROUND
Proton therapy is able to apply high radiation doses to the tumor while sparing healthy tissues by reducing integral dose. Tumor Treating Fields (TTFields) are low intensity (1–3 V/cm) and intermediate frequency (100–300 kHz) alternating electric fields that demonstrated significantly increased survival rates in combination with adjuvant temozolomide (TMZ) in patients with newly diagnosed glioblastoma (ndGBM). Here, we report on a patient with biopsied ndGBM IDH wildtype with complete radiological response.

MATERIAL AND METHODS
Brain MRI demonstrated an occlusive hydrocephalus and a ring enhancing lesion in the right posterior thalamus in a 42 year old male. After endoscopic ventriculostomy and stereotactic biopsy histopathological examination resulted in the diagnosis of a glioblastoma (WHO grade IV), IDH 1 wildtype (R132), IDH 2 wildtype (R172), HIST1H3B/C wildtype, TERT wildtype (C228 and C250), BRAF wildtype, and unmethylated MGMT promotor. The patient received definitive chemoradiation with TMZ to a total dose of 60Gy incl. proton boost of 5x2 GyRBE. TTFields therapy in combination with TMZ was initiated 4 weeks after completion of chemoradiation, TMZ maintenance was completed per protocol after 6 cycles. TTFields therapy was continued for more than 13 month and to-date the patient is still on therapy.

RESULTS
Current follow up time is 20 months after initial diagnosis with the patient showing a radiological complete response. In a MRI 9 months after proton therapy, partial response and perfusion restriction in the tumor area was observed. Another MRI 3 months later showed a complete response without perfusion signal in the tumor area.

CONCLUSION
Complete response was observed following combination treatment of chemoradiation with TMZ including proton boost, TMZ maintenance and TTFields in a patient with pathologically confirmed GBM IDH wildtype. To our knowledge, this is the first report on a ndGBM patient receiving proton therapy followed by TTFields therapy.
INNV-29. PHOTODYNAMIC THERAPY FOR MALIGNANT BRAIN TUMORS
Authors: Tanaka Kazuhiro , Sasayama Takashi , Nakai Tomoaki , Kohmura Eiji 
Published: November 2019

Abstract

INTRODUCTION
Photodynamic therapy (PDT) uses the toxicity of singlet oxygen generated by a reaction between a photosensitizer in tumor cells and light with a specific wavelength. Recently, PDT for primary malignant brain tumors was approved in Japan. We retrospectively analyzed the patients treated with PDT in our hospital.

METHODS
From August 2017 to February 2019, total 16 patients were performed PDT in our hospital. After the tumor had been resected as extensively as possible, the region of probable tumor invasion in the resection cavity were irradiated superficially with a 664-nm diode laser for 180 sec (27 J/cm2) at a power density of 150 mW/cm. The characteristics of patients, the number of irradiation, adverse events, changes of the MR image, and clinical outcome were analyzed.

RESULTS
In histological examination, glioblastoma (GBM) were eleven cases, anaplastic oligodendroglioma were two cases, and other three cases were anaplastic astrocytoma, malignant meningioma, and malignant lymphoma. The mean tumor volume was 46.1 ml. Gross total resection, Subtotal resection, and partial resection were performed in 11 patients, 3 patents, and 2 patients, respectively. The mean number of laser irradiated sites was 15 (5~31 sites). Radiologically, the irradiated region indicated high intensity in diffusion-weighted image, which gradually disappeared for 2 weeks without neurological deterioration. In adverse events, venous congestion and brain swelling were observed in one patient. Three GBM patients were dead with tumor recurrence during a mean follow-up period of 24.4 months.

CONCLUSION
PDT was safe and useful for malignant brain tumors. However, PDT-induced specific changes in the tumor tissue should be monitored carefully.
INNV-32. SUPER-INDUCTION OF IMMUNOSUPPRESSIVE GLIOBLASTOMA EXTRACELLULAR VESICLES BY IFN-γ
Authors: Jung Mi-Yeon , Himes Benjamin , Cumba-Garcia Luz , Parney Ian 
Published: November 2019

Abstract
Glioblastoma (GBM) is the most common and aggressive primary brain tumor. Median survival is 15 months despite surgery, radiation, and chemotherapy. Immunotherapy is promising but GBM-mediated immunosuppression remains a barrier. Recently, extracellular vesicles (EVs) have been implicated in GBM-mediated immunosuppression through expression of the immune checkpoint molecule PD-L1. Data from our group has suggested this is predominantly through induction of immunosuppressive monocytes including myeloid-derived suppressor cells (MDSCs) and non-classical monocytes (NCMs). PD-L1 expression is increased in most nucleated cells following IFN-γ exposure. We, therefore, sought to determine if IFN-γ exposure would result in super-induction of immunosuppressive GBM EVs. EVs were harvested in vitro from matched differentiated and stem-like human GBM cell lines +/- IFN-γ. IFN-γ exposure did not alter EV production or expression of common EV markers but increased PD-L1 expression in EVs from differentiated but not stem-like GBM cells. In keeping with our earlier findings, no direct inhibition of T cell proliferation by stem-like or differentiated GBM EVs was observed regardless of IFN-γ exposure or PD-L1 expression. In contrast, differentiated but not stem-like GBM cell EVs induced MDSC and NCM differentiation from normal monocytes. This was increased following IFN-γ exposure and was dependent upon PD-L1 expression. Monocytes exposed to differentiated but not stem-like GBM cell EVs inhibited T cell proliferation in a similar manner (increased with IFN-γ exposure, decreased with PD-L1 knockdown). Thus, IFN-γ exposure results in super-induction of immunosuppressive EVs from differentiated but not stem-like GBM cells that increase MDSC and NCM differentiation in normal monocytes and increase their ability to inhibit T cell proliferation. These effects are dependent upon PD-L1 up-regulation induced by IFN-γ. This may be an important mechanism GBMs utilize to suppress anti-tumor T cell responses that are typically accompanied by increased IFN-γ expression.
INNV-39. THE IMPACT OF MULTIDISCIPLINARY MANAGEMENT ON THE OVERALL SURVIVAL OF GLIOBLASTOMA AND ANAPLASTIC GLIOMA PATIENTS IN THE ERA OF PRECISION MEDICINE-A COMMUNITY PHYSICIAN’S EXPERIENCE AND DILEMMA
Authors: Ranjan Tulika , Yu Alexander , Wegner Rodney , Karlovits Stephen , Xu Linda , Hameed Muhammad 
Published: November 2019

Abstract
The newer modalities of GBM treatment on the horizon are targeted therapy utilizing precision medicine, immunotherapy, Laser interstitial thermal therapy (LITT), ChemoID, CAR-T cell therapy, etc. There is always dilemma about referring a patient to the clinical trials which restrict the patient to one therapeutic agent Vs using a multi-disciplinary approach to improve patient’s survival. We present a single- institution retrospective data of the multidisciplinary management of our high grade glioma patients and their outcome. A chart review is being performed on high grade glioma patients (GBM, Gliosarcoma, Anaplastic Astrocytomas and Anaplastic Oligodendrogliomas) who had genomic alterations identified by commercial next generation sequencing. Thus far 100 patients had molecular profiling done at our institution and precision medicine was implemented in >50 patients along with other treatments. Of 100 patients 82 were GBM and 18 were Anaplastic gliomas. There were 61 males and 39 females. MGMT methylation was seen in 36 patients and 12 patients had IDH1 mutation. The actionable mutations seen EGFR, EGFRvIII, TERT, PDGFR, CDKN2A-20, BRAF, PTEN, NF1- PD/PD-L1. The targeted therapy used were imatinib, sirolimus, afinotor, debrfenib, pembrolizumab, EGFR vIII vaccine. The chemotherapies utilized were BCNU,CCNU, CPT-11, Etoposide, carboplatin. Of 100 high grade glioma patients 8 patients underwent LITT, 24 patients received SRS, 58 patients received Avastin. All patients are being followed for overall survival (OS) and progression free survival (PFS-6) at this point. Of the 82 GBM patients 35 are still alive at a median 21 months. The median overall survival of the 47 dead GBM patients was 24 months. CONCLUSION: In high grade Glioma patients a multi-disciplinary approach may prolong the survival and the genomic analysis does impact the outcome of these patients. When we implement more than one therapy at the same time overall survival can’t be credited to one specific mode of therapy.
INNV-41. PROSPECTIVE SELECTION OF RECURRENT GLIOBLASTOMA PATIENTS FOR TAILORED THERAPIES. RESULTS OF AN INSTITUTIONAL EXPERIENCE
Authors: Giorgio D’Alessandris Quintino , Montano Nicola , Martini Maurizio , Cenci Tonia , Di Bonaventura Rina , Giordano Martina , Caccavella Valerio , Stumpo Vittorio , Cocomazzi Alessandra , Lauretti Liverana , Fernandez Eduardo , Olivi Alessandro , Larocca Luigi , Pallini Roberto 
Published: November 2019

Abstract

INTRODUCTION
Failure of clinical trials with targeted therapies in glioblastoma (GBM) is probably due to the enrollment of molecularly unselected patients. In preliminary studies, we prospectively selected recurrent GBM patients on the basis of molecular pattern and administered targeted therapy accordingly. This tailored approach gave encouraging results in term of low recurrence rate (RR) and high 6-month progression free survival (PFS-6). Here, we present the long-term results of our work.

METHODS
On recurrent tumor samples of 34 adult patients, we assessed the expression of VEGF and PTEN through immunohistochemistry and of EGFRvIII through RT-PCR. Patients with VEGF overexpression were treated with bevacizumab (10 mg/Kg i.v. every 2 weeks in 6-week cycles). Patients with EGFRvIII expression and normal PTEN expression added erlotinib (150 mg/day orally). Patients with loss of PTEN expression, irrespective of EGFRvIII status, added sirolimus (1–10 mg/day orally).

RESULTS
Sixteen patients received bevacizumab alone (bev), 14 bevacizumab plus erlotinib (bev+erl) and 4 bevacizumab plus sirolimus (bev+sir). RR was 50% in the whole cohort and 37.5%, 57.1% and 75% in bev, bev+erl and bev+sir groups, respectively. PFS-6 was 55.9% in the whole cohort and 50%, 64.3% and 50% in bev, bev+erl and bev+sir groups, respectively. Our data compare favorably with those from the large EORTC 26101 trial, which showed a RR of 41.5% and a PFS-6 lower than 30%. When considering sustained response (defined as PFS ≥ 12 months), we overall observed a 20.6% rate, with the highest value in bev+erl subgroup (28.6%). Interestingly, in EORTC 26101 trial, less than 10% of patients achieved PFS ≥ 12 months.

CONCLUSIONS
Our results confirm that the tailored approach in recurrent GBM provides an advantage in terms of RR, PFS and, above all, of long-term responses, compared with trials without molecular selection.
INNV-42. VENOUS THROMBOEMBOLISM RISK ASSESSMENT IN PATIENTS WITH GLIOMA
Authors: Unruh Dusten , Lamano Jonathan , Haider Qazi , Judkins Jonathon , Schwartz Margaret , Li Yuping , McCortney Kathleen , Amidei Christina , Scholtens Denise , Horbinski Craig 
Published: November 2019

Abstract

BACKGROUND
Venous thromboembolism (VTE) is a debilitating and life-threating condition that is common in patients with cancer, especially glioma. Antithrombotic prophylaxis is controversial in glioma patients because of possible intracerebral hemorrhage. Effective VTE prediction models exist for patients with other cancers, but not glioma. Our prior publications suggested a protective role of IDH1 mutations (IDHmut) against VTE, as well as a positive association between elevated circulating Tissue Factor (TF), a procoagulant secreted by cancers, and VTE in glioma patients. Others have recently found a correlation between podoplanin, a platelet activator, and tumor-associated VTE, but this has not been proven in gliomas. Our objective is to develop a multidimensional VTE prediction tool to improve glioma patient care, incorporating clinical, blood-based, histologic, and molecular markers.

METHODS
The Northwestern University Nervous System Tumor Bank provided preoperative arterial blood, tumor tissue, and clinical-pathologic data from 265 grade II-IV glioma patients over a 3-year interval. Molecular profiling was done by GlioSeq NGS.

RESULTS
Seventy-seven out of 265 grade II-IV glioma patients (29%) experienced VTE during their disease course. VTE was itself a negative prognostic marker for median overall survival (18 vs. 54 months, P< 0.001). Positive risk factors for VTE included advanced patient age, high body mass index, high tumor grade, prior history of VTE, coronary artery disease, hyperlipidemia, hypertension, and elevated circulating TF activity. While tumor expression of podoplanin positively correlated with VTE, circulating podoplanin did not. Among molecular markers, only IDHmut correlated with VTE risk, and it was associated with greatly reduced risk (OR=0.28; 95% CI=0.12–0.64, P=0.001).

CONCLUSIONS
This study identified multiple risk factors for glioma-associated VTE. Using these data, we are developing a multivariable prediction calculator that will improve patient care by identifying patients who would benefit most from prophylactic anticoagulation.
MNGI-01. A PHASE 0 TRIAL OF RIBOCICLIB IN AGGRESSIVE MENINGIOMA PATIENTS INCORPORATING A TUMOR PHARMACODYNAMIC- AND PHARMACOKINETIC-GUIDED EXPANSION COHORT
Authors: Tien An-Chi , Li Jing , Bao Xun , DeRogatis Alanna , Fujita Yoko , Pennington-Krygier Chelsea , Kim Seongho , Mehta Shwetal , Sanai Nader 
Published: November 2019

Abstract

BACKGROUND
New approaches are urgently needed for aggressive meningiomas, which remain largely incurable. Forkhead Box M1 (FOXM1) has been identified as a master transcription factor in aggressive meningiomas and Cyclin D-dependent Kinases (CDK) are positive regulators of cell-cycle entry, promoting tumorigenesis through FOXM1 activation. We evaluated the tumor pharmacokinetics (PK), tumor pharmacodynamics (PD), and preliminary clinical response of ribociclib, a selective CDK4/6-inhibitor, in aggressive meningioma patients.

METHODS
Eight aggressive WHO Grade II/III meningioma patients with intact RB expression were enrolled and administered oral ribociclib daily for 5 days prior to tumor resection. Plasma, tumor, and cerebrospinal fluid (CSF) samples were collected at 2, 8, or 24 h after the last dose. Total and unbound drug concentrations were determined using a validated LC-MS/MS method. PD effects, including RB and FoxM1 phosphorylation, were compared to matched archival tissue. Patients with PK and PD responses in tumor tissue, defined as unbound ribociclib concentration > 5-fold in vitro IC50 (0.04µM) and >20% decrease in pRB levels, respectively, were enrolled into an expansion cohort for preliminary assessment of progression-free survival.

RESULTS
The median CSF concentration of ribociclib was 0.25 µM. In tumor tissue, the median unbound ribociclib concentration was 1.36 µM and the median unbound tumor-to-plasma ratio was 5.34. Suppression of G1-to-S phase was inferred in tumors with declining FoxM1 phosphorylation (50%), RB phosphorylation (38%), and cellular proliferation (75%). Four patients demonstrated concurrent PK and PD responses and were graduated to continuous ribociclib therapy. At 14 months, two of these patients (one Grade II and one Grade III) demonstrate partial responses per RANO criteria.

CONCLUSION
Ribociclib achieves pharmacologically-active concentrations in aggressive meningioma tissue. Target modulation was demonstrated by a decrease in FOXM1-mediated tumor proliferation. Further investigation of ribociclib as a therapeutic strategy for aggressive meningiomas is warranted.
MNGI-11. HIGH-GRADE AND LOW-GRADE MENINGIOMAS HARBOR DIFFERING METABOLOMIC PROFILES
Authors: Fitzpatrick Garrett , Rahman Maryam , Garrett Timothy , Kresak Jesse 
Published: November 2019

Abstract

BACKGROUND
Meningiomas are the most common primary brain tumor in adults. While the majority of meningiomas are low-grade and effectively treated by resection alone, there is a subset of tumors that have a high incidence of recurrence, metastatic potential, and morbidity. Radiation has been employed with variable success for high-grade meningiomas. No chemotherapeutic approaches have proven effective against these tumors to date. There is a need for a better understanding of this tumor type in order to provide our patients with better treatment options.

OBJECTIVE
The purpose of this study is to investigate the metabolomic profile of meningiomas with a focus on comparing low- and high-grade tumors and identifying biologically significant metabolites which could correlate with overall and disease-free survival.

METHODS
Ten tumor samples of each meningioma grade (WHO grades I-III) were collected from the Florida Center for Brain Tumor Research. Global metabolomic profiling by liquid chromatography mass spectrometry was performed on the frozen tumor samples. Statistical analyses were performed using the Southeast Center for Integrated Metabolomics Galaxy interface. Select metabolites which significantly differed between low-grade (WHO Grade I) and high-grade (WHO grade II-III) were identified using the Human Metabolome Database.

RESULTS
Differing metabolomic profiles between low-grade and high-grade meningiomas were confirmed by multivariate analysis and demonstrated by unsupervised hierarchical clustering. Notably, lysophospholipid and sphingolipid metabolism was increased in the high-grade tumors, while FAPy-adenine, an oxidized nucleoside which may serve as a tumor marker, was decreased. Guanine was found to be consistently decreased in patients with negative outcomes.

CONCLUSIONS
High-grade and low-grade meningiomas harbor different metabolomic profiles. The significance of these specific differences requires further investigation.
PATH-08. CHALLENGES IN OPTIMIZATION OF MGMT PROMOTER METHYLATION ASSAYS FOR DEVELOPMENT OF COMPANION DIAGNOSIS IN GLIOBLASTOMA
Authors: Nagane Motoo , Saito Kuniaki , Kobayashi Keiichi , Shimizu Saki , Sasaki Nobuyoshi , Yamagishi Yuki , Shiokawa Yoshiaki 
Published: November 2019

Abstract

BACKGROUNDS
Despite recent limelight of precision medicine in oncology, effective targeted drugs and diagnostics for molecular markers have not been developed or approved for glioblastoma (GBM) yet. Notably, there remain multiple issues in MGMT testing, including determination of optimal assays and cutoff for methylation status, and its value as “companion diagnostics.” We compared two of MGMT assays, qualitative standard MSP and pyrosequencing, in light of compatibility, predictability, and cutoff points.

METHODS
Sixty-five newly diagnosed GBMs with two MGMT assays performed since 2006. Survival was analyzed for 48 GBMs with wildtype IDH and initial temozolomide use. Extracted DNA was subjected to bisulfite treatment, thereby MGMT status was determined.

RESULTS
Among 65 GBMs, MGMT was methylated (M) in 34, and unmethylated (U) in 31, by MSP. Median methylation rate at CpG sites by Pyro was 15.9%, with average 23.0% for M and 9.5% for U (Mann-Whitney-U, P< 0.001). MGMT status by MSP significantly correlated with that by Pyro with cutoff between 10 – 16% (Fisher, P< 0.001). Patients with MGMT M by MSP showed significantly longer PFS and OS than with U (PFS 13.5 m vs. 5.6 m, P = 0.005; OS 37.7 m vs. 15.8 m, P = 0.001). In contrast, by Pyro (cutoff 14%), only PFS was significantly better in M (11.7 m vs 5.6 m, P = 0.014), but not OS (27.9 m vs. 15.8 m, P = 0.249). No substantial gain for PFS was noted in MGMT M GBMs beyond cutoff 12% by Pyro. Multivariate analysis revealed MGMT M and KPS 70 or higher as independent factors for better PFS and OS using MSP, but only for PFS with Pyro.

CONCLUSIONS
In this study, qualitative MSP exhibited rather better discrimination of prognosis than quantitative Pyro, although showing a high concordance for MGMT status, necessitating further confirmation among assays.