bluuebunny/crossref_metadata_2025 huggingface dataset:
IMMU-44. INHIBITING IMMUNOSUPPRESSIVE IDO1 IN ADULTS WITH MALIGNANT GLIOMA – A MOVING TARGET THAT CHANGES WITH TREATMENT, CELL OF ORIGIN, AND AGING
Authors: Ladomersky Erik , Zhai Lijie , Lauing Kristen , Qian Jun , Bell April , Otto-Meyer Sebastian , Dussold Corey , Lukas Rimas , Wainwright Derek
Published: November 2019

We previously demonstrated that glioblastoma (GBM) cell IDO1 increases intratumoral immunosuppressive regulatory T cells (Tregs; CD4+CD25+FoxP3+) and decreases overall survival (OS) in the syngeneic GL261 model. IDO1 is characterized as an enzyme that converts the amino acid, tryptophan, into kynurenine. With the finding that IDO1 expression by GBM cells promotes intratumoral Treg accumulation, it was surprising to find that this process was unaffected by the pharmacological treatment with an IDO1 enzyme inhibitor (IDO1i). This led us to question the optimal therapeutic strategy for leveraging an IDO1i against GBM. Utilizing simultaneous whole brain radiation (RT), anti-PD-1 mAb, and an IDO1i, we discovered a long-term survival advantage in ~40% of young WT mice engrafted with either GL261 or CT-2A (n=9–10/group; p< 0.01). Unexpectedly, dual treatment with RT and anti-PD-1 achieved a similar long-term survival advantage in IDO1KO-, but not in WT mice with GBM (n=14/group; p< 0.01), confirming that the therapeutic target of IDO1i was in non-GBM cells. Notably, the triple immunotherapeutic treatment was less effective in elderly mice analogous to the median age of a GBM patient diagnosis (n=20–22/group; p< 0.01) and coincident with increased IDO1 expression in the elderly human brain (n=1,152; p< 0.01). Our working hypothesis is: (i) advanced aging increases IDO1 levels in the brain; (ii) RT elicits the release of GBM cell neoantigens; (iii) IDO1+ lymph node (LN) DCs process/present GBM cell neoantigens to cognate CD8+ T cells; (iv) IDO1i treatment decreases the suppression of IDO1+ DC:CD8+ T cell priming; (v) anti-PD1 treatment enhances LN priming initialized by RT + IDO1i; (vi) brain-resident IDO1+ DCs accumulate during advanced aging and suppress the newly-generated brain-infiltrating CD8+ GBM-specific T cells independent of IDO1i. Our work highlights the immunosuppressive role of advanced aging and the need to better understand gero-neuro-immuno-oncology interactions for enhancing future immunotherapeutic efficacy in adults with GBM.
IMMU-46. EXAMINATION OF THE EFFECTS OF DEXAMETHASONE ON THE EFFICACY OF IMMUNOTHERAPY IN GLIOMA USING GENE-MEDIATED CYTOTOXIC IMMUNOTHERAPY
Authors: Koch Marilin , Zdioruk Mykola , Oskar Nowicki M , Aguilar Estuardo , Aguilar Laura , Guzik Brian , Chiocca Ennio , Lawler Sean
Published: November 2019

RATIONALE

Dexamethasone is frequently used in symptomatic treatment of glioma patients, although it is known to cause immune suppression. Checkpoint inhibitor immunotherapies have not yet been successful in glioma treatments. Gene-mediated cytotoxic immunotherapy (GMCI) is an immunotherapeutic approach that uses aglatimagene besadenovec with an anti-herpetic prodrug to induce immunogenic tumor cell death and immune cell attraction to the tumor site with potent CD8 T cell activation. GMCI is currently in clinical trials for solid tumors including glioblastoma, where it showed encouraging survival results in a Phase 2 study that did not limit the use of dexamethasone. However, the effects of dexamethasone on its efficacy have not been explored.

METHODS

We investigated the effects of dexamethasone on GMCI in vitro using cytotoxicity and T-cell-killing assays in glioblastoma cell lines. The impact of dexamethasone in vivo was assessed in an orthotopic syngeneic murine glioblastoma model.

RESULTS

Cyotoxicity assays showed that Dexamethasone has a slight impact on GMCI in vitro. In contrast, we observed a highly significant effect in T-cell-functional assays in which killing was greatly impaired. Immune cell response assays revealed a reduced T-cell proliferation after co-culture with supernatant from dexamethasone or combination treated glioblastoma cells in contrast to GMCI alone. In a murine model, the combination of GMCI and dexamethasone resulted in a significant reduction in median symptom-free survival (29d) in comparison to GMCI alone (39.5d) (P = 0.0184).

CONCLUSION

Our data suggest that high doses of dexamethasone may negatively impact the efficacy of immunotherapy for glioma, which may be a consequence of impaired T cell function. These results support the idea that there is a need in identifying possible alternatives to dexamethasone to maximize the effectiveness of immunostimulatory therapies such as GMCI.
INNV-01. KETOGENIC METABOLIC THERAPY SIGNIFICANTLY IMPROVES RADIOGRAPHIC AND CLINICAL RESPONSE TO SALVAGE TEMAZOLAMIDE IN PATIENTS WITH RECURRENT HIGH GRADE GLIOMAS
Authors: Smith Kris
Published: November 2019

Ketogenic Metabolic Therapy (KMT), by the proposed Warburg effect, has been shown in animal studies to augment responses to chemotherapy in laboratory models of high grade gliomas. Anecdotal responses in human patients have also been reported. We advised patients in our clinic to adhere to a low-carbohydrate, high-fat diet to obtain a state of nutritional ketosis while undergoing temazolamide (TMZ) chemotherapy for recurrent high-grade gliomas. A registered dietitian, specifically trained in KMT was utilized as a consultant for all of these patients. Blood ketone levels were checked frequently to assure ketone levels above 0.5 mmol/L. Nine patients have documented a near-continuous state of ketosis for at least 3 months while on TMZ therapy and have shown significant radiographic resolution of recurrent disease based on serial high resolution MRI surveillance imaging. All of these patients had shown progressive recurrent disease on serial MRI imaging prior to initiation of KMT. 4 of the 9 patients obtained a complete response, while the other 5 experienced a partial response. None of the patients failed to show any improvement in their imaging follow-up while on KMT. Three of the 9 patients also had salvage radiation therapy to some local area of recurrence prior to initiating KMT. There were no adverse effects related to the KMT diet. Most patients stated that they felt an overall improvement in quality of life while on the diet and embraced the diet as a means of feeling more in control of their disease. The diet was well tolerated and not felt to be a hardship or burdensome after an initial learning curve transition period was overcome. Based on these highly positive preliminary results, we suggest that KMT be included in larger prospective randomized trials for up-front and recurrent high-grade glioma trials to augment standard and experimental therapies.
INNV-05. SOCIAL MEDIA AND “TWEET CHAT ANALYSES” TO INFORM QOL AND PALLIATIVE CARE NEEDS IN PATIENTS WITH PRIMARY BRAIN TUMORS
Authors: Salmi Liz , Otis-Green Shirley , Hayden Adam , Taylor Lynne , Kwan Bethany
Published: November 2019

BACKGROUND

Despite a standard of care protocol for the treatment of brain cancer, patients often suffer motor and cognitive deficits and chronic exposure to stress and anxiety, detrimental to patient quality of life (QOL). Palliative care addresses patient and care partner (caregiver) QOL needs as a complement to curative treatment, using a team-based, multidisciplinary approach. Elements of palliative care that are highest priority for patients with brain cancer are not known.

METHODS

A multi-stakeholder group including clinicians, researchers, patients, and care partners convened (hereafter: “stakeholders”), led jointly by a brain cancer patient and health services researcher. The stakeholders identified QOL needs for patients with brain cancer and their care partners, and mapped these needs onto a brain cancer-specific palliative care model. In 2018, patients, researchers, and clinicians participated in two moderated “tweet chats” to test and further inform QOL definitions and palliative care needs (n=79).

RESULTS

Thematic analysis of tweet chat transcripts revealed patients and care partners were most concerned by: challenging behaviors resulting from tumor and resulting treatment; depression and anxiety; changes in sexuality/intimacy loss; grief over the loss of identity and things one previously enjoyed/was able to do; financial toxicity; changes in close relationships; and dependence on a broader social network. The stakeholders used this work to inform a set of QOL needs and corresponding palliative care elements. Each need was mapped onto a corresponding element for development of a palliative care model. Further research questions were identified to inform further research in this area.

CONCLUSIONS

Patients with brain cancer have complex QOL needs beyond symptom management. A palliative care model for brain cancer should include a multidisciplinary care team including care partner support and education. In addition to the palliative care physician, additional disciplines may include a social worker, chaplain, mental health professional, and rehabilitative services therapists.
INNV-11. THE RISK OF HEMORRHAGE ASSOCIATED WITH THROMBOCYTOPENIA IN PATIENTS UNDERGOING OMMAYA RESERVOIR PLACEMENT FOR INTRATHECAL CHEMOTHERAPY: A SINGLE INSTITUTION RETROSPECTIVE ANALYSIS
Authors: Patel Arpan , Amar Surabhi , Lettieri Salvatore , Gridley Daniel , Bhattarai Bikash , Feiz-Erfan Iman
Published: November 2019

PURPOSE

Ommaya reservoirs are frequently inserted in patients requiring regular delivery of intrathecal medications. The incidence of intracranial hemorrhage following insertion ranges from 1–3% and is typically associated with thrombocytopenia. However, the exact platelet count at which it is considered safe to insert an Ommaya reservoir has not been previously reported. The purpose of this study is to investigate the nature of the relationship between thrombocytopenia and post-operative hemorrhage following insertion of Ommaya reservoirs for intrathecal chemotherapy.

METHODS

Consecutive patients requiring insertion of an Ommaya reservoir were enrolled in the study with no minimum platelet count as an exclusion criterion. Patients data were retrospectively reviewed with thrombocytopenia defined as platelet count < 100,000. All thrombocytopenic patients received at least one unit of intraoperative platelet transfusion. Post-operative incidence of hemorrhage, determined through CT scan, was compared between the thrombocytopenic group and normal platelet group.

RESULTS

53 patients were enrolled within the study with 23 patients determined to be thrombocytopenic at the time of insertion. Thrombocytopenic patients were found to have 18.6 times the odds of post-operative bleeding when compared to patients with normal platelet counts (p< 0.001). However, no patient in the thrombocytopenic group had a clinically significant bleed, defined as being symptomatic or requiring intervention.

CONCLUSIONS

Although thrombocytopenia increases the risk of post-operative hemorrhage associated with Ommaya reservoir placement, there is no increase in clinically significant bleeding. With concurrent platelet transfusion and use of neuronavigation, Ommaya reservoir may be safely placed in thrombocytopenic patients.
INNV-14. ADJUVANT CHEMOTHERAPY AFTER SEVERE MYELOTOXICITY DURING TEMOZOLOMIDE CHEMORADIATION IN GLIOMAS. IT IS FEASIBILE?
Authors: Villani Veronica , Fabi Alessandra , Gaviani Paola , Rudà Roberta , Lombardi Giuseppe , Simonetti Giorgia , Silvani Antonio , Pronello Edoardo , Minniti Giuseppe , Pace Andrea
Published: November 2019

INTRODUCTION

Malignant gliomas are aggressive primitive brain tumor in adults. Today, the standard of care is Temozolomide (TMZ) administered daily with radiation therapy, followed by adjuvant TMZ. TMZ treatment has been considered to have a low toxicity profile. However, during concomitant treatment some patient may develop a severe myelosuppression. This toxicity may be in some cases prolonged and lead to treatment discontinuation.

METHODS

We have retrospectively collected data from 5 Italian neuro-oncological centers, about glioma patients who developed severe and prolonged hematological toxicity during concomitant chemoradiotherapy with TMZ. The purpose of this study is to evaluate: percentage of patients receiving adjuvant chemotherapy after severe myelotoxicity; rate of toxicity observed during adjuvant chemotherapy.

RESULTS

54 glioma patients who developed myelosuppression of grade 3 or 4 were considered. Histology was Glioblastoma in 45 patients (83%); 63% of patients were female. Myelotoxicity during concomitant phase occurred at a median of 4 weeks (range 1–8) from the start of treatment. After recovery of myelotoxicity 19 patients did not received any treatment while 35 (65%) were treated with chemotherapy (28 received standard TMZ, one TMZ with metronomic schedule, 2 lomustine and 4 other agents). Among patients treated with TMZ, 13 patients presented hematological toxicity grade 3–4 which required treatment discontinuation in 7 cases (20%).

CONCLUSION

the results of our study show that 80% of glioma patients presenting severe myelotoxicity during concomitant radiochemotherapy may be treated with maintenance TMZ after recovery of myelosuppression.
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

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

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

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

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

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

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

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

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

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

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.
PATH-11. THE PROGNOSTIC ROLE OF IDH MUTATIONS IN HOMOGENEOUSLY TREATED PATIENTS WITH MALIGNANT DIFFUSE ASTROCYTOMAS
Authors: Christians Arne , Banan Rouzbeh , Stockhammer Florian , Hartmann Christian
Published: November 2019

Detection of IDH mutations in patients with diffuse malignant astrocytomas resulted in substantial modifications in the WHO classification. An important observation was that patients with anaplastic astrocytomas (AA) IDH-wt had a clinical course similar to that glioblastoma (GBM) patients. The observations of the GGN and NOA-04, were based on mixed cohorts. While most GBM patients received combined radiochemotherapy, patients with AA usually only had radiotherapy or chemotherapy. This shortcoming raises the question whether AA IDH-wt patients did not behave prognostically better than GBM patients when receiving combined radiochemotherapy. Thus, the question remains whether the established histopathological grading criteria for malignant astrocytomas in the absence of IDH mutations are important if vascular proliferation or necrosis are undetectable. All patients investigated here with diagnosis of a malignant astrocytoma received combined standard radiochemotherapy independently of the histopathological diagnosis. Thus, the analysis allows to clarify whether patients with AA of IDH-wt have a prognosis similar to that of GBM patients under equivalent therapeutic conditions. We determined the IDH1/2 status by sequencing, the MGMT status by pyrosequencing. Patients with the histopathological diagnosis of an AA IDH-wt showed a comparable and therefore no better prognosis (median overall survival (mOS) 16 months) than patients with a glioblastoma (mOS 13 months). Instead, patients with an AA IDH-mut receiving same therapy had a mOS of 54 months. Thus, it can be concluded that in absence of IDH mutations, the established histopathological grading criteria ‘necrosis’ and ‘vascular proliferation’ lose their prognostic significance. If, on the other hand, patients with malignant astrocytomas and IDH mutations are examined, there is a difference between patients showing necrosis and/or vascular proliferation and those whose tumors do not. Accordingly, for patients with malignant astrocytomas with IDH mutations it can be concluded that differentiation between AA IDH-mut and GBM IDH-mut remains beneficial from a prognostic perspective.
PATH-15. IDENTIFICATION OF SUBSETS OF IDH-MUTANT GLIOBLASTOMAS WITH DISTINCT EPIGENETIC AND COPY NUMBER ALTERATIONS AND STRATIFIED CLINICAL RISKS
Authors: Ka-Wai Li Kay , Chen Hong , Noushmehr Houtan , Ng Ho-Keung
Published: November 2019

IDH-mutant glioblastoma is classified by the 2016 CNS WHO as a group with good prognosis. However, the actual number of cases examined in the literature is relatively small. We hypothesize that IDH-mutant glioblastoma is not a uniform group and should be further stratified. We conducted methylation profiles and estimated copy number variations of 57 IDH-mutant glioblastomas. Our results showed that 59.6%, and 40.4% of tumors belonged to G-CIMP-high and G-CIMP-low methylation subgroups, respectively. G-CIMP-low subgroup was associated with significantly worse OS as compared to G-CIMP-high (P=0.005). CDKN2A deletion (42.1%) was the most common gene copy number variation, and was significantly associated with G-CIMP-low subgroup (P=0.004). Other frequent copy number changes included MET (5.3%), CCND2 (19.3%), PDGFRA (14.0%), CDK4 (12.3%), and EGFR (12.3%) amplification. Both CDKN2A deletion (P=0.036) and MET amplification (P< 0.001) were associated with poor OS in IDH-mutant glioblastomas. Combined epigenetic signatures and gene copy number variations separated IDH-mutant glioblastomas into Group 1 (G-CIMP-high), Group 2 (G-CIMP-low without CDKN2A nor MET alterations), and Group 3 (G-CIMP-low with CDKN2A and/or MET alterations). Survival analysis revealed Groups 1 and 2 exhibited a favorable OS (median survival: 619 days (20.6 months), and 655 days (21.8 months), respectively). Group 3 exhibited a significant shorter OS (median survival: 252 days (8.4 months)). Multivariable analysis confirmed the independent prognostic significance of our Groups. IDH-mutant glioblastomas should be stratified for risk with combined epigenetic signature and CDKN2A/MET status and some cases have poor outcome.
PATH-28. ANGIOTENSINOGEN PROMOTER METHYLATION TO PREDICT BEVACIZUMAB RESPONSE IN RECURRENT GLIOBLASTOMA PATIENTS
Authors: Urup Thomas , Gillberg Linn , Kaastrup Katja , Schuang Lü Maja , Regner Michaelsen Signe , Larsen Vibeke A , Jarle Christensen Ib , Broholm Helle , Lassen Ulrik , Grønbæk Kirsten , Skovgaard Poulsen Hans
Published: November 2019

Recurrent glioblastoma patients achieving response to bevacizumab combination therapy have clinical improvement and prolonged survival. High gene-expression of angiotensinogen (AGT) is associated with a poor response to bevacizumab combination therapy. Because AGT gene-expression is epigenetically regulated, we investigate if lower AGT promoter methylation in tumor tissue predicts a poor response to bevacizumab combination therapy in recurrent glioblastoma patients. Methods: Patients were assessed for eligibility using our clinical database comprising all recurrent glioblastoma patients consecutively treated with bevacizumab combination therapy at our center. The study included 159 response and biomarker evaluable patients: A training cohort of 77 patients and a validation cohort of 82 patients treated in the period between year 2005–2011 and 2012–2015. DNA methylation of 4 CpG sites in the AGT promoter was measured using pyrosequencing. Using logistic regression analysis, a predictive model for non-response was established. Results: In the training cohort, lower methylation of each of the four CpG sites was significantly associated with non-response (p < 0.05). Lower mean methylation of the AGT promoter was significantly associated with non-response (2-fold decrease: OR &eq; 3.01; 95% CI:1.41–6.44; p &eq; 0.004). A predictive model able to predict bevacizumab non-response in clinical practice was established. This predictor was significantly associated with non-response in the validation cohort (p &eq; 0.037). Conclusion: AGT promoter methylation is lower in tumor tissue from non-responsive recurrent glioblastoma patients treated with bevacizumab combination therapy. A predictive model for non-response was established and successfully validated. This model can be used to identify patients who will not benefit from bevacizumab combination therapy.
PATH-35. RETROSPECTIVE ANALYSIS OF 145 PATIENTS WITH GLIOBLASTOMA; CORRELATING MOLECULAR ALTERATION INCIDENCE WITH DEMOGRAPHICS, TUMOR LOCATION, AND PROGNOSIS
Authors: Lobbous Mina , Tucker ZacK , Coffee Elizabeth , Nabors Louis
Published: November 2019

Glioblastoma is the most common and most aggressive primary brain tumor in adults. Glioblastoma was the first neoplasm to be systemically studied by The Cancer Genome Atlas and is one of the most molecularly well-characterized tumors in humans. Molecular profiling of glioblastoma is increasingly available and had led to the identifications of multiple prognostic factors as well as potential actionable targets for novel therapies. We identified 145 patients diagnosed with glioblastoma whose tumor tissue was analyzed using next generation sequencing (NGS). The NGS was performed using validated, commercially available panels. We studied somatic genetic alterations with a particular focus on TERT (which was altered in 55.9% of patients in the dataset), CDKN2A (44%), TP53 (39%), EGFR (38.6%), PTEN (31%), IDH1 (20%), and CDK4 (9%). These molecular alterations were analyzed in relation to the patients’ tumor locations, demographics, and outcomes. We used multiple binary logistic regressions to assess whether demographics and tumor location were predictive of the above alterations We also assessed the relationship between molecular alterations and outcomes when controlling for treatment and demographic variables. Among demographic variables, age predicted alterations in IDH1, EGFR, TERT, TP53, and PTEN. Frontal lobe tumors were more likely to be IDH1-mutated, irrespective of patient age. Sex and race did not predict the incidence of the molecular alterations of interest. Analysis of outcomes revealed that, when controlling for treatment and demographic variables, TERT promoter mutations, TP53 nonsense mutations, and EGFR A289V were predictive of a decreased progression-free survival, while CDKN2A deletion, PTEN missense mutations, and EGFR A289V were predictive of decreased overall survival. Our experience highlights the importance of incorporating routine NGS in the management of patients with glioblastoma. More studies are required to evaluate the predictive and/or prognostic values of different molecular alterations.
PATH-36. MACHINE LEARNING TO DETECT GLIOMAS IN URINE-BASED LIQUID BIOPSY
Authors: Kitano Yotaro , Aoki Kosuke , Yasui Takao , Motomura Kazuya , Ohka Fumiharu , Tanahashi Kuniaki , Hirano Masaki , Nishikawa Tomohide , Shimizu Hiroyuki , Yamaguchi Junya , Maeda Sachi , Yamazaki Shintaro , Wakabayashi Toshihiko , Natsume Atsushi
Published: November 2019

BACKGROUND

Diffuse gliomas are the most common primary malignant brain tumors, whose overall prognosis is quite dismal. Tumor-cell-secreted extracellular vesicles (EVs) participate in physiological and pathological processes and have potential applications to diagnostics of malignant tumors including diffuse gliomas. Because urine is less invasive to collect, development of early diagnosis based on urine EVs is eagerly awaited. In this study, we captured urine EVs of patients with gliomas efficiently with the nanowire device and compared expression profile of microRNAs (miRNAs) within urine EVs with that of healthy donors to identify diagnostic accuracy by a machine learning algorithm.

METHODS

62 patients with diffuse gliomas, including 27 glioblastoma and 35 lower grade gliomas, and 100 healthy donors were analyzed, along with orthotopic transplant mouse model. Urinary EVs were obtained with the nanowire device which could collect EVs more efficiently than the conventional ultracentrifugation method (Yasui et.al., Science Adv.2017). Machine learning methods were performed to select the miRNAs which could distinguish patients with gliomas from healthy control.

RESULTS

More than 2400 miRNAs were obtained from all urine samples. We identified miRNA panels that provided high diagnostic accuracy of diffuse gliomas (92.5%). There were 440 miRNAs whose expression increased by more than 1.5 fold (p< 0.05) as compared to healthy donor samples (glioma-upregulated miRNAs), whereas the expression of 87 miRNAs decreased to less than 2/3-fold (p< 0.05) (glioma-downregulated miRNAs). Mouse miRNAs which were homologous to glioma-upregulated and -downregulated miRNAs showed significantly high and low level expressions, respectively, in glioma mouse models as compared to normal control mice, confirming the reliability of urine miRNA-based diagnosis. Furthermore, some of these glioma-upregulated miRNAs has been reported to be involved in tumor progression.

CONCLUSIONS

miRNAs obtained from urine could be biomarkers for detection of gliomas by machine learning and some of these could be associated with tumor progression.