bluuebunny/crossref_metadata_2025_split huggingface dataset:
ACTR-51. REMARKABLE RESPONSE OF A PATIENT WITH SECONDARY GBM TO A HISTONE DEACETYLASE INHIBITOR
Authors: Shu Hui-Kuo , Gurbani Saumya , Ramesh Karthik , Weinberg Brent , Voloschin Alfredo , Olson Jeffrey , Shim Hyunsuk 
Published: November 2019

Abstract
Glioblastomas are highly aggressive, grade IV tumors of glial cells that arise either as de novo primary tumors or as secondary tumors, which malignantly transformed from lower grade gliomas. Secondary glioblastomas have a relatively low incidence making up 5–10% of all glioblastoma diagnoses and tend to occur in younger patients. However, these tumors are still quite aggressive with survival outcomes that do not differ substantially from primary glioblastomas. Secondary glioblastomas also often harbor mutation of isocitrate dehydrogenase (IDH) enzyme, which produces the oncometabolite 2-hydroxyglutarate (2-HG) from alpha-ketoglutarate (α-KG). The accumulation of 2-HG has several downstream effects due to its competitive inhibition of α-KG-dependent enzymes, including epigenetic modification via hypermethylation of histones. Histone deacetylase inhibitors (HDACi) are a class of molecules that inhibit histone deacetylation and have been shown to have anti-tumor effect in part due to this epigenetic modification. Thus, because of their shared targets with regard to histone modification, it is plausible that HDACi could counter the oncometabolite effects of accumulated 2-HG in IDH1 mutant tumors. Since belinostat is a pan-HDACi that has improved blood-brain barrier penetration compared to many other HDACis, we conducted a pilot study that enrolled 15 patients examining its upfront use for the treatment of glioblastomas and found that it was well tolerated. One patient in particular, likely with secondary glioblastoma harboring the typical IDH1 mutation, underwent treatment with standard chemoradiation as well as belinostat on this study. For this case, a remarkable improvement in tumor burden with very significant decrease in enhancing residual tumor and restoration of magnetic resonance spectroscopy (MRS)-detectable metabolism was noted. Furthermore, improved neurocognitition and quality-of-life were also observed in this patient during the 18-month follow-up period. Collectively, these outcomes potentially support the use of belinostat as an adjuvant therapy for patients with secondary glioblastoma that harbor a mutant IDH enzyme.
ACTR-54. VIGILANT OBSERVATION OF GLIADEL WAFER IMPLANT (VIGILANT) REGISTRY: INTERIM ANALYSIS
Authors: Lillehei Kevin , Kalkanis Steven , Liau Linda , Olson Jeffrey , Paleologos Nina , Ryken Timothy , Johnson Tania , Scullin Evan 
Published: November 2019

Abstract

INTRODUCTION
The Vigilant ObservatIon of GlIadeL WAfer ImplaNT (VIGILANT) registry (NCT02684838) was initiated to evaluate the use of BCNU wafers for treatment of CNS malignancies in contemporary practice and in the new era of molecular analysis.

METHODS
The VIGILANT registry is an observational study. Each patient receives usual care from treating physicians in routine quarterly visits, with no registry-specific visits required. The VIGILANT registry will enroll up to 500 patients at 35 US sites. Patients must be ≥18 years of age with no medical conditions increasing risk through participation. Patient follow-up will last 3 years.

RESULTS
The interim analysis is ongoing, with the following preliminary data. Of the 143 patients enrolled to date (mean age 59.8 ± 13.41 years, 60.1% male, 82.5% white), BCNU wafers have been implanted for newly diagnosed glioblastoma (GBM) in 49 (34.3%); for recurrent GBM in 48 (33.6%); for brain metastases in 28 (19.6%); for anaplastic oligodendroglioma in 4 (2.8%); and for other CNS tumors in 14 (9.8%). For patients with recurrent GBM, the median time from prior to current CNS tumor diagnosis was 341.5 days (IQR 88, 890). The majority of recurrent GBM patients had previously undergone systematic chemotherapy (87.5%) and radiation therapy (70.8%); only 8 (16.7%) had previously received BCNU wafers and only 4 (8.3%) had previously undergone alternating electric-field therapy. Of patients with brain metastases, 15 (51.7%) had previously undergone stereotactic radiosurgery. Of GBM patients with baseline biomarker assessments, MGMT promoter status was methylated in 52.1% (37/71), and IDH1 mutation status was positive in 15.9% (11/69). Median survival and contemporary practice patterns will be available at the time of presentation.

CONCLUSIONS
In the VIGILANT registry to date, BCNU wafers have been implanted most often and with equal frequency for treatment of newly diagnosed and recurrent GBM. Preliminary safety and efficacy data are pending.
SURG-15. SURVIVAL OUTCOMES FOLLOWING RE-RESECTION FOR RECURRENT GLIOBLASTOMA MULTIFORME
Authors: Hennessy Maeve , Dablouk Mohamed , Mullally William , O’Halloran Philip , MacNally Stephen , Morris Patrick 
Published: November 2019

Abstract

BACKGROUND
While the treatment of primary Glioblastoma Multiforme (GBM) is well defined, the role of surgical resection in recurrent GBM is not firmly established.1 Treatment options for recurrent GBM include second-line chemotherapy, re-irradiation and surgical re-resection.2 This review examines current practice in a national neuro-oncology centre. AIMS: To investigate survival outcomes in patients undergoing surgical re-resection for recurrent GBM in our institution and to compare our findings to the relevant published literature.

METHODS
A retrospective review of our institution’s neuro-oncology database was performed. We evaluated all patients who underwent re-resection for recurrent GBM following standard adjuvant treatment between 2015–2018. Patients who did not have an initial diagnosis of Grade 4 GBM and patients who were re-operated on within one month were excluded. We analysed overall survival using Kaplan Meier curves. Patients not known to have died were censored to the last known alive date. We also examined factors which may affect patient outcome, including age, sex, extent of resection, tumour characteristics and tumour location.

RESULTS
34 patients were eligible for inclusion into this study, of these 21 (61%) were male. Median age was 52. A radiologically confirmed initial resection of > 80% was achieved in 52% of patients. Median time from initial surgery to re-resection was 13.5 months. Median survival from initial surgery was 28.6 months and median survival after re-resection was 9.5 months.

CONCLUSION
Re-operation appears to have a role in the management of recurrent GBM in carefully selected cases. Overall survival in this patient cohort remains poor and further studies into the benefit of re-resection in comparison to second-line chemotherapy and re-irradiation would be of value.
SURG-18. 5-AMINOLEVULINIC ACID FLUORESCENCE (5-ALA) GUIDED RESECTION OF GLIOBLASTOMA, LESSON LEARNED FROM 19 CASES
Authors: Cho Jinmo 
Published: November 2019

Abstract

BACKGROUND
5-ALA is known as useful tool for high grade glioma resection and the accumulation extent of 5-ALA is known as far beyond gadolinium enhancement. Extent of resection is key factor for favorable outcome and long-term survival for high grade glioma patients and 5-ALA might increase extent of resection. We present our experience of 5-ALA guided glioma surgeries

METHODS
Total 19 patients were performed 5-ALA guided surgery. They ingested 20mg/kg, four hours before craniotomy. We tried to perform supra-total resection rather than gross total resection according to the tumor consistency and if the tumor located relatively non-eloquent area, we tried to perform lobectomy rather than lesionectomy. After tumor resection, we inspect the tumor bed under 5-ALA fluorescence, and we confirmed the complete loss of fluorescence on the tumor resected bed. We check the MRI within 48 hour after operation and assess the extent of resection

RESULTS
Among the 19 patients, 15 patients were confirmed glioblastoma and 3 anaplastic astrocytoma and 1 anaplastic oligoastrocytoma. We confirmed all enhancing lesion was completely removed, however, 2 patients show residual non-enhancing lesion in post-operative MRI. Two patients suffered temporary hemiparesis and 2 patients show permanent visual field defect.

CONCLUSION
5-ALA is useful tool for glioma surgery. Resection extent could be increased, however, non-enhancing lesion in the high grade gliomas, might be missed under 5-ALA guidance.
ACTR-60. A PHASE 2, HISTORICALLY CONTROLLED STUDY TESTING THE EFFICACY OF TTFIELDS WITH ADJUVANT TEMOZOLOMIDE IN HIGH-RISK WHO GRADE II AND III ASTROCYTOMAS (FORWARD)
Authors: Tran David , Ghiaseddin Ashley , Allen Anne 
Published: November 2019

Abstract

BACKGROUND
A long-standing observation in neuro-oncology concerns a group of patients with WHO Grade II and III gliomas expressing isolated hTERT promoter mutations, which exhibit indolent histological features but are highly aggressive and resistant to standard chemoradiation therapy. These patients show an overall survival rate similar to glioblastoma WHO Grade IV, necessitating new treatment options. This represents the first study of its kind testing novel treatment for this rare subgroup of lower grade gliomas with high-risk cytogenetics.

METHODS
This Phase 2, single arm, multicenter open label study [NCT03906448] will enroll 100 adult patients with newly diagnosed WHO grade II and III astrocytoma without IDH mutations and 1p/19q codeletions and with isolated hTERT promoter mutations who have completed standard radiotherapy with concurrent temozolomide, followed by adjuvant temozolomide for 12 cycles in combination with 24 months of TTFields therapy. The primary endpoint is overall survival compared to historical controls. Secondary endpoints are safety, quality of life, and progression free survival. Correlative studies will examine the effect of TTFields on intratumoral immune microenvironment and the role of electric field distribution on disease control and outcomes. Sample size was based on improvement in median OS versus historical controls (N=59; median survival 22 months). Improvements in median overall survival was based on a one-sided Wald test of the Weibull regression coefficient (H0: beta=0, alpha=0.05). A consortium of 15 institutions across the US will participate, with the first enrollment May 2019. Total accrual of 100 is planned over 36 months. The survival results and the correlative studies are designed to provide new insights for future therapeutic development for these patients.
SURG-25. LASER INTERSTITIAL THERMAL THERAPY (LITT) FOR INTRACRANIAL LESIONS: A SINGLE- INSTITUTIONAL SERIES, OUTCOMES AND REVIEW OF THE LITERATURE
Authors: Dabecco Rocco , Yu Alexander , Ranjan Tulika , Xu Linda , Aziz Khaled 
Published: November 2019

Abstract

INTRODUCTION
Laser interstitial thermal therapy (LITT) is a minimally invasive treatment method that provides surgeons with cytoreductive techniques to treat neurosurgical conditions such as primary brain neoplasms, brain metastases, radiation necrosis, and epileptogenic lesions, many of which are located in operative corridors that would be difficult to address via open surgical or are amenable via minimally invasive approaches. Although the use of lasers is not a new concept in neurosurgery, advances in technology have enabled surgeons to perform laser treatment with the aid of real-time MRI thermography as a guide. In this report, we present our institutional series and outcomes of patients treated with LITT for 8 glial neoplasms 12 brain metastases.

METHODS
We retrospectively evaluated 20 patients (7 male, 13 female; age range, 28–77 years) who underwent LITT at one or more targets from 2015–2019.

RESULTS
In our series, all patients included had prior craniotomy for either primary glioma or metastatic disease. Mean extent of ablation (EOA) was 98% on post-op MRI. Mean progression free survival varied depending on the intracranial pathology, with the glioma cohort (5 months (SDD: 3.51)) demonstrating worse outcomes than metastatic disease (8.2 months (SDD: 4.83)). Only 1 patient experienced immediate post-operative morbidity, 1 patient experienced post-operative mortality secondary to hemorrhage. Mean follow-up was 9.7 months (SDD: 5.35), with one patient lost to follow up immediately post-procedure and excluded from the study. Average hospitalization was 2.4 days (SDD: 1.0). Mean overall survival, post-diagnosis of intracranial lesion, is more favorable for metastatic lesions (48 months (SDD: 27.14)), as compared to primary glial neoplasms (31 months SDD: 11.63)).

CONCLUSION
Laser interstitial thermal therapy (LITT) is a safe, minimally invasive treatment method that provides surgeons with cytoreductive techniques to treat neurosurgical conditions. In properly selected patients, this modality offers improved survival outcomes in conjunction with other salvage therapies.
SURG-31. SPECTROSCOPIC MRI TO GUIDE BIOPSY OF LOWER GRADE GLIOMAS
Authors: Olson Jeffrey , Weinberg Brent , Gurbani Saumya , Ramesh Karthik , Schreibmann Eduard , Shu Hui-Kuo , Shim Hyunsuk 
Published: November 2019

Abstract
Primary brain tumors are serious and life-threatening; thus, accurate histopathologic diagnosis is critical for determining the proper clinical treatment regimen. Grade II/III gliomas (lower grade gliomas, or LGGs), including astrocytomas and oligodendrogliomas, are heterogeneous and potentially contain low- and high-grade areas within the same tumor. Therefore, it is critical to target biopsies to the most aggressive portion of the tumor to avoid tumor under-grading and under-treatment. While glioblastomas are typically targeted based on contrast-enhanced MRI, LGGs have little contrast enhancement to define targets for biopsy treatment guidance. Spectroscopic MRI (sMRI) is a high-resolution MRI imaging method which allows for detection of metabolic abnormalities such as choline and NAA in the entire brain without injection of a contrast agent. We have previously evaluated the relationship between sMRI Cho/NAA ratios and tumor infiltration in surgical specimens from high grade gliomas, demonstrating a strong correlation between sMRI results and glioma infiltration. We also used the location information to correlate sMRI data to genetic and histologic biomarkers (such as 1p19q, IDH, and MGMT). An IRB-approved pilot study to obtain sMRI prior to stereotactic biopsy has been done in 20 non-enhancing LGG cases. Patients with a suspected LGG diagnosis underwent sMRI at the time of their surgical planning MRI. sMRI images were then registered to the T1w-CE and T2/FLAIR images and imported into the Stealth neuronavigation system for biopsy planning. We found that all astrocytomas (regardless of grades) showed strongly elevated Cho/NAA, while the LGGs were hardly delineated on T1w and T2/FLAIR. We found that pathology-confirmed grade II oligodendroglioma do not have choline elevation; however, NAA was mildly decreased, myo-inositol was elevated, and creatine (Cr) was mildly elevated. sMRI is a useful tool to improve biopsy targeting in LGG patients by ensuring that the highest risk regions are sampled.
SURG-32. THE USE OF 5-AMINOLEVULINIC ACID IN LOW-GRADE GLIOMA RESECTION: A SYSTEMATIC REVIEW
Authors: Almekkawi Ahmad , El Ahmadieh Tarek , Abi-Aad Karl , Aoun Salah , EL Tecle Najib , Patel Toral , Bendok Bernard 
Published: November 2019

Abstract

BACKGROUND
5-aminolevulinic acid is a reliable tool for optimizing high-grade glioma resection. However, its efficacy in low-grade glioma resection remains unclear.

OBJECTIVE
To study the role of 5-aminolevulinic acid in low-grade glioma resection and assess positive fluorescence rates and effect on the extent of resection.

METHODS
A systematic review of PubMed, Google Scholar, and Cochrane was performed from the date of inception to February 1, 2019. Studies that correlated 5-aminolevulinic acid fluorescence with low-grade glioma in the setting of operative resection were selected. Studies with biopsy only were excluded. Positive fluorescence rates were calculated. Quality index of the selected papers using the Downs and Black criteria checklist was provided.

RESULTS
Twelve articles met the selection criteria with 244 histologically-confirmed low-grade glioma patients who underwent microsurgical resection. All patients received 20 mg/kg body weight of 5-aminolevulinic acid. Only 60 patients (n=60/244; 24.5%) demonstrated visual intra-operative 5-aminolevulinic acid fluorescence. The extent of resection was reported in 4 studies, however, the data combined low- and high-grade tumors. Only 2 studies reported on tumor location. Only 3 studies reported on clinical outcomes. The Zeiss OPMI Pentero microscope was most commonly used across all studies. The average quality index was 14.58 (range: 10–17) which correlated with an overall good quality.

CONCLUSION
There is an overall low correlation between 5-aminolevulinic acid fluorescence and low-grade glioma. Advances in visualization technology and using standardized fluorescence quantification methods may further improve the visualization and reliability of 5-aminolevulinic acid fluorescence in low-grade glioma resection.
TMIC-07. SYMBIOTIC MACROPHAGE-GLIOMA CELL INTERACTIONS REVEAL SYNTHETIC LETHALITY IN PTEN NULL GLIOMA
Authors: Chen Peiwen , DePinho Ronald , Alan Wang 
Published: November 2019

Abstract
Heterotypic interactions across diverse cell types of the tumor microenvironment (TME) can enable tumor progression and offer points for potential therapeutic intervention. Employing Glioblastoma Multiforme (GBM) as a model system, we sought to (i) understand the nature of specific oncogenic signals in glioma cells that affects immune cells, and (ii) identify immune cell factors which may support glioma growth and survival. Combined profiling and functional studies of glioma cells established that PTEN deficiency, a signature GBM alteration, specifically tracks with an immune profile dominated by tumor-associated macrophages (TAMs, a key type of immune cells in GBM which can constitute up to half of the tumor mass) via upregulation of lysyl oxidase (LOX). Mechanistically, the PTEN-SRC/AKT axis regulates YAP1, which directly upregulates LOX expression and secretion in glioma cells via binding to the LOX promoter. The secreted LOX from glioma cells functions as a potent macrophage chemoattractant to promote macrophage recruitment via activation of the beta1 integrin-PYK2 pathway in macrophages. Consequently, these infiltrating macrophages secrete SPP1 (secreted phosphoprotein 1) which sustains glioma cell survival and stimulates angiogenesis. In human and mouse PTEN-null GBM models, but not PTEN-intact GBM models, LOX inhibition markedly inhibits tumor growth and extends the survival of tumor-bearing mice by decreasing macrophage infiltration, impairing SPP1 expression and attenuating angiogenesis. In silico analysis of human GBM shows that increased YAP1-LOX and b1 integrin-SPP1 signaling positively correlates with higher macrophage density and lower overall survival. Together, the symbiotic glioma (PTEN-YAP1-LOX) and macrophage (beta1 integrin-PYK2-SPP1) interactions provide novel therapeutic targets for this intractable disease.
TMIC-09. MULTIMODAL VISIBLE LIGHT OPTICAL COHERENCE MICROSCOPY AND FLUORESCENCE IMAGING OF GLIOBLASTOMA REGIONAL SAMPLES
Authors: Gesperger Johanna , Lichtenegger Antonia , Roetzer Thomas , Widhalm Georg , Kiesel Barbara , Woehrer Adelheid , Baumann Bernhard 
Published: November 2019

Abstract
Optical coherence tomography (OCT) is an imaging modality based on the inherent backscattering of light within different tissue types. OCT was introduced in the early 1990s and has since become a standard diagnostic tool in ophthalmology. Images can be acquired non-destructively, in real time and three dimensions at micrometer resolution. Only recently, OCT has been increasingly recognized in other fields such as neuroimaging. Here we present a multimodal imaging approach using a custom-built visible light optical coherence microscope (OCM) combined with a fluorescence imaging mode for the evaluation of different tumor compartments in glioblastoma (GB) samples retrieved during 5-aminolevulinic acid (5-ALA) fluorescence-guided surgery. 18 biopsies of ten GB patients were imaged using the visible light OCM system, providing the three-dimensional morphologic structure of the tissue on a cellular level (axial resolution in brain tissue 0.88 µm, penetration depth 100 µm). Attenuation coefficients, i.e., indicators for light penetration and scattering, were calculated for each sample. Tumor-specific contrast enhanced by 5-ALA was evaluated in co-registered images from the fluorescence channel. Samples were ultimately processed for histopathologic work-up and compared to OCM findings. Three different groups of biopsies could be defined based on quantitative 5-ALA fluorescence [normalized between 0 and 1], attenuation [mm-1] and histological H&E stainings: tumor core (n=8; fluorescence [median ± standard deviation]=0.72±0.13, attenuation [median ± standard deviation]=3.9±0.66), infiltration zone (n=6; fluorescence=0.5±0.19, attenuation=4.4±0.5), and adjacent brain parenchyma (n=4; fluorescence=0.3±0.12, attenuation=5.0±0.79). Concurrent increase in fluorescence intensity and cell density was significantly associated with tissue malignancy (tumor core: 3849±1028 nuclei/mm²; brain parenchyma: 1364±236 nuclei/mm². p=0.024). Furthermore, a negative correlation between fluorescence and attenuation coefficient was detected (r=0.51, p=0.032). Aforementioned results suggest that this multimodal imaging setup is a promising approach for non-destructively investigating the three-dimensional morphologic structure at microscopic resolution whilst at the same time leveraging tumor-specific contrast through 5-ALA fluorescence.
TMIC-10. THE ROLE OF THE BRAIN MICROENVIRONMENT IN THE MIGRATION OF BREAST CANCER CELLS IN BRAIN METASTASES
Authors: Kersch Cymon , Muldoon Leslie , Morris DreeAnna , Neuwelt Edward 
Published: November 2019

Abstract

BACKGROUND
Breast cancer brain metastases have poor prognosis and few treatment options. When breast cancer cells invade the brain they interact with the vasculature and resident brain cells including microglia and astrocytes. We hypothesize that brain cells produce factors that enhance the growth and invasion of breast cancer cells in the brain.

METHODS
Human breast cancer cell lines (MDA-MB231BR-HER2 and HCC1954) were inoculated intracranially in athymic rats as xenograft models of brain metastasis. Brains were analyzed for pro-tumorigenic factor expression in the tumor microenvironment using fluorescent immunohistochemistry. In vitro assays assessed factors involved in breast cancer cell proliferation, morphology, and migration.

RESULTS
The tumor xenografts showed infiltration intothe perivascular space. Galectin-3 (Gal3), heparin-binding epidermal growth factor (HB-EGF), and Neuregulin (NRG1), factors known to interact with receptors expressed by breast cancer cells, co-localized with reactive microglia (Gal3) and astrocytes (HB-EGF and NRG1) in and around xenografts. In vitro, these factors individually increased HCC1954 cell proliferation and/or migration. In transwell co-culture assays, BV2 microglial cells increased the migration of HCC1954 cells >25 fold, which was prevented by cilengitide, an inhibitor of αvβ3-integrin cell adhesion protein. ELISA analysis demonstrated that BV2 microglia secrete Gal3 in the presence of HCC1954 cells. Gal3 is known to bind and induce clustering of αvβ3-integrin which is expressed on metastatic breast cancer cells. Immunohistochemistry of clinical specimens revealed that Gal3 is expressed in/around human breast cancer brain metastases.

CONCLUSIONS
These data suggest that factors produced in the tumor microenvironment promote the growth and migration of breast cancer cells in the brain. Gal3, produced and secreted by activated microglia in vitro and expressed in and around brain metastases, increases the invasive capability of breast cancer cells. The interactions of neoplastic cells with the brain environment may provide a target to improve therapy of brain metastases.