bluuebunny/crossref_metadata_2025_split huggingface dataset:
SURG-13. DAY-CASE IMAGE-GUIDED BIOPSY FOR BRAIN TUMOURS: A DECADE OF EXPERIENCE FROM A SINGLE NEUROSURGICAL UNIT IN THE UNITED KINGDOM
Authors: Wykes Victoria , McElligott Simon , Roach Joy , Duffill Jonathan , Weidmann Crispin , Grundy Paul 
Published: November 2019

Abstract

In the United Kingdom widespread adoption of day-case image-guided biopsy (DIB) for brain tumour has yet to develop. We review a decade of experience of DIB for suspected supra-tentorial brain tumour and recommend discharge criteria for patients post-operatively. 30-day complications, post-operative admissions into hospital and patient satisfaction are examined.

METHODS
Published protocols and procedures for DIB of brain tumours were used. Tissue samples were sent for fixed histological preparation without intraoperative neuropathological assessment. All patients undergoing an image-guided biopsy for tumour were retrospectively identified from operative logbooks (01/10/2006–30/09/2016), and information recorded from online records. Patients completed satisfaction questionnaires.

RESULTS
706 image-guided biopsies for supratentorial tumour were performed of which approximately 60% were identified pre-operatively as candidates for DIB. 92% of DIB patients were successfully discharged 6 hours postoperatively. 4.5% of DIB patients were admitted directly from the day-case unit following identification of a postoperative haematoma >2 cm diameter on CT head performed at 4 hours. 3/401 DIB patients (< 1%) required surgical evacuation for the haematoma, all made a full recovery, with no delay to commencing their oncological management. A diagnostic accuracy of 98% was achieved. Overall 90% of patients were satisfied about the timing of their discharge from hospital and 92.5 % felt they had enough medical support following discharge.

DISCUSSION
Conscious sedation with enhanced recovery techniques, lack of intra-operative neuropathological analysis and a stream lined service with robust communication between patients, carers/families and the oncology allied medical professionals has ensured that DIB for diagnosis of tumour is safe, reliable and feasible for most patients and is not associated with increased morbidity or mortality. The procedure is well tolerated with good patient satisfaction. We recommend that patients with a good pre-operative functional baseline, requiring a supra-tentorial biopsy are offered day-case surgery in a dedicated unit specialising in this procedure.
SURG-26. READMISSION FOLLOWING RESECTION FOR PATIENTS WITH BRAIN METASTASES IN THE UNITED STATES
Authors: Kotecha Rupesh , Rubens Muni , Gonzalez-Arias Sergio , Siomin Vitaly , Hall Matthew , Odia Yazmin , Vogelbaum Michael , Mehta Minesh 
Published: November 2019

Abstract

OBJECTIVE
Up to 30% of cancer patients will develop brain metastasis during the course of their systemic disease with a significant proportion undergoing resection of at least one lesion. The objective of the present study was to characterize the rates, predictors, and costs of 30-day readmissions following craniotomy for brain metastases using a nationally representative database.

METHODS
This study was a retrospective analysis of data from the Nationwide Readmissions Database (NRD) from 2010–2014. We included patients who underwent craniotomy for brain metastasis, identified using ICD-9-CM diagnosis (198.3) and procedure (01.59) codes. The primary outcome of the study was unplanned 30-day all-cause readmission rates. Secondary outcomes included predictors and costs of readmissions.

RESULTS
During the study period, there were 44,846 index hospitalizations for patients who underwent resection of brain metastasis. Among this cohort, 17.8% (n=7,965) had unplanned readmissions within the first 30 days after discharge from the index hospitalization. The readmission rate did not change significantly during the study period (P=0.286). The odds of unplanned readmission were significantly greater in patients with thromboembolic complications (aOR, 1.53; 95% CI: 1.18–2.01), patients with Elixhauser comorbidities >3 (aOR, 1.35; 95% CI: 1.22–1.50), male patients (adjusted odds ratio [aOR], 1.29; 95% CI: 1.17–1.42), patients with an initial length of stay ≥5 days (aOR, 1.02; 95% CI: 1.01–1.03). The median per-patient cost for 30-day unplanned readmission was $11,109 and this accounted for a total cost of $132.1 million during the study period.

CONCLUSIONS
Unplanned readmissions after resection for brain metastases involve substantial healthcare expenditures. Though there have been many interventions for improving surgical quality, post-operative care, and cost metrics, unplanned readmission rates have not changed. Key patient-specific variables and high rates of comorbidities should be considered to focus our efforts on patient selection for resection, and for strengthening existing interventions for high-risk patients.
SURG-33. IMMUNO-STIMULATION THROUGH SURGICALLY ADMINISTERED MECHANICAL HIGH INTENSITY FOCUSED ULTRASOUND
Authors: Wang James , Huang Chin-Hsin , Echeagaray Oscar , Amirfakhri Siamak , Blair Sarah , Trogler William , Kummel Andrew , Chen Clark 
Published: November 2019

Abstract

INTRODUCTION
While immunotherapy through anti-PD1 checkpoint inhibition has demonstrated impressive clinical efficacy against a number of tumor types, its application has been ineffective against glioblastomas.

METHODS
We wished to determine whether high intensity focused ultrasound (HIFU) augment the efficacy of anti-PD1 checkpoint inhibition against glioblastomas. HIFU can be surgically administered through low-duty cycle to induce subcellular fragmentation without causing temperature elevation (termed mechanical HIFU). Alternatively, HIFU delivered through high duty cycle can induce foci of temperature elevation and thermal ablation (termed thermal HIFU). We tested the impact of mechanical and thermal HIFU on the anti-glioblastoma effects of the immune checkpoint inhibitor, ipililumab.

RESULTS
In an in vivomurine glioblastoma model, sites targeted by mechanical HIFU exhibited a 10–100 fold increase in accumulation in tumor infiltrating lymphocytes and interferon-γ (IFN-γ) in the presence of PD-1 blockade. At least 75% of mice engrafted with glioblastomas achieved remission when treated with mechanical HIFU and PD-1 blockade. In contrast, none of the mice treated with single therapies achieved durable remission. Likelihood of remission correlated with the abundance of tumor infiltrating lymphocytes (p< 0.001) and IFN- γ levels (p=0.001). The synergy observed between mechanical HIFU and PD-1 blockade was not seen when combining thermal HIFU and PD-1 blockade, suggesting thermal protein denaturation is prohibitive to immune-stimulatory effects of HIFU.

CONCLUSION
Mechanical HIFU, but not thermal HIFU, augments the anti-glioblastoma effects of PD-1 blockade. Our findings inform the utility of HIFU as an immune-adjuvant in glioblastoma therapy that can be surgically administered.
TMIC-04. CANCER STEM CELL GENETIC AND GENOMIC ALTERATIONS DIFFERENTIALLY DICTATE STROMAL CELL REGULATION OF LOW-GRADE GLIOMA GROWTH
Authors: Guo Xiaofan , Pan Yuan , Gutmann David 
Published: November 2019

Abstract

BACKGROUND
Children with the Neurofibromatosis type 1 (NF1) brain tumor predisposition syndrome are prone to the formation of low-grade gliomas (LGGs) of the optic pathway (optic pathway glioma; OPG). While all tumors harbor bi-allelic NF1 gene inactivation, there is significant clinical variability in affected children with respect to tumor growth, associated neurologic deficits, and response to therapy. In order to identify the potential factors that contribute to glioma biological variability, we leveraged a series of Nf1 mutant optic glioma mouse strains with different germline Nf1 gene mutations and secondary genomic alterations.

METHODS
Cancer stem cells (optic glioma stem cells; o-GSCs) were isolated from these Nf1 mutant optic glioma mouse strains, and their intrinsic growth properties and chemokine expression profiles determined.

RESULTS
Differences in the intrinsic o-GSC growth properties did not account for the observed differences in Nf1 optic glioma tumor growth. Instead, Nf1 optic glioma tumor growth correlated with the differential recruitment of T cells and microglia by chemokines produced by the o-GSCs. As such, the collective action of T cells and microglia dictated the level of Ccl5 expression, the key stromal factor that determines murine NF1-associated optic glioma growth.

CONCLUSIONS
Taken together, these observations demonstrate that genomic and genetic differences within the cancer cells create unique Nf1 optic glioma growth patterns through the differential elaboration of chemokines that attract T cells and microglia. GRANT SUPPORT: This work was funded by grants from the National Cancer Institute (1-R01-CA195692-01) and the National Institute of Neurological Disorders and Stroke (1-R35-NS07211-01) to D.H.G, as well as to the Hope Center Viral Vectors Core and the Genome Technology Access Center (UL1-TR000448). Y.P. was supported by a fellowship grant from the James S. McDonnell Foundation.
TMIC-21. TARGETING INVADOPODIA TO BLOCK IONIZING RADIATION-INDUCED GLIOBLASTOMA CELL INVASION
Authors: Decotret Lisa , Bennewith Kevin 
Published: November 2019

Abstract

BACKGROUND
Glioblastoma multiforme (GBM) is a highly heterogeneous and aggressive brain tumour that is considered incurable. The majority of GBM patients have a median survival of 15 months despite undergoing extensive treatment. The principal reason for poor outcome is a high rate of recurrence, often due to the tumours cells escaping therapy by infiltrating into the surrounding healthy brain tissue. Previous work from our lab suggests tumour cells that survive radiation therapy (RT) exhibit a more aggressively metastatic phenotype. We hypothesize that RT may increase GBM cell invasion by promoting the activity of invadopodia. Invadopodia are protrusions of the plasma membrane that secrete matrix metalloproteinases to degrade surrounding tissue. Further understanding of the mechanisms by which RT regulates invadopodial biology may lead to new therapeutic strategies to slow or halt the invasion of GBM cells and extend the lives of patients.

RESULTS
Three human GBM cell lines were exposed to 0, 2, or 5 Gy of ionizing radiation (IR) prior to quantification of cell viability by clonogenic survival assays. Invasion was investigated using a Transwell Matrigel Invasion Assay 48 hours post-IR. Exposure to 2 Gy IR increased invasion of LN229 and U87-MG cells but not LN18 cells. These data suggest that clinically relevant levels of radiation (2 Gy) increases the invasiveness of a subset of GBM cells in vitro. We are currently analyzing proteomic changes in LN229, U87-MG, and LN18 cells post-IR to identify novel drivers of IR-induced GBM cell invasion. Future work will involve genetically or pharmacologically inhibiting the proteins identified via mass spectrometry to determine their role in therapy induced invadopodia-mediated GBM cell invasion. SIGNIFICANCE: Recent evidence suggests tumour cells that survive RT exhibit a more aggressive phenotype. Identifying novel therapeutic targets to limit IR-induced GBM invasion may help to increasing the efficacy of current brain cancer therapy.
TMIC-23. A SEQUENTIAL IMAGING STRATEGY TO STUDY ONCOLYTIC VIRUS INFILTRATION, REPLICATION AND TUMOR MICROENVIRONMENTAL PERTURBATIONS, EX VIVO
Authors: Smalley Munisha , Thyiagarajan Saravanan , Jain Misti , Best Douglas , Saha Suniti , Prasad Komal , Alonzo Emiliy , Hathaway Erin , Henderson Kira , Chiocca Antonio , Lawler Sean , Goldman Aaron 
Published: November 2019

Abstract
The use of oncolytic viruses (OV) as therapeutic agents for glioblastoma multiforme (GBM) is an emerging clinical focus. OV have the potential to reinvigorate the immune contexture in the tumor microenvironment (TME). However, current pre-clinical models are insufficient to study the immune effects of OV. Here, we describe an imaging approach using a human ex-vivo platform to study the effects of OV on tumor-associated immune cells in GBM. Using the rQNestin34.5v.1 herpes simplex virus (rQNestin) we treated human GBM ex-vivo, incorporating autologous patient-derived peripheral-blood mononucleated cells and whole tissue fragments. We treated GBM (n=10) with rQNestin, capable of expressing GFP, and profiled GFP expression as a proxy for replication. We analyzed serial sections of H&E, HSV-1, and multiplex immunohistochemistry (mIHC) to investigate the impact of rQNestin on the spatial context of the immune compartment. Cell Signaling Technology antibodies, CD3e (D7A6E™,ID:85061), CD68 (D4B9C,ID:76437), CD11c (D3V1E,49420), MHC-Class II ((HLA-DRB)LGII-612.14,NA) and Pan-keratin (C11,4545) were optimized for identifying intratumoral T-cells (CD3e+), macrophages (CD68) and dendritic cells (CD11c+MHCII+) in relation to the surrounding tissue architecture (pan cytokeratin). Using the serial-section imaging approach, we overlaid infiltration and replication of rQNestin. Additionally, strategic sectioning identified dynamic spatial alterations in the immune compartment, via visualization of the tumor-immune interface with indications of infiltration and replication. Quantitative pathology showed dynamic re-arrangement of immune cells - in spatial orientation, quantity and localization, relative to the tumor, under rQnestin pressure, ex-vivo. Here, we report that our ex-vivo human tumor model can be used to evaluate the effects of OV in the TME – not only viral replication but also the direct effect on the immune compartment. In particular, we can assess changes in immune subsets post-OV treatment in a 3-D manner, therefore providing greater insight into their spatial arrangement and distribution. These findings could develop our understanding of anti-tumor OV mechanisms.
TMIC-29. METABOLIC INTERACTIONS BETWEEN TREATMENT-RESISTANT SLOW-CYCLING CELLS AND THE IMMUNE SYSTEM IN HIGH-GRADE GLIOMA
Authors: Sayour Elias , Yang Changlin , Tian Guimei , Grippin Adam , Dajac Mariana , Nazareth Brian , Andrews Michael , Karachi Aida , Mendez-Gomez Hector , Stover Brian , Moore Ginger , Flores-Toro Joseph , Divita Bayli , Kresak Jesse , Rahman Maryam , Flores Catherine , Huang Jianping , Harrison Jeffrey , Mitchell Duane , Deleyrolle Loic 
Published: November 2019

Abstract

INTRODUCTION
Intratumoral heterogeneity is increasingly recognized as a determinant of therapy resistance and disease recurrence; this is exemplified by glioblastoma (GBM), one of the most lethal malignancies. We recently revealed that GBM contain cell subpopulations with distinct metabolic requirements, with fast-cycling cells (FCCs) harnessing aerobic glycolysis, and treatment-resistant slow-cycling cells (SCCs) preferentially engaging lipid metabolism. How the different tumor cell populations interact with immune cells and how this metabolic heterogeneity shapes the immune landscape in GBM has yet to be understood. OBJECTIVES: The objectives of this study are to understand the mechanisms of communication in the tumor microenvironment, specifically to characterize the metabolic interactions between SCCs (a therapeutically resistant population of cancer cells that drive disease progression and recurrence) and the immune compartment.

METHODS
The murine glioma cell line KR158 (derived from a Nf1;Trp53 mutant mouse) was used to establish the slow-cycling cell paradigm and metabolic heterogeneity in an immune-competent model of glioma.

RESULTS
Similar to what we observed in patient-derived specimens, mouse KR158-derived SCCs demonstrate tumorigenicity, treatment resistance and up-regulation of stemness programs and lipid metabolic pathways. We determined that tumor progression is regulated by the interaction of SCCs with the immune system and established that these cells are driving a pro-tumorigenic microenvironment via the recruitment of immune suppressive myeloid cells. Importantly, the immune microenvironment shaped by SCCs is marked by specific metabolic features showing enhanced lipid exchange capacities that we propose are exploited by SCCs to support their survival and functions.

CONCLUSION
Our study indicates that SCCs play a pivotal role in shifting the GBM milieu toward an immune regulatory phenotype but importantly reveals an unprecedented metabolic cooperation, which represents a novel therapeutic target to antagonize GBM.
TMIC-31. IMPACT OF IRON ON MACROPHAGE IMMUNE PHENOTYPE IN THE GLIOBLASTOMA TUMOR MICROENVIRONMENT
Authors: Shenoy Ganesh , Madhankumar Achuthamangalam , Slagle-Webb Becky , Mrowczynski Oliver , Schell Todd , Nesterova Darya , Lee Sang , Davalos Dimitrios , Berens Michael , Lathia Justin , Barnholtz-Sloan Jill , Rubin Joshua , Connor James 
Published: November 2019

Abstract
The tumor microenvironment (TME) in glioblastoma presents a significant hurdle to effective immunotherapies as it consists of an immunosuppressive niche that results in inhibition of anti-tumor immunity. Macrophages comprise a large portion of the glioblastoma TME as they are prolific secretors of immunosuppressive cytokines and can comprise of up to 30% of tumor volume. In addition to their crucial role in immune function, macrophages are important players in iron regulation owing to their ability to efficiently sequester and release iron. We studied the impact of iron status in macrophage anti-tumor immune functions and phenotypic plasticity using RAW264.7 macrophages and bone-marrow-derived macrophages (BMDMs). Using RAW264.7 cells, we found that the iron status of macrophages impacts their immune function by modulating expression of the co-stimulation membrane proteins CD80 and CD86 as well as the mannose receptor CD206. Interestingly, the iron-mediated immunomodulation was dependent on the formulation of iron with nanoparticle formulations such as ferumoxytol (Fe-NP) upregulating CD80, CD86, and decreasing CD206 while ferric ammonium citrate (FAC) downregulated CD80, CD86 and upregulated CD206. We analyzed expression of inflammatory cytokines in BMDMs with multiplex cytokine analysis and found that both FAC and Fe-NP increased expression of the chemotactic signals CXCL10, CCL1, CCL3, and CCL4. Additionally, we found that iron status impacts the ability of macrophages to repolarize from an inflammatory, immune-activating phenotype into an immunosuppressive phenotype upon exposure to glioblastoma tumor-conditioned media. We used qRT-PCR to examine gene expression of the tumor immunity-related genes TNFa, IL1B, NOS2, and IL10 and found that iron loaded RAW264.7 macrophages stimulated with lipopolysaccharide resisted repolarization into an immunosuppressive phenotype 24 hours after exposure to glioblastoma tumor-conditioned media. Our results suggest that understanding the link between iron status and immune function in the tumor microenvironment may be an important step in improving therapies against glioblastoma.
TMIC-33. INVESTIGATING S1PR3-MEDIATED GLIOBLASTOMA INVASION MECHANISMS USING 3D HYDROGEL - TISSUE CULTURE INSERT MODEL
Authors: Tate Kinsley , Chase Cornelison R , Bhargava Saloni , Munson Jennifer 
Published: November 2019

Abstract
Glioblastoma (GBM) is the most common malignant brain tumor and is characterized by its ability to invade into the surrounding microenvironment of the brain. The invasiveness of GBM makes this cancer extremely hard to treat, leading to a median patient survival of less than 16 months. Interactions between the tumor and surrounding tumor microenvironment (TME) play a key role in glioma invasion. Previous data from our xenograft mouse tumor implant model displays increased invasion in regions of fluid flow. Using this model, we identified an upregulation of sphingosine-1-phosphate receptor 3 (S1PR3) in the TME in regions of flow. We used a syngeneic GL261 mouse model and found S1PR3-/- mice display decreased flow-mediated glioma invasion in comparison to wild type mice. To further understand the individual contributions of the S1PR3-presenting cells in the TME, we have examined the role of S1PR3 in our in vitro system. This system is based on patient derived cellular ratios and incorporates collagen-hyaluronan hydrogels placed within 96 well tissue culture insert plates. The tunability of this model allows for interactions between various cell types and the impact of fluid flow on invasion to be examined. To examine the role of S1PR3 on invasion, TY52156 (an S1PR3 inhibitor) was applied to different cellular combinations including: G34 alone (a patient-specific cell line), +astrocytes, +microglia, +TME (astrocytes and microglia). A significant decrease in G34 flow stimulated invasion was observed with TY52156 but only in the presence of the TME or microglia alone. This data suggests that TY52156 thwarts the effects of flow and the microglia contributions to invasion. To further this work we plan to identify and evaluate other S1PR3-expressing cell types from mouse tumor implant samples using immunohistochemistry staining. This information will be used to determine further components that can be examined in our in vitro model.
TMIC-54. COMPARISON OF CELLULAR FEATURES AT AUTOPSY IN GLIOBLASTOMA PATIENTS WITH STANDARD TREATMENT OF CARE AND TUMOR TREATMENT FIELDS
Authors: Lowman Allison , Barrington Alexander , Cochran Elizabeth , Connelly Jennifer , Mueller Wade , LaViolette Peter 
Published: November 2019

Abstract

BACKGROUND
The FDA has approved the use of tumor treatment fields (TTFields) on patients with recurrent glioblastoma (GBM). A recent clinical trial showed that the use of TTFields along with standard treatment of care resulted in increased quality of life and survival over five years. TTFields work by delivering low intensity electric fields that disrupt GBM tumor cell division. This works to slow or even stop GBM tumor cells from dividing.

METHODS
Brain tissue samples were taken from thirteen GBM patients, diagnosed at autopsy. Three patients underwent standard clinical treatment and ten patients underwent TTField therapy in addition to the standard. Tissue samples were acquired from regions where enhancement was seen on the last clinical T1 plus contrast MRI prior to death. Samples were paraffin embedded and stained with hematoxylin and eosin (H&E) and Ki67. The slides were digitized, allowing analysis of the cellular features.

RESULTS
Using the H&E stained slides we compared cellular density between both groups. We found that there was not a noticeable difference in the nuclei density in areas of tumor between the groups. The percent of positive nuclei on the Ki67 stained slides was calculated and there was increased mitotically active cells per area of tissue in patients that did not undergo TTField therapy.

CONCLUSION
These findings suggest there is a difference in the cellular features in areas of tumor in patients treated with TTFields compared to those with standard treatment alone. Additional research needs to be done evaluating more patients.