bluuebunny/crossref_metadata_2025_split huggingface dataset:
SURG-02. NEUROSURGICAL RESECTION FOR LOCALLY RECURRENT BRAIN METASTASIS
Authors: Hulsbergen Alexander , Abunimer Abdullah , Ida Fidelia , Kavouridis Vasileios , Cho Logan , Tewarie Ishaan , Mekary Rania , Schucht Philippe , Phillips John , Verhoeff Joost , Broekman Marike , Smith Timothy 
Published: November 2021

Abstract

BACKGROUND
In patients with locally recurrent brain metastases (LRBMs), the role of (repeat) craniotomy is controversial. This study aimed to analyze long-term oncological outcomes in this heterogeneous population.

METHODS
Craniotomies for LRBM were identified from a tertiary neuro-oncological institution. First, we assessed overall survival (OS) and intracranial control (ICC) stratified by molecular profile, prognostic indices, and multimodality treatment. Second, we compared LRBMs to propensity score-matched patients who underwent craniotomy for newly diagnosed brain metastases (NDBM).

RESULTS
Across 180 patients, median survival after LRBM resection was 13.8 months and varied by molecular profile, with &gt;24 months survival in ALK/EGFR+ lung adenocarcinoma and HER2+ breast cancer. Furthermore, 102 patients (56.7%) experienced intracranial recurrence; median time to recurrence was 5.6 months. Compared to NDBMs (n = 898), LRBM patients were younger, more likely to harbor a targetable mutation and less likely to receive adjuvant radiation (p &lt; 0.05). After 1:3 propensity matching stratified by molecular profile, LRBM patients generally experienced shorter OS (hazard ratio 1.67 and 1.36 for patients with or without a mutation, p &lt; 0.05) but similar ICC (hazard ratio 1.11 in both groups, p &gt; 0.20) compared to NDBM patients with similar baseline. Results across specific molecular subgroups suggested comparable effect directions of varying sizes.

CONCLUSIONS
In our data, patients with LRBMs undergoing craniotomy comprised a subgroup of brain metastasis patients with relatively favorable clinical characteristics and good survival outcomes. Recurrent status predicted shorter OS but did not impact ICC. Craniotomy could be considered in selected, prognostically favorable patients.
SURG-13. THE TENTATIVE APPLICATION OF EN BLOC CONCEPT IN THE PEDIATRIC BRAIN TUMOR: EXPERIENCE FROM A LARGE PEDIATRIC CENTER IN CHINA
Authors: Cao Liangliang , Ma Jie 
Published: November 2021

Abstract

BACKGROUND
The less allowable blood loss and tolerance of intraoperative blood loss of children lead to the high rate of massive blood transfusion. The surgical concepts of en bloc resection may contribute to the improvement of brain tumor resection.

OBJECTIVE
To investigate the effects of en bloc concept on short outcomes of pediatric brain tumors and factors associated with the application of en bloc concept.

METHODS
According to the surgical concept involved, the patients were divided into three subgroups-complete en bloc concept, partial en bloc concept and piecemeal concept. The matching-comparison(en bloc group consisting of the first two subgroups and piecemeal group) was conducted to investigate the effect of the en bloc concept on the short-term outcomes. Then the patient data after January 2018, when the en bloc concept was routinely integrated into brain tumor surgery in our medical center, were reviewed and analyzed to find out the predictors associated with the application of en bloc concept.

RESULTS
In the en bloc group, the perioperative outcomes, including hospital stay(p=0.001), PICU stay(p=0.003), total blood loss(p=0.015), transfusion rate(p=0.005) and complication rate(p=0.039), were all significantly improved. The multinomial logistic regression analysis showed that tumor volume, bottom vessel, and imaging features, like encasing nerve or pass-by vessel, finger-like attachment, ratio of “limited line” and ratio of “clear line” remained independent predictors for the application of en bloc concept in our medical center.
TAMI-01. BRAIN METASTASES: CURRENT LITERATURE REVIEW
Authors: Raval Ruchi , Pandya Aadi , Behl Jaspreet , Raval Sumul 
Published: November 2021

Abstract

PURPOSE
As more information is gathered about brain metastases, it still remains that the current prognosis of brain metastases is very poor. Due to this, it is imperative that physicians are aware of the most important components regarding brain metastases. This literature review will encompass the most current literature in order to highlight the most crucial information.

METHODS
All mentioned studies and literature reviews cited in the paper were obtained through various sites, and were published between 1996 and 2017. The main components that were required from the papers reviewed included where in the body the brain metastases originated from, where in the brain they tended to spread to, what the signs and symptoms typical of patients with brain metastases are, and what the options are in terms of treatment.

RESULTS
Using the results from a variety of studies performed within the past three decades, it is apparent that brain metastases most commonly originate from, in order of increasing frequency, lung cancer, breast cancer, melanoma, and colorectal cancer. In addition, it is reaffirmed that the magnetic resonance imaging (MRI) is the best diagnostic tool to be used when dealing with brain metastases. The most frequent signs and symptoms of a brain metastases include cognitive changes, headaches, weakness, and seizures. Finally, supportive treatment includes use of corticosteroids, antiepileptic drugs (AEDs), and anticoagulation therapy. Definitive treatment for brain metastases varies based on size, location, and prevalence in the brain, but the most effective options include chemotherapy, radiation therapy, and surgery.

CONCLUSIONS
The study’s results confirm the need for more research to be done regarding brain metastases, and better options to increase the survival of patients.
TAMI-04. OLFACTORY RECEPTOR 5B21 DRIVES BREAST CANCER BRAIN METASTASIS THROUGH STAT3/NFΚB/CEBPΒ PATHWAY
Authors: Li Mao , Schweiger Markus , Ryan Daniel , Nakano Ichiro , Carvalho Litia , Tannous Bakhos 
Published: November 2021

Abstract
Olfactory receptors (ORs), responsible for the sense of smell, play an essential role in various physiological processes outside the nasal epithelium, including cancer. In breast cancer, however, the expression and function of ORs remain understudied. We established a breast cancer metastasis model by intracardiac injection of MDA-MB-231 (231P) in immunocompromised mice and produced a series of derivative cell lines from developed metastatic sites, including the brain-seeking clone (231Br). We examined the significance of ORs transcript abundance in primary and metastatic breast cancer to different tissues, including the brain, bone, and lung. While 20 OR transcripts were differentially expressed in distant metastases, OR5B21 displayed high expression in all three metastatic sites with respect to the primary tumor, especially in brain metastasis with 13 fold higher than the primary site. Metastatic clones showed distinguishing higher invasion biological characteristics compared to parental cells in vivo and in vitro. Knockdown of OR5B21 significantly decreased the invasion and migration of MDA-MB-231 Brain-seeking metastatic cell as well as metastasis to different organs, including the brain, while overexpression of OR5B21 had the opposite effect. Mechanistically, OR5B21 expression was associated with epithelial to mesenchymal transition through the STAT3/NFkB/CEBPβ signaling pathway. We propose OR5B21 (and potentially other ORs) as a novel oncogene contributing to breast cancer brain metastasis and a potential target for adjuvant therapy.
TAMI-08. THE CCL2-CCR2 ASTROCYTE-CANCER CELL AXIS IN TUMOR EXTRAVASATION AT THE BRAIN
Authors: Hajal Cynthia , Shin Yoojin , Li Leanne , Serrano Jean Carlos , Jacks Tyler , Kamm Roger 
Published: November 2021

Abstract
Although brain metastases are common in cancer patients, little is known about the mechanisms of extravasation across the blood-brain barrier (BBB), a key step in the metastatic cascade that regulates the entry of cancer cells into the brain parenchyma through its selective endothelial barrier. Progress in this area has been impeded by challenges in conducting high spatio-temporal resolution imaging in vivo and isolating factors and cellular interactions directly contributing to extravasation rather than cancer survival and proliferation in the brain tissue. To address these limitations, we engineered a three-dimensional in vitro BBB microvascular model with endothelial cells derived from induced pluripotent stem cells, brain pericytes, and astrocytes, into which we perfused cancer cells to recapitulate their circulation and extravasation at the BBB. With this platform, we revealed that astrocytes play a major role in promoting cancer cell transmigration via their secretion of C-C motif chemokine ligand 2 (CCL2). We found that this chemokine promoted the chemotaxis and chemokinesis of cancer cells via their C-C chemokine receptor type 2 (CCR2), with no significant changes in vascular permeability. These findings were validated in vivo, where CCR2-deficient cancer cells exhibited significantly reduced cancer cell arrest and transmigration in mouse brain capillaries. Our results attest to the translational value of our BBB-on-a-chip model and reveal that the CCL2-CCR2 astrocyte-cancer cell axis plays a fundamental role in extravasation and consequently metastasis to the brain.
TAMI-17. INDUCTION OF SYNTHETIC LETHALITY BY ACTIVATION OF MITOCHONDRIAL CLPP AND INHIBITION OF HDAC1/2 IN GLIOBLASTOMA
Authors: Nguyen Trang , Shang Enyuan , Schiffgens Salveena , Torrini Consuelo , Bianchetti Elena , Shu Chang , Akman Hasan Orhan , Prabhu Varun , Allen Joshua , Westhoff Mike-Andrew , Karpel-Massler Georg , Siegelin Markus D 
Published: November 2021

Abstract
Activation of the mitochondrial ClpP protease is an innovative therapeutic concept and the identification of synthetic lethal interactions may foster the development of novel therapies for glioblastoma (GBM). By integration of a transcriptome, metabolite and U-13C-glucose tracing analyses, we showed that activation of the mitochondrial ClpP protease through constitutively active ClpP (Y118A) or utilization of second-generation imipridone compounds (ONC206 and ONC212) in combination with genetic interference of HDAC1 and HDAC2 as well as with global (Panobinostat) and selective (Romidepsin) HDAC inhibitors caused synergistic reduction of viability in established, neuro-sphere and patient-derived xenograft (PDX) cultures of human GBM, which was mediated by interference with tricarboxylic acid cycle activity and GBM cell respiration. Notably, human astrocytes were significantly less susceptible to the combination treatment of HDAC-inhibitors and ClpP activators. The reduction of GBM viability occurred independent of TP53 status and was accompanied by activation of cell death with apoptotic features along with cleavage of caspases regulated chiefly by Bcl-xL and Mcl-1. Importantly, knockdown of the ClpP protease or ectopic expression of a ClpP D190A mutant almost completely rescued from the inhibition of oxidative energy metabolism as well as from the reduction of cellular viability by ClpP activators and the combination treatment, suggesting critical involvement of this protein. Finally, utilizing GBM PDX models, we demonstrated that the combination treatment of HDAC-inhibitors and imipridones reduced tumor growth and prolonged host survival more potently than single treatments or vehicle in vivo. Collectively, these observations suggest that the efficacy of HDAC inhibitors might be significantly enhanced through ClpP activators in model systems of human GBM.
TAMI-22. SEGMENTATION OF DISTINCT TUMOR HALLMARKS OF GLIOBLASTOMA ON DIGITAL HISTOPATHOLOGY USING A HIERARCHICAL DEEP LEARNING APPROACH
Authors: Sandino Alvaro , Verma Ruchika , Chen Yijiang , Becerra David , Romero Eduardo , Tiwari Pallavi 
Published: November 2021

Abstract

PURPOSE
Glioblastoma is a highly heterogeneous brain tumor. Primary treatment for glioblastoma involves maximally-safe surgical resection. After surgery, resected tissue slides are visually analyzed by neuro-pathologists to identify distinct histological hallmarks characterizing glioblastoma including high cellularity, necrosis, and vascular proliferation. In this work, we present a hierarchical deep learning-based strategy to automatically segment distinct Glioblastoma niches including necrosis, cellular tumor, and hyperplastic blood vessels, on digitized histopathology slides.

METHODS
We employed the IvyGap cohort for which Hematoxylin and eosin (H&E) slides (digitized at 20X magnification) from n=41 glioblastoma patients were available. Additionally, expert-driven segmentations of cellular tumor, necrosis, and hyperplastic blood vessels (along with other histological attributes) were made available. We randomly employed n=120 slides from 29 patients for training, n=38 slides from 6 cases for validation, and n=30 slides from 6 patients to feed our deep learning model based on Residual Network architecture (ResNet-50). ~2,000 patches of 224x224 pixels were sampled for every slide. Our hierarchical model included first segmenting necrosis from non-necrotic (i.e. cellular tumor) regions, and then from the regions segmented as non-necrotic, identifying hyperplastic blood-vessels from the rest of the cellular tumor.

RESULTS
Our model achieved a training accuracy of 94%, and a testing accuracy of 88% with an area under the curve (AUC) of 92% in distinguishing necrosis from non-necrotic (i.e. cellular tumor) regions. Similarly, we obtained a training accuracy of 78%, and a testing accuracy of 87% (with an AUC of 94%) in identifying hyperplastic blood vessels from the rest of the cellular tumor.

CONCLUSION
We developed a reliable hierarchical segmentation model for automatic segmentation of necrotic, cellular tumor, and hyperplastic blood vessels on digitized H&E-stained Glioblastoma tissue images. Future work will involve extension of our model for segmentation of pseudopalisading patterns and microvascular proliferation.
TAMI-27. METABOLIC MANIPULATION OF T CELLS TO TREAT BRAIN TUMORS
Authors: Tian Guimei , Jin Linchun , Doshi Devshri , Karachi Aida , Dajac Mariana , Pohl-Guimaraes Fernanda , Moore Ginger , Rahman Maryam , Flores Catherine , Sarkisian Matthew , Huang Jianping , Mitchell Duane , Deleyrolle Loic 
Published: November 2021

Abstract

INTRODUCTION
Glioblastoma are a challenge for neuro-oncologists and current therapies are minimally effective. Standard-of- care treatment is almost inevitably followed by disease recurrence. Adoptive T cell transfer has emerged as a viable therapeutic for brain malignancies. While promising, the efficacy of this approach is often limited by a complex immunosuppressive tumor microenvironment. These complexities mean that more sophisticated T cell products are required.

OBJECTIVES
The brain tumor microenvironment provides local restraints via metabolic competition suppressing antitumor immunity, specifically inhibiting infiltration and tumoricidal functions of host and adoptively transferred tumor-reactive T cells. The overall goal of this project is to test new treatments to reverse immune dysfunction in cancer through the regulation of T cell metabolic signaling. We propose that modulating glucose pathway in T cells can potentiate their anti-tumor activity once adoptively transferred.

METHODS
T cells glucose metabolic pathway was modulated via glucose transporters overexpression. The functionality of metabolically modified T cells was investigated in murine and human models.

RESULTS
We demonstrated the existence of a competition for glucose between T cells and tumor cells, with tumor cells imposing glucose restriction mediating T cell hyporesponsiveness. Overexpression of glucose transporters such as Glut1 and Glut3 increased T cell glucose utilization and provide survival/growth advantage and enhanced T cell activation in glucose-restricted conditions. We also established that glucose transporter overexpression improves intratumoral infiltration of adoptively transferred T cells.

CONCLUSION
This project integrates fundamental concepts of tumor and immune metabolism in the design of immunotherapy and confirms that immunometabolism represents a viable target for new cancer therapy to treat brain tumors.
TAMI-36. TAMEP ARE BRAIN TUMOR PARENCHYMAL CELLS CONTROLLING NEOPLASTIC ANGIOGENESIS AND PROGRESSION
Authors: Kälin Roland , Cai Linzhi , Li Yuping , Hellmann Ines , Glass Rainer 
Published: November 2021

Abstract
Aggressive brain tumors like glioblastoma depend on support by their local environment and subsets of tumor-parenchymal cells may promote specific phases of disease-progression. We investigated the glioblastoma microenvironment with transgenic lineage-tracing models, intravital imaging, single-cell transcriptomics, immunofluorescence analysis as well as histopathology and characterized a previously unacknowledged population of tumor-associated cells with a myeloid-like expression profile (TAMEP) that transiently appeared during glioblastoma growth. TAMEP of mice and humans were identified with specific markers. Strikingly, TAMEP did not derive from microglia or peripheral monocytes but were generated by a fraction of CNS-resident, SOX2-positive progenitors. Abrogation of this progenitor cell-population, by conditional Sox2-knockout, drastically reduced glioblastoma-vascularization and -size. TAMEP manipulation profoundly altered vessel function and strongly attenuated the blood-tumor barrier. Hence, our data indicate TAMEP and their progenitors as new targets for glioblastoma therapy.
TAMI-58. TARGETING GLIOBLASTOMA BY ACTIVATING VIRAL SPECIFIC TISSUE-RESIDENT MEMORY T CELLS
Authors: Ning Jianfang , Gavil Noah , Wu Shaoping , Ma Jun , Li Ming , Grigore Florina , Dhawan Sanjay , Masopust David , Chen Clark , Rosato Pamela 
Published: November 2021

Abstract
Immunotherapy with the success of checkpoint blockade brings hope for cancer treatment with enduring or complete responses in various types of advanced malignancies, however, it has not benefited a number of so called “cold tumors”, such as glioblastoma multiforme (GBM), the most common and aggressive adult brain cancer. GBM is invariably lethal with a median survival of less than 15 months and characterized by a highly immunosuppressive tumor microenvironment, which desires new means of GBM immune-reactivation. Tissue-resident memory CD8+ T (TRM) cells are non-recirculating memory T cell subpopulation that resides permanently in peripheral tissues. TRM cells provide long-lived protective immunity against not only local pathogen infection but also tumor development through immediate effector function and recruitment of circulating immune cells upon antigen re-exposure. In this study, we found that memory T cells specific to some common human viruses that have infected almost everybody exist in clinical GBM specimens and can be activated by viral peptides, which are MHC I restricted CD8+ T cell epitopes derived from those viruses. In orthotopic GBM immunocompetent mouse models, we detected abundant virus specific TRM cells in the tumor microenvironment of GBMs intracranially established in mice that were previously exposed to the virus. Excitingly, intratumoral injection of viral peptides stimulated the reactivation of TRM cells, indicated by secretion of immuno-stimulatory cytokines, and demonstrated significant anti-tumor efficacy. This study provides proof of principle for TRM cell-based GBM therapy, which is a novel therapeutic paradigm with the translational potential for this deadly malignancy.
TAMI-61. EXAMINING THE ROLE OF HYPOXIA INDUCED GENES CXCR4 AND NXPH4 IN INVASION OF HYPOXIC GLIOBLASTOMA CELLS
Authors: Marallano Valerie , Sattiraju Anirudh , Zou Hongyan , Friedel Roland 
Published: November 2021

Abstract
Hypoxia (low oxygen) has been associated with adverse effects in tumor biology by exaggerating the capabilities of invasion, proliferation, and survival of tumor cells within the tumor microenvironment. We engineered glioblastoma (GBM) proneural cells with a novel hypoxia reporter, HRE-UnaG, to study areas of tumor hypoxia and the effects that these hypoxic cells have on tumorigenesis. Single cell RNA-seq analysis from a mouse intracranially injected with our HRE dUnaG GBM cells revealed a shift to a mesenchymal state upon hypoxia (detected by expression of UnaG). Two genes, CXCR4 and NXPH4, were identified as being specifically induced in the hypoxic population. Our studies focus on the hypothesis that these two hypoxia induced genes, CXCR4 and NXPH4, are upregulated in hypoxic GBM cells, which may allow tumor cells to become more aggressive and resistant to conventional forms of therapies. GBM cells will be transduced with lentiviral vectors for Dox inducible shRNA knockdown of CXCR4 or NXPH4 to test specific contribution of these genes to the phenotype of the hypoxic population, with particular focus on the change in invasion and overall tumor burden upon gene silencing.
TAMI-69. NF1 MUTATION DRIVES NEURONAL ACTIVITY-DEPENDENT OPTIC GLIOMA INITIATION
Authors: Pan Yuan , Hysinger Jared , Barron Tara , Schindler Nicki , Cobb Olivia , Guo Xiaofan , Yalçın Belgin , Anastasaki Corina , Mulinyawe Sara , Ponnuswami Anitha , Scheaffer Suzanne , Ma Yu , Chang Kun-Che , Xia Xin , Toonen Joseph , Lennon James , Gibson Erin , Huguenard John , Liau Linda , Goldberg Jeffrey , Monje Michelle , Gutmann David 
Published: November 2021

Abstract
Neurons have recently emerged as essential cellular constituents of the tumor microenvironment, where their activity increases the growth of a diverse number of solid tumors. While the role of neurons in tumor progression has been previously demonstrated, the importance of neuronal activity to tumor initiation is less clear, particularly in the setting of cancer predisposition syndromes. In the Neurofibromatosis-1 (NF1) cancer predisposition syndrome, in which tumors arise in close association with nerves, 15% of individuals develop low-grade neoplasms of the optic pathway (optic pathway gliomas [OPGs]), during early childhood, raising the intriguing possibility that postnatal light-induced optic nerve activity drives tumor initiation. Here, we employ an authenticated murine model of Nf1-OPG to demonstrate that stimulation of optic nerve activity increases optic glioma growth, while decreasing visual experience via light deprivation prevents tumor formation and maintenance. We show that Nf1-OPG initiation depends on visual experience during a developmental period susceptible to tumorigenesis. Germline Nf1 mutation in retinal neurons results in aberrantly high optic nerve neuroligin-3 (Nlgn3) shedding in response to retinal neuronal activity. Moreover, genetic Nlgn3 loss or pharmacological inhibition of Nlgn3 shedding blocks murine Nf1 optic gliomagenesis and progression. Collectively, these studies establish an obligate role for neuronal activity in the development of certain brain tumors, elucidate a therapeutic strategy to reduce OPG incidence or mitigate tumor progression, and underscore the role of Nf1 mutation-mediated dysregulation of neuronal signaling pathways in the NF1 cancer predisposition syndrome.