bluuebunny/crossref_metadata_2025_split huggingface dataset:
TMOD-03. A SWINE MODEL OF GLIOBLASTOMA INDUCED BY SOMATIC GENE MODIFICATION
Authors: Taisto Mandy , Tschida Barbara , Coutts Alexander , Campbell Jarryd , Corbiere Stanislas , Duerre Dylan , Watson Adrienne 
Published: November 2021

Abstract
Glioblastoma (GBM) is the most common and malignant primary brain tumor. Novel therapeutic development for GBM is desperately needed, as the standard of care universally fails to cure patients and the 5-year survival rate remains extremely low. GBM therapeutic development is hampered by the lack of relevant preclinical models for preclinical studies. To mitigate this problem, we have developed a genetic model of GBM in outbred, immune-proficient swine which have comparable brain size and anatomy to humans. We developed methods for introducing genome engineering tools to minipig brain in vivo by direct injection of gene delivery reagents to the lateral ventricle, altering major signaling pathways frequently changed in human GBM. Using this technique, we have delivered a combination of expression vectors for oncogenes and targeted nucleases to disrupt tumor suppressor genes commonly altered in human GBM. We have altered six major human GBM-associated signaling pathways and modeled molecular GBM subclasses. We have also engineered a secreted tumor reporter that can be used to monitor tumor size through a simple blood test. This somatic cell gene-modification platform we have developed in the minipig allows us to reproduce the genetic heterogeneity seen in GBM and understand the impact of the tumor microenvironment, immune system, and response to therapy. This minipig model of GBM Is being used to test the standard of care against novel therapies in preclinical studies, and biopsy, surgical, imaging, and radiation therapy techniques are being optimized in this mode to improve clinical trial success rates and patient outcomes. Funding for this study is provided by the National Institutes of Health though SBIR grant # 1R43CA235837-01A1.
TMOD-05. GENETIC AND MOLECULAR PROPERTIES OF LONG-TERM PROLIFERATING TUMORSPHERE -FORMING GLIOMA DERIVED CELLS
Authors: Kijima Noriyuki , kanematsu Daisuke , Shofuda Tomoko , Yoshioka Ema , Yamamoto Atsuyo , Handa Yukako , Fukusumi Hayato , Katsuma Asako , Moriuchi Shusuke , Nonaka Masahiro , Okita Yoshiko , Tsuyuguchi Naohiro , Uda Takehiro , Kawashima Toshiyuki , Fukai Junya , Kodama Yoshinori , Mano Masayuki , Higuchi Yuichiro , Suemizu Hiroshi , Kanemura Yonehiro 
Published: November 2021

Abstract
Long-term proliferating tumorsphere (LTP-TS)-forming glioma derived cells (GDCs) and patient derived xenografts (PDXs) are essential tools for translational research for glioma. However, only small subsets of glioma samples are established as LTP-TS and/or PDXs and little is known about the genetics and molecular properties of LTP-TS -forming GDCs and PDX. In this study, we aim to analyze the characteristics of LTP-TS -forming GDCs and PDXs. We tried primary sphere cultures from 56 glioma patient-derived samples and established 14 LTP-TS -forming GDCs out of 48 glioblastoma samples and no long-term sphere culture was isolated from grade3 and grade 2 gliomas. LTP-TS -forming GDCs had self-renewal ability and possessed certain multipotency. However, they significantly less expressed SOX1 FOXG1 and TUBB3, whereas they expressed LGALS1 significantly higher than normal neural stem/progenitor cells. In addition, we found that LTP-TS -forming GDCs shared the same genetic profiles with original patients’ tumors. Furthermore, we investigated the genetic differences between the glioma tissues which were successfully established as LTP-TS -forming GDCs and those which were not. We found that glioma tissues with TERT promotor mutations and triple CNA (EGFR, CDKN2A, and PTEN loci) are significantly established as LTP-TS -forming GDCs. Lastly, we next investigated in vivo characteristics of glioma PDXs. We have injected glioma PDXs lines into immunodeficient mice and histopathologically analyzed the characteristics of xenografts. Each xenograft well recapitulated histological features of original patients’ tumors and tumor cells remarkably invade through subventricular zone. In conclusion, each LTP-TS -forming GDCs and PDXs had various gene expression profiles, reflecting intratumoral and interpatient heterogeneities of glioma. In addition, TERT promotor mutations and triple CNA significantly correlated with success rate of LTP-TS -forming GDCs. These findings will be of use and advance the preclinical and translational researches of glioma.
TMOD-22. DIFFERENTIAL DRUG SENSITIVITY ANALYSIS IN PAIRED PATIENT-DERIVED CELL LINES OF GLIOBLASTOMA
Authors: Panovska Dena , Shetty Aniket , Derweduwe Marleen , Claeys Annelies , Van der Voordt Marine , Smets Tina , Versele Matthias , Monaco Giovanni , De Moor Bart , Chaltin Patrick , Clement Paul , Ligon Keith , De Vleeschouwer Steven , Sciot Raf , Pey Jon , Antoranz Asier , De Smet Frederik 
Published: November 2021

Abstract
Glioblastoma (GBM) remains the most aggressive adult brain tumour with dismal prognosis. Even when treated by the most optimal standard-of-care modalities, disease progression remains consistently inevitable. Understanding how tumours evolve from a newly diagnosed to a recurrent setting is therefore critical, but research models to functionally test how therapeutic interventions evolve accordingly remain scarce. Here, we describe our efforts to develop paired models including newly diagnosed and recurrent GBM cell lines derived from the same patients. Overall, we collected 50 tumour samples originating from 24 patients at different time points in their treatment scheme. This resulted in the generation of 27 models overall, from which 18 originated from 9 patients at different timepoints. The latter were subsequently investigated extensively. First, using genomic profiling, we consistently observed an increase in mutational burden and chromosomal aberrations in the recurrent samples, while transcriptomic profiling showed that tumour subtypes evolved in a very patient-specific way. A large fraction of the recurrent models showed resistance to temozolomide (TMZ), which coincided with a downregulation of DNA repair (MMR) pathways or mutations. Half of the tested models also acquired resistance to radiation therapy. Next to standard-of-care therapy, we investigated several small molecule inhibitors that are currently in clinical evaluation, which also showed differential sensitivity. Overall, the developed paired cell lines recapitulate the most important features related to tumour recurrence, and offer the opportunity for more elaborate dependency screening efforts.
CNTM-04. Alterations in structural connectomic properties associated with neurocognitive changes following glioma resection
Authors: Noll Kyle , Mitchell Drew , Chen Henry , Wefel Jeffrey , Kumar Vinodh , Hou Ping , Ferguson Sherise , Rao Ganesh , Johnson Jason , Schomer Donald , Prabhu Sujit , Liu Ho-Ling 
Published: November 2021

Abstract

BACKGROUND
Patients with brain tumors often experience decline in neurocognitive functioning (NCF) following surgical tumor resection. Connectomic studies have begun to uncover how abnormalities to underlying cerebral networks contribute to NCF deficits; however, few studies have investigated relationships between pre- to postoperative changes in structural connectomics and NCF.

METHODS
Fifteen right-handed adults with left perisylvian tumors underwent MRI of the brain with diffusion tensor imaging (DTI) and neuropsychological assessment before and after awake tumor resection. Graph theoretical analysis was applied to DTI-derived connectivity matrices to calculate structural network properties. Structural network properties and NCF measures were compared across the pre- to postoperative periods with matched pairs Wilcoxon signed-rank tests. Associations between pre- to postoperative change in network properties and change in NCF were determined with Spearman rank-order correlations (ρ).

RESULTS
Nearly 90% of the sample showed postoperative decline on 1 or more NCF measures. Significant postoperative NCF decline was found across measures of verbal memory, processing speed, executive functioning, receptive language, and the Clinical Trial Battery Composite (CTB COMP) index. Regarding connectomic properties, significant postoperative changes were observed in global and local efficiency, characteristic path length, clustering coefficient, betweenness centrality, and assortativity, with medium effect sizes. Significant associations (ρ = .59 to .62, all p &lt; .05) were observed between changes in aspects of NCF and connectomic properties.

CONCLUSIONS
Decline in NCF was common following resection and some postoperative outcomes were associated with changes in structural connectomic properties following surgery.
CNTM-05. Left hemisphere gliomas induce a plastic bi-hemispheric language network further characterized by lobe specific glioma data
Authors: Ramsey Matthew , Tripathi Shashwat , Saxena Mohit , Tate Matthew 
Published: November 2021

Abstract
Primary brain tumors are among the most burdensome diagnoses patients can receive as they often carry with them externally obvious and significant detriments to motor and speech. The stroke model is severely limited by the inherent nature of the insult to the brain: binary, relatively instantaneous and defined by vascular boundaries. We instead have chosen to study glioma-induced neuroplasticity in patients with gliomas as presentation is over a significantly longer time course with a gradient of insult to language activation areas instead of immediate ablation. Chart review was conducted on 545 patients who completed fMRI imaging from 2013–2019 while completing 1+ of the following language tasks: antonyms, reading comprehension, rhyming, word generation and picture naming. A total of 117 patients’ fMRI scans were included in the final analysis which entailed both a cluster-based analysis in FSL and a 34 gyral, mask-based analysis using FEATquery. Right hemisphere gliomas (RHG) were first established as a reliable control group by averaging anatomically significant voxels across all five language tasks (LT) yielding a core conserved network. Left hemisphere gliomas (LHG) were then directly compared to the RHG language tasks. We found LHG induced global reorganization of the conserved language network with little evidence for direct homologous recruitment of functional structures. Instead, a generalized right hemisphere recruitment is observed with 87% of non-zero masks shifting their laterality index to the right hemisphere. Furthermore, in each of the five LT, the LHG activates fewer total suprathreshold voxels in both the mask and cluster based analyses while having a higher peak intensity within the activated clusters. A preliminary analysis of frontal LHG compared to temporal LHG reveals increased contralateral recruitment in the frontal subgroup with more direct homologous recruitment. This nuanced understanding of existing mechanisms for neuroplasticity can aid in our future intentional manipulation for therapeutic benefit.
FLGS-01. Development of novel topical fluorescent probe for intraoperative rapid detection of glioma
Authors: Tanaka Shota , Kitagawa Yosuke , Kamiya Mako , Shimizu Takenori , Urano Yasuteru , Saito Nobuhito 
Published: November 2021

Abstract

PURPOSE
Fluorescence imaging is an important surgical adjunct in malignant glioma surgery. 5-aminolevulinic acid (5-ALA) has been proven effective for radical tumor resection and extended progression-free survival in a phase III randomized trial and therefore integrated into surgery for malignant glioma. Importantly, however, some limitations still exist in its use, which include false positivity and false negativity as well as inability of re-administration. In this study, we aimed to develop a novel, spray-type fluorescent probe using hydroxymethyl rhodamine green (HMRG) as a fluorescent scaffold.

METHODS
We have previously established a fluorescent probe library comprised of more than 320 kinds of HMRG probes. They have HMRG as a fluorescent scaffold with various types of dipeptides attached to it. Primary probe screening was performed using the homogenized tumor samples from patients with glioblastoma operated at our institution. Secondary screening followed using the selected probes and fresh tumor samples obtained from patients with glioblastoma operated from 2016 until 2018. Diced electrophoresis gel (DEG) assay, two-dimensional gel electrophoresis followed by a multi-well plate-based fluorometric assay, was performed to identify responsible enzymes for the selected probe. Further experiments with inhibitors, real-time PCR, immunohistochemistry, and western blotting were performed for confirmation.

RESULTS
Proline-arginine-HMRG (PR-HMRG) was selected as a candidate probe based upon the above two-step screenings. It achieved 79.4% accuracy in receiver operating characteristic curve analysis. Calpain-1 was found to be responsible to cleave PR-HMRG probe by DEG-proteome analysis. Calpain-1 protein was highly expressed in tumor tissues which reacted to PR-HMRG probe.

CONCLUSIONS
Our innovative screening method was able to find PR-HMRG as a novel fluorescent probe effective for rapid detection of glioblastoma. A preclinical study is planned to assess the efficacy and safety of the selected probe.
ITVT-03. Use of Functional MRI and DTI for Surgical Planning of Maximal Extent of Resection of CNS Tumors - A Single Neurosurgical Center’s Experience
Authors: Lam Fred , Algethami Hanan , Ekkehard Kasper 
Published: November 2021

Abstract
Use of functional neuroimaging capabilities such as fMRI, DTI, MRP, MRS, AS-PET-CT, SPECT, and TMS as noninvasive tools to visualize intrinsic brain and spine morphology in relation to function have developed over the past 30 years. Amongst these imaging modalities, functional magnetic resonance imaging (fMRI) is of particular interest since it follows the physiological coupling between neuronal electrical activity and metabolic structural (cellular) activity as it relates to tissue vascularity and perfusion states. As an adjunct to this modality, MRI-based diffusion tensor imaging (DTI) allows further detailed radiographic assessment of fiber tracts in the brain in relationship to the surgical lesion of interest. In addition, combination of other imaging modalities including MR perfusion and intraoperative tools such as neuronavigation and direct cortical stimulation can help guide the extent of maximal safe resection. Herein we present a case series from our neurosurgical institution of primary intra-axial, extra-axial, supratentorial, and brainstem tumors resected using fMRI and DTI for presurgical planning allowing for maximal safe extent of resection and outcomes.
ITVT-08. Combined use of awake surgery and intraoperative MRI augments extent of resection in eloquent gliomas without neurological impairment
Authors: Jungk Christine , Trong Philip Dao , Eisner Christoph , Haehnel Stefan , Unterberg Andreas 
Published: November 2021

Abstract
Maximizing the extent of resection (EOR) while preserving functional integrity is a mainstay of glioma surgery. Intraoperative MRI (iMRI) helps to augment the EOR. However, in eloquently located gliomas the significance of iMRI is controversial since the EOR is limited by functional rather than image-based boundaries. Thus, we sought to determine the impact of iMRI in our institutional series of awake glioma resections within or adjacent to eloquent (language, motor, sensory) areas since the implementation of a 1.5 Tesla iMRI in 2009. Tumor- and procedure-related data and functional outcome were assessed through medical charts review. The EOR was determined volumetrically on pre-, intra- and postoperative T1 contrast-enhanced (CE) and FLAIR MR images. 131 of 166 awake surgeries (79%) were performed under iMRI-guidance with concurrent language (n=72) and/or motor (n=50) mapping. iMRI was done when functional boundaries were reached (62%), for resection control (28%) or for other reasons (10%). Additional resection after iMRI (AR) was performed in 63 cases (73%); otherwise resection was terminated because the targeted EOR or functional boundaries were reached. New or deteriorated neurological deficits occurred in 20 patients prior and 15 patients post iMRI; however, all but 3 resolved within 6 months. Median EOR significantly increased after AR from 92.6% to 98.4% (∆5.8%; p&lt;0.0001) in CE tumors and from 64.5% to 85.8% (∆21.3%; p&lt;0.0001) in non-enhancing tumors. Remarkably, the reason to perform iMRI (resection control or functional limitations), did not affect the frequency of AR, deficits acquired post iMRI or the increase in EOR after AR. In conclusion, iMRI is a valuable adjunct to maximize the EOR in awake glioma resections without increasing the risk for functional impairment, particularly in non-enhancing tumors. Importantly, iMRI contributes to a maximized EOR even in cases where the resection had to be stopped because functional boundaries were reached.
Postmortem brain donations vs premortem surgical resections for glioblastoma research: viewing the matter as a whole
Authors: Griffin Cassandra P , Paul Christine L , Alexander Kimberley L , Walker Marjorie M , Hondermarck Hubert , Lynam James 
Published: November 2021

AbstractThere have been limited improvements in diagnosis, treatment, and outcomes of primary brain cancers, including glioblastoma, over the past 10 years. This is largely attributable to persistent deficits in understanding brain tumor biology and pathogenesis due to a lack of high-quality biological research specimens. Traditional, premortem, surgical biopsy samples do not allow full characterization of the spatial and temporal heterogeneity of glioblastoma, nor capture end-stage disease to allow full evaluation of the evolutionary and mutational processes that lead to treatment resistance and recurrence. Furthermore, the necessity of ensuring sufficient viable tissue is available for histopathological diagnosis, while minimizing surgically induced functional deficit, leaves minimal tissue for research purposes and results in formalin fixation of most surgical specimens. Postmortem brain donation programs are rapidly gaining support due to their unique ability to address the limitations associated with surgical tissue sampling. Collecting, processing, and preserving tissue samples intended solely for research provides both a spatial and temporal view of tumor heterogeneity as well as the opportunity to fully characterize end-stage disease from histological and molecular standpoints. This review explores the limitations of traditional sample collection and the opportunities afforded by postmortem brain donations for future neurobiological cancer research.
Anatomical and topographical variations in the distribution of brain metastases based on primary cancer origin and molecular subtypes: a systematic review
Authors: Cardinal Tyler , Pangal Dhiraj , Strickland Ben A , Newton Paul , Mahmoodifar Saeedeh , Mason Jeremy , Craig David , Simon Thomas , Tew Ben Yi , Yu Min , Yang Wensha , Chang Eric , Cabeen Ryan P , Ruzevick Jacob , Toga Arthur W , Neman Josh , Salhia Bodour , Zada Gabriel 
Published: November 2021

Abstract

Background
While it has been suspected that different primary cancers have varying predilections for metastasis in certain brain regions, recent advances in neuroimaging and spatial modeling analytics have facilitated further exploration into this field.

Methods
A systematic electronic database search for studies analyzing the distribution of brain metastases (BMs) from any primary systematic cancer published between January 1990 and July 2020 was conducted using PRISMA guidelines.

Results
Two authors independently reviewed 1957 abstracts, 46 of which underwent full-text analysis. A third author arbitrated both lists; 13 studies met inclusion/exclusion criteria. All were retrospective single- or multi-institution database reviews analyzing over 8227 BMs from 2599 patients with breast (8 studies), lung (7 studies), melanoma (5 studies), gastrointestinal (4 studies), renal (3 studies), and prostate (1 study) cancers. Breast, lung, and colorectal cancers tended to metastasize to more posterior/caudal topographic and vascular neuroanatomical regions, particularly the cerebellum, with notable differences based on subtype and receptor expression. HER-2-positive breast cancers were less likely to arise in the frontal lobes or subcortical region, while ER-positive and PR-positive breast metastases were less likely to arise in the occipital lobe or cerebellum. BM from lung adenocarcinoma tended to arise in the frontal lobes and squamous cell carcinoma in the cerebellum. Melanoma metastasized more to the frontal and temporal lobes.

Conclusion
The observed topographical distribution of BM likely develops based on primary cancer type, molecular subtype, and genetic profile. Further studies analyzing this association and relationships to vascular distribution are merited to potentially improve patient treatment and outcomes.
Metabolics risk factors in a New Zealand glioblastoma cohort
Authors: McManus Eileen J , Frampton Chris , Tan Alvin , Phillips Matthew C L 
Published: November 2021

Abstract

Background
Glioblastoma multiforme (GBM) is the most aggressive form of glioma. There is growing recognition that mitochondrial metabolism plays a role in cancer development. Metabolic syndrome is a risk factor for several cancers; however, the prevalence in GBM patients in New Zealand (NZ) is unknown. We hypothesized that patients with GBM would show a higher prevalence of metabolic syndrome compared to the general NZ population and that metabolic syndrome may be associated with worsened overall survival (OS) in GBM.

Methods
We performed a retrospective analysis in 170 patients diagnosed and treated for GBM between 2005 and 2020. Clinical and biochemical data were collected with regard to 5 metabolic criteria. OS was determined from the date of initial surgical diagnosis to the date of death or date of data acquisition.

Results
Of 170 patients, 31 (18.2%) met the diagnostic criteria for metabolic syndrome. The prevalence of metabolic syndrome in our cohort did not significantly differ from that of the general NZ population. However, OS in patients with metabolic syndrome was significantly worse compared to patients without metabolic syndrome (8.0 vs 13.0 months, P = .016). Patients who received a lower dexamethasone dose had significantly better survival outcomes (15.0 vs 5.0 months, P &lt; .01). Differences in OS did not differ by gender or ethnicity.

Conclusions
We have shown that metabolic syndrome is associated with reduced OS in a NZ cohort of GBM patients. This finding further strengthens the possibility that a metabolic pathogenesis may underpin GBM. However, prospective clinical trials are needed.