bluuebunny/crossref_metadata_2025_split huggingface dataset:
TMOD-18. DIRECT IN VIVO CRISPR SCREEN IDENTIFIES COOPERATING TUMOR SUPPRESSORS THAT DRIVE PROGRESSION OF IDH1-MUTANT LOW-GRADE GLIOMA TO AGGRESSIVE GLIOBLASTOMA
Authors: Yanchus Connor , Drucker Kristen , Kollmeyer Thomas , Tsai Ricky , Jiang Lingyan , Ali Asma , Carson Brittany , Pawling Judy , Malik Ahmad , Al-Zahrani Khalid , Loganathan Sampath Kumar , Fortin Jerome , Zhou Lily , Elia Andrew , Dennis James W , Mak Tak , Taylor Michael , Zadeh Gelareh , Dirks Peter , Jenkins Robert , Schramek Daniel 
Published: November 2021

Abstract
Low-grade glioma (LGG) are generally slowly growing brain cancers, that frequently undergo malignant progression to aggressive, secondary glioblastoma with a dismal prognosis. By combining genetically engineered Idh1-mutant mice with in vivo CRISPR gene editing we generated a mouse model faithfully recapitulating the founder mutations of LGG. Clonal activation of the neomorphic Idh1 R132H mutation cooperates with Trp53 and Atrx mutations to trigger development of brain tumors but only with ~30% penetrance and very long latency. To elucidate the molecular mechanisms underlying the malignant progression of IDH1-mutant LGG, we devised and deployed a direct in vivo CRISPR screen targeting genes commonly mutated in human IDH-mutant secondary glioblastoma. Stereotaxic delivery of a lentiviral sgRNA library targeting the mouse orthologs of these genes into the brain of Idh1 R132H ;Trp53;Atrx;Cas9 and control Idh1 wt ;Trp53;Atrx;Cas9 compound mutant mice resulted in rapid formation of tumors that recapitulate human Idh1-mutant glioblastoma. Deconvoluting the screen showed that PI3K pathway members Pten and Pik3ca as well as Notch1, Smarca4 and Fat1 are preferentially enriched in Idh1 R132H-tumors, while Rb1 and NF2 were enriched in Idh1 wt tumors. Co-mutation analysis further identified additional co-occurring driver combinations such as Bcor-Met, Olig2-Met, Olig2-Med12 or Bcor-Olig2. We validated the tumor suppressive function of Notch1 and Pten using conventional floxed knock-out alleles and found that Notch1 functions in a haploinsufficient manner. Interestingly, Idh1 R132H did not alter tumor latency or pathology in a high grade p53;Pten;Rb1 mutant background, indicating that the neomorphic IDH-mutations can drive low but not high grade glioma development. Our study provides a functional landscape of gliomagenesis suppressors in vivo.
TMOD-21. A NOVEL IN-VITRO METHOD TO MODEL MACROPHAGES IN GLIOBLASTOMA
Authors: Alrefai Hasan , Beierle Andee , Nassour Lauren , Eustace Nicholas , Patel Zeel , Anderson Joshua , Hicks Patricia , King Peter , Willey Christopher 
Published: November 2021

Abstract

BACKGROUND
The GBM tumor microenvironment (TME) is comprised of a plethora of cancerous and non-cancerous cells that contribute to GBM growth, invasion, and chemoresistance. In-vitro models of GBM typically fail to incorporate multiple cell types. Others have addressed this problem by employing 3D bioprinting to incorporate astrocytes and macrophages in an extracellular matrix; however, they used serum-containing media and classically polarized anti-inflammatory macrophages. Serum has been shown to cause GBM brain-tumor initiating cells to lose their stem-like properties, highlighting the importance of excluding it from these models. Additionally, tumor-associated macrophages (TAMs) do not adhere to the traditional M2 phenotype.

METHODS
THP-1 monocytes and normal human astrocytes (NHAs) were transitioned into serum-free HL-1 and neurobasal-based media, respectively. Monocytes were stimulated towards a macrophage-like state with PMA and polarized by co-culturing them with GBM patient-derived xenograft(PDX) lines, using a transwell insert. CD206 expression was used to validate polarization and a cytokine array was used to characterize the cells.

RESULTS
There was no difference in proliferation rates at 72 hours for THP-1 monocytes grown in serum-free HL-1 media compared to serum-containing RPMI 1640 (p &gt; 0.95). Macrophages polarized via transwell inserts expressed the lymphocyte chemoattractant protein, CCL2, whereas resting(M0), pro-inflammatory(M1), and anti-inflammatory(M2) macrophages did not. Additionally, these macrophages expressed more CXCL1 and IL-1ß relative to M1 macrophages. We have also demonstrated a method to maintain a tri-culture model of GBM PDX cells, NHAs, and TAMs in a serum-free media that supports the growth/maintenance of all cell types.

CONCLUSIONS
We have demonstrated a novel method by which we can polarize macrophages towards a tumor-supportive phenotype that differs in cytokine expression from traditionally polarized macrophages. This higher-fidelity method of modeling TAMs in GBM can aid in the development of targeted therapeutics that may one day enter the clinic in hopes of improving outcomes in GBM.
TMOD-27. IDENTIFYING ONCOGENIC C-MYC AND MYCN COMPLEXES IN HIGH-RISK PEDIATRIC CANCERS
Authors: Qiu Bo , Qiu Bo , Qiu Bo 
Published: November 2021

Abstract
The MYC family of proto-oncogenes is activated in a variety of cancers, including multiple high-risk pediatric malignancies. c-MYC (MYC) is ubiquitously expressed in human tissues, while MYCN (MYCN) has tissue and developmentally restricted expression patterns. In both neuroblastoma and medulloblastoma, enhanced activity of either MYCN or c-MYC drives high-risk disease. As transcription factors, MYC proteins exert oncogenic functions through protein-protein interaction networks that alter gene expression, but also mediate a growing list of target-gene independent nuclear functions (transcriptional elongation, chromatin changes throughout the cell cycle, etc…). While c-MYC and MYCN share many functions, they also regulate distinct cellular processes, and within medulloblastoma, they are activated in distinct molecular sub-groups (i.e. MYCN amplification is found in aggressive sonic hedge hog (SHH) subgroup tumors, while MYC amplification is found in aggressive group 3 and group 4 tumors). Here, we present an approach to identify oncogenic functions of c-MYC and MYCN in medulloblastoma and neuroblastoma using human induced pluripotent stem cell (iPSCO based orthotopic model systems. We hypothesize that the protein interaction networks and oncogenic functions of c-MYC and MYCN are impacted by cellular context, which are recapitulated in our orthotopic models (cell transcriptional and epigenetic landscape, tumor microenvironment). This premise is supported by recent single cell sequencing efforts in medulloblastoma and neuroblastoma, where primary human tumor cells are found to recapitulate specific transcriptional cell states found in normal hindbrain and sympathetic nervous system development, respectively. Through proximity labeling and quantitative mass spectrometry, we aim to identify tumor and oncogene specific protein interaction networks. This information will guide functional screening approaches to identify tumor-specific vulnerabilities. * Note MYC(N) refers to c-MYC and MYCN.
BRMP-05. Intraoperative neural tract positioning method for the maximal safe resection of tumors
Authors: Yamaguchi Fumio 
Published: November 2021

Abstract
Brain mapping is a gold standard for the surgery of tumors in eloquent area. Especially subcortical mapping is an essential method for the preservation of important neural fibers conveying motor, sensory and even higher brain functions such as language control. The efforts to estimate the fiber localizations in brain white matter sometimes result in the unprecise identification that is caused by several factors including electrical heterogeneity of brain tissues. To solve this long-standing problem, NY Tract Finder (Yamaguchi Tract Finder) was invented and has been used for intraoperative brain mappings. Now this electrode and method is used in more than 30 major hospitals in Japan, China, Taiwan and Russia. The novel and unique neural fiber positioning technique and our efforts for the maximal preservation of patients’ QOL will be introduced.
FLGS-05. Maximal safe glioma resection using high resolution exoscope with 5-ALA-induced fluorescence
Authors: Saito Kuniaki , Sasaki Nobuyoshi , Kobayashi Keiichi , Nakatomi Hirofumi , Shiokawa Yoshiaki , Nagane Motoo 
Published: November 2021

Abstract

INTRODUCTION
5-aminolevulinic acid (5-ALA) guided surgery has been reported to prolong progression-free survival of patients with high grade glioma. Although blue-light capable microscope enables us to detect fluorescence intraoperatively, visualization of anatomy is difficult under blue-light microscope. On the other hand, exoscope permits to visualize both fluorescence and anatomy under blue-light conditions. We introduce our glioma surgery using an exoscope equipped with a 5-ALA fluorescence visual system.

METHODS
We attempted maximal safe resection for the patients with high grade glioma using 3D/4K exoscope with 5-ALA-induced fluorescence, neuronavigation, and electrophysiological monitoring or awake mapping. Visualization of fluorescence and anatomy under blue light, extent of resection, morbidity, and postoperative infarction were retrospectively reviewed.

RESULTS
Twenty patients (age 26–79, male 10/female 10, glioblastoma 11/lower grade glioma 9) underwent exoscopic tumor removal. Intraoperative fluorescence was observed in 100% of the tumor with gadolinium enhancement. Surrounding structures such as white matter, vessels and nerves were clearly visualized under blue light. Even perforators were visible and could be preserved. Supra-total resection and gross total resection of gadolinium-enhancing tumor was achieved in 6 (30%) and 10 (50%) patients, respectively. Surgical morbidity included hemianopsia in 1 patient and transient hemiparesis in 1 patient. Postoperative infarction was observed in 2 (10%) patients, which tended to be lower compared to 23 of 77 (29.9%) patients with glioblastoma who underwent tumor resection with fluorescence-equipped microscope(p=0.05).

CONCLUSION
Clear visualization of 5-ALA-indced tumor fluorescence and anatomical structures with use of high resolution exoscope help maximal safe tumor resection. Longer progression-free survival is expected as a result of greater extent of tumor resection.
IOTG-03. Rapid intraoperative flow cytometry of brain tumor useful for surgical decision-making
Authors: Muragaki Yoshihiro , Koriyama Shunichi , Saito Taiichi , Nitta Masayuki , Komori Takashi , Kawamata Takakazu 
Published: November 2021

Abstract
Flow cytometry is a measuring device frequently used in basic research, we have developed a fully automatic flow cytometer device that performs cell isolation, staining of cell nuclei, and measurement for intraoperative diagnosis. Placing a small specimen in a reagent containing PI calculates, the total number of cells, the DNA histogram, and the Malignancy Index (MI), which means in the proliferation phase, the ratio of the number of cells (S, G2, M) / total number of cells. The major feature of this device is that calculating takes only 10 minutes by thoroughly reviewing the process. We here introduce our study of this device, rapid diagnosis, WHO grading, prognosis in glioma, and differentiation from malignant lymphoma (PCNSL), then how to use it in decision making in the operation. In the analysis of 323 gliomas, the threshold between the peripheral brain and the tumor was 7%, and the MI value was correlated with WHO grade (II 13%, III 35%, IV 47%) (J Neurosurg 2013). A correlation was also found between the MI value and the number of residual tumors (Brain Tumor Path 2018). Furthermore, it was also useful for differentiating from PCNSL with many S-phase cells (World Neurosurg 2018). In addition, the relationship between the presence of DNA aneuploidy and poor prognosis in 102 grade II patients (Clin Neuro Neurosurg 2018), and the high MI in 102 grade IV patients showed a good prognosis and an inverse correlation with expectations (Neurosurg 2018). Intraoperative flow cytometry has enabled various intraoperative decision-making support by converting intraoperative histology, which was an analog-like transmission, into digitized histological information. In the future, the development of this research makes expectations for more accurate diagnosis and prediction by artificial intelligence and the development of other departments.
ITVT-05. Intraoperative Ultrasound Guidance Improves Resection In Gliomas – Results From A Single Centre Propensity Matched Comparative Cohort Analysis Of 2D Vs Navigated 3D Ultrasound In 500 Gliomas
Authors: Moiyadi Aliasgar , Shetty Prakash , Singh Vikas 
Published: November 2021

Abstract

INTRODUCTION
Intraoperative ultrasound (iUS) is a promising tool for glioma surgery. Navigated 3-D (n3D) iUS has many benefits over standard 2-D iUS.

METHODS
This was a retrospective comparative cohort study using propensity score matching (PSM). 500 consecutive histologically confirmed gliomas were divided into 2 cohorts – 2DiUS - Cohort A; and n3DiUS -Cohort B. PSM was used to account for known confounders (250 in each group; 1:1 matching). Gross total resection rates (based on iUS findings as well as postoperative MR) and perioperative morbidity were analyzed across the groups as were factors influencing these outcomes (using univariate as well as multivariate regression models).

RESULTS
Overall, the majority of the patients were adults (94%), males (71%) with hemispheric tumors (96%). 35% had tumors close to eloquent regions and 23% had received some prior treatment. The majority were high-grade gliomas (85%). 2D iUS was employed mainly for localization (80%) whereas n3D was used predominantly for resection control (84%) [p &lt; 0.001]. GTR rate was higher in the n3D cohort (55.2% vs 38.4% in 2D; p = 0.001). The odds of having a complete resection in the n3D cohort was twice that of the 2D. Prior treatment, hemispheric location, and use of fluorescence were also significantly associated with higher GTR rates on univariate analysis. On multivariate analysis, all of these remained significant. There was no difference in the morbidity rates in the two cohorts. N3D iUS had a higher specificity and positive likelihood ratio in detecting tumor residue.

CONCLUSION
For hemispheric gliomas undergoing resective surgery, the use of navigated 3D ultrasound improves GTR rates, with no added morbidity. It is more likely to be used for resection control mode than is 2DUS and this is probably because n3DUS is more specific and likely to pick up tumor residues contributing to its better accuracy.
ITVT-07. Robotic alignment module Cirq for navigated brainstem tumor biopsies
Authors: van Baarsen Kirsten , Woerdeman Peter , Slot Mariam , Hoving Eelco 
Published: November 2021

Abstract

BACKGROUND
With the incorporation of the robotic alignment module Cirq (Brainlab, Germany) into our neurosurgical armamentarium, we aimed to know our baseline accuracy in stererotactic biopsies. We therefore retrospectively reviewed our data on biopsy accuracy for brain(stem) tumors using the non-robotic alignment instrument Varioguide (Brainlab, Germany). Because of unexpectedly large deviations from the intended target, we sought to improve our registration accuracy when we introduced Cirq. Intraoperative 3D CT with bone fiducials was added to the pre-operative 3D T1 MRI with skin fiducials. This made it possible to compare surgical devices as well as registration methods.

AIMS
To share our experience with the new robotic alignment module Cirq for navigated brain(stem) tumor biopsies and to evaluate its target accuracy with bone fiducial registration, as compared to the previously used Varioguide with skin fiducial registration.

METHODS
All patients (0–18 years old) that underwent a brain(stem) biopsy in our institution were included. Over 2018–2020, data were collected retrospectively (cohort Varioguide with 3D T1 MRI registration with skin fiducials). From 2021, data were collected prospectively (cohort Cirq with both 3D T1 MRI registration with skin fiducials and intraoperative CT registration with bone fiducials). For both cohorts, Euclidian distances were calculated between the intended target and the obtained target. For the prospective cohort, registration errors were calculated for bone versus skin fiducials.

PRELIMINARY REUSLTS
The deviation from the intended target was much smaller in the Cirq cohort versus the Varioguide cohort. Within the Cirq cohort, registration errors were submillimetric for bone fiducial registration as compared to several millimeters for skin fiducial registration. CONCLUSION: The Cirq robotic arm is convenient, safe and highly accurate, especially when combined with intraoperative 3D CT bone fiducial registration. Skin fiducial registration does not offer the level of precision that is mandatory in brainstem tumor biopsies.
TWMP-02. Supplementary motor area syndrome in glioma surgery - towards a classification system based on clinical and imaging data
Authors: Tuncer Mehmet Salih , Fekonja Lucius , Ott Stefanie , Pfnür Andreas , Karbe Anna-Gila , Engelhardt Melina , Faust Katharina , Picht Thomas , Coburger Jan , Dührsen Lasse , Vajkoczy Peter , Onken Julia 
Published: November 2021

Abstract

OBJECTIVES
Surgical resection of gliomas involving the supplementary motor area (SMA) frequently results in a symptom complex commonly described as „SMA syndrome“, which is characterized by transient contralateral akinesia and mutism. As factors potentially influencing the severity and duration of symptoms still remain elusive, we aim to further investigate potential predictors in a multicentric cohort of glioma patients.

METHODS
Fifty patients with gliomas located in the superior frontal gyrus from 3 centers were included in this retrospective study. Patients with injury of M1 and/or the corticospinal tract were excluded. Early postoperative motor outcome, the occurrence of mutism and duration of acute symptoms in days were assessed. The long-term outcome was assessed in follow-up examinations 3 months after surgery. Atlas-based lesion-symptom mapping was performed using postoperative MR imaging estimating surgical grey matter damage as well as white matter disconnection severity. Associations between functional outcome and imaging findings were analyzed using group tests and correlation analyses.

RESULTS
Median duration of symptoms in the cohort was 3 days (range: 1 – 42 days). Persistent deficits concerning fine motor movements and speech after initial recovery were found in 27 patients (54%). Disconnection of the central segment of the corpus callosum was associated with longer symptom duration (FDR corr. p &lt; 0.05), while disconnection of the mid-posterior segment of the corpus callosum was associated with persistent deficits at follow-up (FDR corr. p &lt; 0.05).

CONCLUSIONS
The present study shows a high variability regarding the recovery time of postoperative SMA syndrome and a high prevalence of persistent deficits in fine motor movements and speech after initial recovery of acute symptoms. The pivotal role of interhemispheric connectivity in the recovery process is reinforced. These findings will help neurosurgeons in patient consultation and provide a foundation for future studies aiming to establish prediction models of the SMA syndrome.
A functional artificial neural network for noninvasive pretreatment evaluation of glioblastoma patients
Authors: Zander Eric , Ardeleanu Andrew , Singleton Ryan , Bede Barnabas , Wu Yilin , Zheng Shuhua 
Published: November 2021

Abstract

Background
Pretreatment assessments for glioblastoma (GBM) patients, especially elderly or frail patients, are critical for treatment planning. However, genetic profiling with intracranial biopsy carries a significant risk of permanent morbidity. We previously demonstrated that the CUL2 gene, encoding the scaffold cullin2 protein in the cullin2-RING E3 ligase (CRL2), can predict GBM radiosensitivity and prognosis. CUL2 expression levels are closely regulated with its copy number variations (CNVs). This study aims to develop artificial neural networks (ANNs) for pretreatment evaluation of GBM patients with inputs obtainable without intracranial surgical biopsies.

Methods
Public datasets including Ivy-GAP, The Cancer Genome Atlas Glioblastoma (TCGA-GBM), and the Chinese Glioma Genome Atlas (CGGA) were used for training and testing of the ANNs. T1 images from corresponding cases were studied using automated segmentation for features of heterogeneity and tumor edge contouring. A ratio comparing the surface area of tumor borders versus the total volume (SvV) was derived from the DICOM-SEG conversions of segmented tumors. The edges of these borders were detected using the canny edge detector. Packages including Keras, Pytorch, and TensorFlow were tested to build the ANNs. A 4-layered ANN (8-8-8-2) with a binary output was built with optimal performance after extensive testing.

Results
The 4-layered deep learning ANN can identify a GBM patient’s overall survival (OS) cohort with 80%–85% accuracy. The ANN requires 4 inputs, including CUL2 copy number, patients’ age at GBM diagnosis, Karnofsky Performance Scale (KPS), and SvV ratio.

Conclusion
Quantifiable image features can significantly improve the ability of ANNs to identify a GBM patients’ survival cohort. Features such as clinical measures, genetic data, and image data, can be integrated into a single ANN for GBM pretreatment evaluation.
Prediction Tool to Identify Children at Highest Risk of Tuberculosis Disease Progression Among Those Exposed at Home
Authors: Brooks Meredith B , Lecca Leonid , Contreras Carmen , Calderon Roger , Yataco Rosa , Galea Jerome , Huang Chuan-Chin , Murray Megan B , Becerra Mercedes C 
Published: November 2021

Abstract

Background
There is a dearth of research to understand which children, among those who are exposed at home to tuberculosis (TB), are at the highest risk of TB disease, to tailor care. We sought to identify predictors of TB progression in children.

Methods
We conducted a prospective cohort study of children living with adults with pulmonary TB in Lima, Peru (2009–2012). We applied classification and regression tree analysis to examine potential predictors of incident TB disease during 12 months in 3 age groups (0–4, 5–9, and 10–14 years). We calculated the relative risk (RR) for top predictors in each age group.

Results
Among 4545 children 0–14 years old, 156 (3.4%) were diagnosed with TB within 1 year of household exposure to TB (3.4%, 2.3%, and 4.7% in children 0–4, 5–9, and 10–14 years old, respectively). The most important predictor of TB was having a positive tuberculin skin test (TST) result, with RRs of 6.6 (95% CI, 4.0–10.7), 6.6 (95% CI, 3.2–13.6), and 5.2 (95% CI, 3.0–9.0) in the age groups 0–4, 5–9, and 10–14 years, respectively. In young children with a positive TST, not using isoniazid preventive treatment further increased risk of disease (RR, 12.2 [95% CI, 3.8–39.2]).

Conclusions
We present a tool that identifies child household contacts at high risk of TB disease progression based on data collected during contact tracing. In addition to the use of TB preventive therapy for all children exposed at home to TB, those children at highest risk of progressing to TB disease may benefit from more frequent follow-up.