bluuebunny/crossref_metadata_2025_split huggingface dataset:
ROBO1 CAR-T CELL THERAPY FOR TREATMENT REFRACTORY BRAIN CANCER
Authors: Shaikh Muhammad Vaseem , Chokshi Chirayu R , Brakel Benjamin , Anand Alisha , Maich William Thomas , Suk Yujin , Kieliszek Agata , Subapanditha Minomi , Alizada Zahra , Venugopal Chitra , Rossotti Martin A , Moffat Jason , Henry Kevin A , Kislinger Thomas , Singh Sheila K 
Published: July 2023

Abstract
BTFC travel award recipient
Glioblastoma (GBM) is the most common malignant adult brain tumor, with a dismal prognosis. Despite the multimodal treatment regimen, tumor recurrence is inevitable, and no standardized treatment exists for recurrent glioblastoma (rGBM). Neurodevelopment signaling pathways are often hijacked during tumor progression. Roundabout guidance receptor 1 (ROBO1) protein is involved in axonal guidance during neurodevelopment. Our preliminary findings implicated aberrant ROBO1 signaling axis to be associated with higher tumorigenecity in GBM, making it a functionally relevant therapeutic target. Moreover, ROBO1 was highly expressed on the surface of malignant and treatment-refractory brain tumor initiating cells (BTICs) in rGBM, brain metastasis (BM) and medulloblastoma (MB), prompting the development of an anti-ROBO1 CAR-T cell therapy. Here we report the development and validation of second-generation CAR-T cells using a single-domain antibody targeting ROBO1 expressing BTICs across three different brain tumors. We validated anti-ROBO1 CAR-T cells in-vitro and in-vivo using our established patient derived tumor models. In-vitro studies demonstrated upregulation of activation markers, enhanced cytokine release, markedly increased proliferation, and induction of potent and specific tumor cell death with ROBO1 CAR-T cells as compared to untransduced cells (UT) in all the three cancers. These findings were further validated in-vivo using 3 different BTIC lines one each from rGBM, MB and BM. ROBO1 CAR-T showed significant reduction in tumor burden and significant increase in survival of the mice treated with ROBO1 CAR-T cells in all the three cohorts. Thus, targeting ROBO1 could be a therapeutically tractable strategy for treating rGBM as well as other brain malignancies.
THE USE OF 5-AMINOLEVULINIC ACID (5-ALA) IN HIGH-GRADE GLIOMA SURGERY, A SINGLE CANADIAN CENTER EXPERIENCE
Authors: LeBlanc Félix , Boone Lyndon , Noble Timothy , Burns Jane , Fawaz Charbel , Charest Dhany , El Helou Antonios 
Published: July 2023

Abstract
5-Aminolevulinic acid (5-ALA) is a prodrug used to selectively illuminate high-grade glioma (HGG) tissue intra-operatively, shown to nearly double complete resection rates in a 2006 multicentre, phase III clinical trial. Here, we review the history of the 2020 approval of 5-ALA in Canada and present some of the first preliminary results on resection rates, survival analysis, and adverse effects from a single Canadian center.
METHODS: We enrolled 76 patients (median age 61 years, 42 male) with suspected HGG amenable to surgical resection to undergo 5-ALA fluorescence-guided surgery between June 2020 and January 2023. Gross total resection was defined by the absence of enhancing l esions on postoperative MRI. We compared the survival distributions of confirmed HGG cases with complete vs. incomplete resection using a log-rank test and Kaplan-Meier statistics. RESULTS: 52 patients were confirmed as having a HGG (grade III or IV) based on a pathological diagnosis. In 32 of these patients (60.3%) a gross total resection was achieved. 46 patients of the initial cohort had their surgery done for more than 180 days. 47.8% had a survival of 600 or more days. CONCLUSIONS: 5-ALA fluorescence-guided surgery resulted in high complete resection rates, comparable to literature with no notable adverse side effects.
ACQUIRED PTEN LOSS MAY MEDIATE DABRAFENIB AND TRAMETINIB RESISTANCE IN BRAF V600E–MUTATED EPITHELIOID GLIOBLASTOMA: A CASE REPORT
Authors: Ahmed Abrar , Nobre Liana , Mason Warren , Bennett Julie , Tabori Uri , Hawkins Cynthia , Climans Seth 
Published: July 2023

Abstract
Epithelioid glioblastoma is a rare variant of glioblastoma that primarily affects children and young adults. This commonly has a BRAF V600E mutation and can be treated with BRAF and MEK inhibitors.
CASE DESCRIPTION: An 18-year-old woman was diagnosed with an epithelioid glioblastoma. She received temozolomide chemoradiotherapy. Upon progression she had redo surgery and received dabrafenib and trametinib. The patient developed a drop metastasis to the cervical spine, and consequently received focal radiotherapy, 20 Gy in five fractions. Treatments were halted six months after her second resection due to further disease progression. She developed uncal herniation, requiring her to have a third resection approximately six months after her second resection. She passed away after this, 12 months following her initial diagnosis. Retrospective genetic analysis of three tumor specimens showed a novel PTEN mutation that arose after her first surgery. We suspect that the acquired PTEN mutation conferred resistance to dabrafenib and trametinib. DISCUSSION: This case offers teaching points and research questions. Firstly, early treatment with BRAF and MEK inhibitors in high grade BRAF V600E–mutated gliomas may be optimal as the patient may have stabilized with earlier treatment on dabrafenib and trametinib. Secondly, further studies are required to investigate whether the addition of PTEN mutation to BRAF V600E leads to aggressive tumor behavior. Lastly, there is a need for investigation into potential benefits of treating similar patients by co-targeting the BRAF and PI3K/AKT pathways.
PREOPERATIVE DETERMINATION OF IDH STATUS AND GRADE IN GLIOMAS USING MRS
Authors: Nguyen Thanh Binh 
Published: July 2023

Abstract

PURPOSE
To evaluate the diagnostic accuracy of preoperative MRS in the determination of the IDH status and grade in patients with newly diagnosed gliomas.

METHODS
MRS was performed using a regular PRESS sequence and a spectral editing sequence (MEGA-PRESS). Concentration of 2-HG was estimated from the subtracted spectra from the edited MRS sequence while NAA, choline and creatinine concentrations were obtained from the regular PRESS sequence. IDH mutation status was assessed by immunohistochemistry for all patients and additional next generation sequencing for all grade 2 and 3 gliomas. Differences in metabolite concentrations between IHD-mutant and wild-type gliomas and between gliomas of various grades were assessed using non parametric tests. TAreas under-the ROC curve (AUC) for different metabolites were calculated with IDH mutation status or glioma grade as the outcome.

RESULTS
There were 29 IDH-mutant gliomas and 52 wild-type gliomas. There was a significant difference in the NAA/Choline ratio among various glioma grades (P&lt;0.05). The AUC for 2HG was 0.74 in the differentiation between IDH-mutant vs wild type gliomas. Using a 2-HG cut-off of &gt;0.96 I.U., sensitivity was 59% and specificity was 90% for the identification of IDH-mutant gliomas. The AUC for the NAA/Choline ratio was 0.74 in the differentiation of high vs low grade gliomas. Using a NAA/Choline cut-off ≤0.53, sensitivity was 45% and specificity was 100% for identification of high grade gliomas.

CONCLUSION
Preoperative MRS can identify IDH-mutant gliomas and high grade gliomas with high specificity.
HIGH-DIMENSIONAL HISTOPATHOLOGIC EVALUATION OF THE HYPOXIC MICROENVIRONMENT IN GLIOBLASTOMA
Authors: Mansouri Sheila , Zaidi Mark , Singh Olivia , Karimi Shirin , Lombard Phoebe , Dvorkin-Gheva Anna , Velasquez Carlos , Ali Hafsah , Devaraja Kaviya , Sosa Julio , Patil Vikas , Wei QingXia , Wu Ronald , Li Mira , Cheung May , Voisin Mathew , Gao Andrew , Hedley David , Aldape Kenneth , Wouters Bradly , Zadeh Gelareh 
Published: July 2023

Abstract
Rapidly growing solid tumors such as glioblastoma (GBM) are characteristically hypoxic, displaying large areas of necrosis surrounded by hyperproliferative pseudopalisading cells. Intra-tumoral hypoxia develops over time in the three-dimensional space and the degree of tissue oxygenation is a dynamic process that varies continuously. Combined with the extensive inter- and intra-tumoral heterogeneity associated with GBM at the bulk and single cell level, hypoxia contributes to a gradient of molecular alterations that are specific to the different cell populations that make up the bulk of the tumor and reside in specific niches. To date, high dimensional histopathologic analyses of the hypoxic regions within GBM tissue have not been performed. Here, we took a combined spatial and single-cell proteomic profiling approach to investigate the histopathologic features of hypoxia by leveraging a unique clinical study where the exogenous hypoxia marker pimonidazole (PIMO) is administered to patients with GBM prior to surgery. Tissue specimens were subjected to imaging mass cytometry and serial immunohistochemistry using a panel of 27 markers associated with cellular hallmarks of hypoxia, metabolism, proliferation, stemness, angiogenesis, and immune cell types. We took high-resolution imaging and statistical approaches to explore the interplay of the different markers within hypoxic regions of primary and recurrent GBMs, in addition to IDH-mutant gliomas. Our findings elucidate the expression pattern of key biological markers relative to one another, altered composition of different cell types, along with differential proliferative, transcriptional, and translational activation states associated with each cell type within the hypoxic regions of GBM.
STEREOTACTIC BODY RADIOTHERAPY (SBRT) FOR SACRAL METASTASES: DEVIATION FROM RECOMMENDED TARGET VOLUME DELINEATION PREDICTS HIGHER RISK OF LOCAL FAILURE
Authors: Moore-Palhares Daniel , Zeng Kang Liang , Myrehaug Sten , Tseng Chia-Lin (Eric) , Soliman Hany , Chen Hanbo , Maralani Pejman , Larouche Jeremie , Wilson Jeff , Ruschin Mark , Zhang Beibei , Atenafu Eshetu G , Sahgal Arjun , Detsky Jay 
Published: July 2023

Abstract
Report outcomes after sacrum SBRT, focusing on the impact of contouring deviation on local failure (LF) risk, with an aim to validate the contouring consensus guidelines.
METHODS/MATERIALS: Patients who underwent sacral SBRT from 2010- 2021 were identified from a prospectively maintained institutional database. Primary outcomes were magnetic resonance-based LF and vertebral compression fracture (VCF). RESULTS: A total of 215 treated sacral segments in 112 patients were reviewed. Most segments were treated with 30 Gy/4 fractions (51%), 24 Gy/2 fractions (31%), or 30 Gy/5 fractions (10%). Thirty-one percent of segments were of radioresistant histology (gastrointestinal, kidney, melanoma, sarcoma, or thyroid primary), and 51% had extraosseous disease. Sixteen percent of segments were under-contoured per consensus guidelines. The cumulative incidence of LF was 18.4% (95% CI 13.5-24.0) at 12-months and 23.1% (95% CI 17.6-29.0) at 24-months. On multivariate analysis (MVA), under- contouring (HR 2.4, 95% CI 1.3-4.7, p=0.008), radioresistant histology (HR 2.4, 95% CI 1,4-4.1, p=0.001), and extraosseous extension (HR 2.5, 95% CI 1.3-4.7, p=0.005) were predictors of increased risk of LF. The LF rates at 12/24-months were 15.1%/18.8% for segments contoured per guideline versus 31.4%/40.0% for those under-contoured. The cumulative incidence of VCF was 7.1% (95% CI 4.1-11.1) at 12-months and 12.3% (95% CI 8.2-17.2) at 24-months. On MVA, female gender predicted increased VCF risk (HR 2.3, 95% CI 1.1-5.2, p=0.04). CONCLUSIONS: Sacral SBRT is associated with high rates of efficacy and an acceptable VCF risk. Adherence to target volume delineation consensus guidelines reduces the risk of LF.
THE ROLE OF ICAM1 IN TUMOR ASSOCIATED MACROPHAGES IN GLIOBLASTOMA TUMORIGENESIS
Authors: Devaraja Kaviya , Mansouri Sheila , Singh Olivia , Ali Hafsah , Patil Vikas , Karimi Shirin , Sosa Julio , Wu Ronald , Wei Qinxqia , Li Mira , Wouters Bradley , Zadeh Gelareh 
Published: July 2023

Abstract
Glioblastoma (GBM) is a fatal brain cancer in adults with ineffective treatment methods. Cell adhesion molecules (CAMs) are proteins that are expressed on the surface of cells and enable them to interact with one another and the surrounding microenvironment. Intracellular adhesion molecule 1 (ICAM-1) is a cell adhesion molecule expressed by various cell types. Preliminary data showed that ICAM-1 is associated with poorer overall and progression free survival in patients and ICAM-1 expression levels increase in recurrent tumors. TAMs enhance GBM tumor growth. The aim of this study was to determine if ICAM-1 expression on TAMs contributes to GBM tumorigenesis, specifically within the hypoxic tumor microenvironment. We hypothesized that ICAM1 facilitates TAM migration, proliferation, cell adhesion and phagocytosis, thus enhancing tumor growth. We found that upon incubation of human and mouse primary macrophages in hypoxia, ICAM-1 expression levels increased and were further exasperated upon culturing with tumor cell-conditioned medium. The migration, cell adhesion and phagocytosis of ICAM-1 deficient macrophages was lower than wild type macrophages, and effects were further exasperated upon culturing with tumor conditioned media and incubation in hypoxia. Intracranial injection of tumor cells into ICAM-1 deficient and wild type mice revealed that ICAM1 deficient mice survived longer with lower overall tumor volume than wild type mice, with survival and volume differences being rescued upon ICAM1 bone marrow reconstitution. In conclusion, the expression of ICAM1 in TAMs likely promotes GBM tumorigenesis and hypoxia further enhances the expression of ICAM-1 in macrophages which is associated with more aggressive GBM.
CORRELATION OF CLINICAL FEATURES TO DNA METHYLATION-BASED PROGNOSTIC SUBTYPES IN CHORODOMA PATIENTS
Authors: Ajisebutu Andrew , Zuccato Jeffrey A , Patil Vikas , Sosa Julio , Zadeh Gelareh 
Published: July 2023

Abstract
Chordomas are rare aggressive primary bone cancers affecting the skull-base and spine. We have previously identified robust DNA methylation-based prognostic groups, immune infiltrated and cellular subtypes. Here we further characterize these prognostic subtypes with an extensively annotated clinical database to identify factors that correlate with subtype, and investigate methylation patterns between existing clinical scoring systems groups.
METHODS: 68 patients from a multi-institutional 20-year series were identified. These patients’ tumor samples had undergone whole genome DNA methylation profiling on the Illumina EPIC array. Baseline clinical features, including clinical features, treatment details, outcomes parameters and imaging were analyzed using chi-squared or kruskal-wallis test, and differential methylation patterns were examined between clinically distinct groups based on the Sekhar scoring system. RESULTS: Of all the variables tested, age of onset (p-value 0.012), location (skull base vs spine vs sacral: p-value 0.0365) and histological subtype (classical vs chondroid: p-value 0.0132) were the only significant predictors of subgroup placement; older age, spinal location, and classical histological typing were predictors of immune infiltrated chordoma subtype, which has a poorer clinical performance. As expected, death from chordoma was significantly different between subtypes (p-value 0.0056). Patients survival stratified based on Shakur grading, and clustered together on unsupervised hierarchical analysis on methylation. CONCLUSION: Overall, there are limited variables that correlate with methylation subtype, meaning that the epigenetic chordoma subtypes cannot be reliably identified using clinical or imaging features in the absence of molecular data. However clinical grading systems remain a valuable tool for prognostication, and display distinct methylation patterns.
PREDICTORS OF TUMOR DYNAMICS DURING A COURSE OF 30-FRACTION RADIOTHERAPY FOR GLIOBLASTOMA
Authors: Ong W L , Stewart J , Sahgal A , Soliman H , Tseng C L , Detsky J , Ho L , Das S , Maralani P , Lipsman N , Stanisz G , Perry J , Chen H , Atenafu E , Lau A , Ruschin M , Myrehaug S 
Published: July 2023

Abstract
We aim to identify predictors of tumor dynamics during radiotherapy for glioblastoma.
METHODS: This is a prospective serial MRI study in patients with glioblastoma. MRIs were obtained at radiotherapy planning (F0), fraction-10 (F10), and fraction-20 (F20). The tumor dynamics metrics (relative to F0) assessed included: relative gross tumor volume (GTV) changes (Vrel) and migration distance (dM). RESULTS: 129 patients were included in this study. Median GTV was 20.9cc at F0, 17.6cc at F10 (Vrel 0.85), and 16.1cc at F20 (Vrel 0.78). Patients with no corpus-callosum involvement (CCI) (vs with CCI) had more marked GTV volume reduction: Vrel 0.82 vs 1.02 at F10 (P=0.05), and Vrel 0.77 vs 0.88 at F20 (P=0.03). Patients with gross total resection (GTR) had more marked GTV volume reduction (vs subtotal resection (STR) vs biopsy (Bx)): Vrel 0.78, 0.85 and 1.07 at F10 (P=0.001), and Vrel 0.69, 0.80, 1.04 at F20 (P=0.001). The median dM were 4.7mm at both F10 and F20. Patients with CCI had larger dM (vs no CCI): 41% vs 12% had dM&gt;10mm at F10 (P=0.01), and 45% vs 9% had dM&gt;10mm at F20 (P&lt;0.001). At F20, 0%, 25% and 19% of patients with GTR, STR and Bx had dM&gt;10mm (P=0.002). Age, sex, MGMT methylation and IDH-mutation status were not associated with tumor dynamics during treatment. CONCLUSION: CCI and extent of surgery predict for tumor dynamics, which may allow us to better select patients who benefit the most from re-planning/ treatment adaptation during radiotherapy.
A RADIATION ONCOLOGIST’S EXPERIENCE TREATING MALIGNANT GLIOMA WITH TUMOR TREATING FIELDS IN CANADA
Authors: Roberge David , Labelle Denys 
Published: July 2023

Abstract
The FDA approved tumor treating fields (TTFields) in 2011. Through Health Canada special access, a limited number of treatments were provided prior to regulatory approval. This work describes a single physician’s experience with TTFields. With ethics approval, charts were retrospectively reviewed. Access provided as an extension of prior research was excluded. Kaplan-Meier estimates were used for survival and time on treatment. From 2013-2022, 62 cases were identified. 65% from Quebec, 21% from Ontario and the rest from either Alberta or British Colombia. TTFields were prescribed as an adjuvant following chemo-radiation in 41 cases and for recurrent disease in 21. Median age was 49 (range 16-75). 76% of patients were male. Median KPS was 75%. 95% of tumors were classified as glioblastoma by the criteria used at the time of diagnosis (IDH positive in 4). Where known, 40% had MGMT promoter methylation. Adjuvant treatment started a median of 1.0 months following radiotherapy. Recurrent patients had had a median of 2 prior lines of treatment (range 1-9). Two young adults discontinued treatment after less than one week but otherwise patients tolerated the device until treatment was recommended to be discontinued. Median OS for adjuvant patients was 15.4 months, 5.3 months for recurrent patients. For adjuvant patients, median estimated time on treatment was 7 months. It was possible to offer TTFields over a wide geographic area with support from device specialists. Treatment may be more easily integrated into care with the development of a larger network of prescribers.
REPURPOSING OF FDA APPROVED COMPOUNDS TO INHIBIT OSM/OSMR SIGNALING IN GLIOBLASTOMA
Authors: Lotfipour Farzaneh , Jahani-Asl Arezu 
Published: July 2023

Abstract
Repurposing of FDA approved compounds to inhibit OSM/OSMR signaling in glioblastoma OSM/OSMR signalling is important in glioblastoma, yet specific inhibitors to suppress this signaling pathway remain to be explored. Here we conducted HTS screening of FDA approved compounds to identify lead compounds that can suppress OSM signalling via OSMR to inhibit STAT3 phosphorylation. The strategy of drug repurposing that have already been approved by FDA, with known pharmacological and safety profiles, offers several advantages including bypassing development costs and rapid and effective translation into phase 2 clinical trials. Importantly, 99% of newly developed drugs fail in clinical trials, further highlighting the significance of drug repurposing. Our HTS screen revealed 456 compounds with &gt; 40% potency. We analyzed the compounds based on their mode of action and physicochemical properties. Our HTS discovered 63 G-protein coupled receptor modulators including 5-Hydroxy tryptamine (5-HT) and Dopamine receptor D2 (DRD2) modulators as OSM/OSMR inhibitors. Following a counter-screen we focused on compounds with highest potency as well as their potential to cross BBB using physicochemical attributes and the safety profiles previously established in human patients. These analyses revealed 7 lead compounds which are presently being tested in vivo in combination with present standards of care of glioblastoma patients.
DETERMINING THE ROLE OF GALECTIN1/HOXA5 INTERACTION AND REGULATION IN GLIOBLASTOMA DEVELOPMENT
Authors: Qu Dianbo , Popatia Alyanna , Jahani-Asl Arezu 
Published: July 2023

Abstract
LGALS1 is directly transcribed by STAT3, which promotes glioblastoma tumorigenesis via its interaction with HOXA5. However, the underling molecular mechanism of this interaction remains uninvestigated. In this study, we predicted the interacting mode between galectin1 and HOXA5 using a protein-protein docking method. Our analysis suggests that the interaction between Galectin1 monomer and the homeobox domain of HOXA5 impedes the interaction between the homeobox domain of HOXA5 and DNA. In contrast, the interaction of Galectin1 homodimer and the N-terminal region of HOXA5 facilitates or stabilizes the homeobox domain of HOXA5 to bind DNA. Based on this predicted binding mode, we hypothesized that HOXA5 transcriptional activity is regulated by phosphorylated HOXA5, which may impact the interaction by attenuating the binding of HOXA5 to negatively charged DNA. To validate this model, we generated a mutant Galectin1 that cannot form dimers by substituting Cys at position 2 with Ser and Val at position 5 with Asp. We also generated functional domain deletion mutants of HOXA5 to confirm the interaction of the N- terminal region of HOXA5 with Galectin1, according to the prediction on functional domains in HOXA5 by Pfam. Using wild type (dimer) and mutant (monomer) recombinant galectin1 proteins and deletion-mutant proteins of HOXA5, we are conducting a binding assay to validate this model. Next, we employed knock-in lines to explore the role of HOXA5 phosphorylation in tumorigenesis using a glioblastoma mouse model. The proposed models will help uncover the underlying regulatory mechanisms of HOXA5/Galectin1 on BTSC self-renewal and glioblastoma tumorigenesis.