bluuebunny/crossref_metadata_2025_split huggingface dataset:
SHH PATHWAY ACTIVATION DRIVES MALIGNANT TRANSFORMATION IN A SUBSET OF MPNSTS AND IS A POTENTIAL THERAPEUTIC TARGET
Authors: Suppiah Suganth , Mansouri Sheila , Liu Jeff , Patel Vikas , Bunda Severa , Zadeh Gelareh 
Published: July 2023

Abstract
BTFC travel award recipient
Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive Schwann-cell derived sarcomas and the leading cause of mortality in Neurofibromatosis Type 1. The molecular pathways driving malignant transformation is not well understood. In this study, we leveraged multi-platform genomic and epigenomic profiling of human neurofibromas and MPNSTs to identify targetable molecular pathways that lead to malignant transformation. Fresh-frozen tumors (N = 108) were studied including methylation profiling, RNA sequencing, and whole exome sequencing. Unsupervised consensus clustering of methylome and transcriptome data identified 2 distinct MPNST subgroups. Pathway analysis showed that MPNST-G1 tumors are characterized by SHH pathway activation (NES=1.9952, p&lt;0. 0001, FDR&lt;0.001), while MPNST-G2 tumors are characterized by WNT pathway activation (NES=1.7630, p&lt;0.0001, FDR=0.0058). We observed significantly higher rates of PTCH1 deletions, a negative regulator of SHH pathway, in MPNST-G1 (62.5% vs 0%, Fisher Exact Test=0.0065, p&lt;0.05) and PTCH1 promoter hypermethylation (mean beta value: 0.2899 vs. 0.06119, p&lt;0.05). A computational drug screen identified sonedigib, a SHH pathway inhibitor, as a potential treatment option for MPSNT-G1. We validated the importance of SHH pathway in malignant transformation by knocking out PTCH1 in neurofibroma cell lines and demonstrated increased cellular proliferation, cellular migration and invasion. In addition, treatment with sonedigib decreased cellular viability in MPNST cell lines and improved survival in mouse xenograft models. These results suggest a targeted approach should be taken for treating MPNSTs, and SHH and WNT pathway inhibition may be promising avenue for therapeutic development.
INTERCEPTING BRAIN METASTASES THROUGH METABOLIC VULNERABILITIES
Authors: Kieliszek A M , Mobilio D , Bassey-Archibong B I , Johnson J W , Piotrowski M L , Aghaei N , Gwynne W D , Escudero L , Chafe S , Zhang K Zhai1 C , Quaile A , McKenna D , Subapanditha M , de Araujo E D , Sedighi A , Gunning P T , Tokar T , Venugopal C , Montenegro-Burke J R , Magolan J , Singh S K 
Published: July 2023

Abstract
BTFC travel award recipient
Patients with brain metastases (BM) face a 90% mortality rate within one year of diagnosis because the current standard of care is mainly palliative. Our patient-derived xenograft models have successfully recapitulated all the stages of the metastatic cascade and captured a “premetastatic” population of BM cells that have just seeded the brains of mice before forming mature, clinically detectable tumors. We applied RNA sequencing of premetastatic BM cells to reveal a unique deregulated transcriptomic profile that is specific to premetastatic cells despite the tumor of origin. Subsequent Connectivity Map analysis led us to identify a tool compound that exhibits anti-BM activity in vitro, while remaining ineffective against normal brain cell controls. Follow up preclinical studies showed that treatment with this tool compound reduces the tumor burden of mice compared to placebo, while providing a significant survival advantage. Mass spectrometry-based metabolomics and CRISPR knock-out studies directly validated our tool compound’s target as a targetable therapeutic vulnerability in BM, where pharmacological and genetic perturbation of the target attenuates BM cell proliferation both in vitro and in vivo. We have now begun a large-scale medicinal chemistry campaign to develop novel, brain penetrant inhibitors of this target with drug-like pre-clinical profiles validated by our in vivo experimental models for later stage preclinical development and subsequent clinical development. This potential first-in-class anti-metastatic therapy may provide an alternative treatment strategy for at-risk patients that are otherwise limited to palliation and could open the gate to future development of other anti-metastatic therapies.
EXPRESSION OF ANDROGEN RECEPTOR IN BREAST CANCER BRAIN METASTASES
Authors: Fan Kevin Yijun , Chehade Rania , Qazi Maleeha A , Moravan Veronika , Nofech-Moses Sharon , Jerzak Katarzyna J 
Published: July 2023

Abstract
Given availability of central nervous system (CNS)-penetrant systemic therapies that target the androgen receptor (AR), we evaluated the expression of the AR “target” in breast cancer brain metastases (BrM).
METHODS: An established, retrospective cohort of 57 patients with metastatic breast cancer who underwent surgery for BrM at the Sunnybrook Odette Cancer Centre (SOCC) between 1999 and 2013 was studied. AR expression in BrM samples was assessed in triplicate using immunohistochemistry (IHC). AR positive status was defined as nuclear AR expression ≥10% in tumor-infiltrating cells as a percentage of tumor area using the SP107 antibody. RESULTS: The median age of patients was 52 years (range 32-85 years). 17 (30%) patients had hormone receptor positive (HR+) /HER2-negative, 28 (49%) had HER2+, and 12 (21%) had triple negative breast cancer (TNBC) BrM. The median expression of AR was 20% (CI 1.6-38.3%) and 32 of 57 (56%) BrM were AR positive based on a cut-point of ≥10%. A significantly smaller proportion of patients with TNBC had AR+ BrM (n=2/12, 17%), compared to patients with HR+/HER2-ve (n= 9/17, 53%) or HER2+ (n=21/28, 75%) disease (p=0.04). Patients with AR positive versus AR negative BrM had similar overall survival (12.5 vs. 7.9 months, p= 0.6), brain-specific progression-free survival (8.0 vs. 5.1 months, p= 0.95), and time from breast cancer diagnosis to BrM diagnosis (51 vs. 29 months, p=0.16). CONCLUSION: AR is expressed in the majority of breast cancer BrM and represents a promising therapeutic target.
TREATMENT, HEALTHCARE UTILIZATION AND OUTCOMES IN PATIENTS WITH GLIOBLASTOMA IN ONTARIO: A 10-YEAR COHORT STUDY
Authors: Rzadki Kathryn , Baqri Wafa , Habbous Steven , Das Sunit 
Published: July 2023

Abstract
Glioblastoma (GBM) is the most common malignant primary brain tumour in adults. Receipt of adjuvant therapies has been shown to exert a significant positive effect on patient survival. Little is known however about how changes in standards of care and healthcare system factors, such as access, affect real-world outcomes. In this study, we provide an overview of GBM in Ontario and examine elements of care, including treatment patterns and healthcare utilization, from 2010-2019. Using linked health- administrative databases from Ontario, Canada, we conducted a population-based cohort study to examine the clinical and biological characteristics, treatment, and healthcare utilization patterns of adult GBM patients diagnosed between 2010-2019. The primary outcomes were enrollment in adjuvant chemoradiation treatment and 1-, 2-, and 5-year survival. All analyses were performed using the Statistical Analysis Software (SAS). 5392 patients were diagnosed with GBM in Ontario from 2010-2019 (58% male, 42% female). The median age at diagnosis was 64. Receipt of adjuvant chemoradiation within one year of diagnosis increased from 51% in 2010 to 63% in 2019. 1-year, 2-year, and 5-year overall survival plateaued, ranging between 40-43%, 15-19%, and 5-7%, respectively. For patients above the age of 65, however, 1-year survival increased from 19% in 2010 to 26% in 2019. This Ontario- based study provides insight into the effect of practice evolution and healthcare utilization on the real-world overall survival of patients with GBM. Overall survival for most patients with glioblastoma has remained stagnant over the past decade. Changes intreatment standards and expansion of access to treating centres have been associated with prolonged survival in elderly glioblastoma patients.
CHOREOGRAPHED EXPANSION OF SERVICES RESULTS IN DECREASED PATIENT BURDEN WITHOUT COMPROMISE OF OUTCOMES: AN ASSESSMENT OF THE ONTARIO EXPERIENCE
Authors: Rzadki Kathryn , Baqri Wafa , Yermahanova Olga , Habbous Steven , Das Sunit 
Published: July 2023

Abstract
Neuro-oncology care in Ontario has been historically centralized, at times requiring significant travel on the part of patients. Toward observing the goal of patient-centred care and reducing patient burden, two additional regional cancer centres (RCC) capable of neuro-oncology care delivery were introduced in 2016. This study evaluates the impact of increased regionalization of neuro-oncology services on healthcare utilization and travel burden for glioblastoma (GBM) patients in Ontario. We present a cohort of GBM patients diagnosed between 2010-2019. Incidence of GBM and treatment modalities were identified using provincial health administrative databases. A geographic information system and spatial analysis were used to estimate travel time from patient residences to neuro-oncology RCCs. Among the 5242 GBM patients, 79% received radiation as part of treatment. Median travel time to the closest RCC was higher for patients who did not receive radiation as part of treatment than for patients who did (p=0.03). After 2016, the volume of patients receiving radiation at their local RCC increased from 62% to 69% and median travel time to treatment RCCs decreased (p=0.0072). The two new RCCs treated 35% and 41% of patients within their respective catchment areas. Receipt of standard of care, surgery, and CRT, increased by 11%. Regionalization resulted in changes in the health care utilization patterns in Ontario consistent with decreased patient travel burden for patients with GBM. Focused regionalization did not come at the cost of decreased quality of care, as determined by delivery of a standard of care.
BIOMARKER STATUS PREDICTS FOR LOCAL CONTROL (LC) FOLLOWING SPINE STEREOTACTIC BODY RADIOTHERAPY (SBRT) IN NON-SMALL CELL LUNG CANCER (NSCLC) PATIENTS WITH SPINAL METASTASES
Authors: Shor Dana , Zeng Kang Liang , Chen Hanbo , Menjak Ines , Atenafu Eshetu , Tseng Chia-Lin , Detsky Jay , Larouche Jeremie , Zhang Beibei , Soliman Hany , Maralani Pejman , Myrehaug Sten , Louie Alexander V , Sahgal Arjun 
Published: July 2023

Abstract
Report of spine SBRT outcomes in NSCLC patients and impact of death-ligand 1 (PD-L1) status and epidermal growth factor (EGFR) mutation on LC.
METHODS: 165 patients and 389 spinal segments were retrospectively reviewed. Primary endpoint was LF and secondary outcomes included overall survival (OS) and vertebral compression fracture (VCF) rates. RESULTS: Median follow-up, OS and age was 13 months (range, 0.5-95 months), 18.4 months (95% CI 11.4-24.6), and 67 years (range, 28.2-89.9) respectively. 52% were female and 76% had adenocarcinoma. 29% had an EGFR mutation, 16% were PD-L1 ≥ 50%, 20% PD-L1 1-49% and 35% PD-L1 &lt;1%. Of 389 segments, 79% were denovo. At baseline, 35% had VCF, 27% epidural disease and 27% paraspinal extension. 61% were treated with 24 or 28 Gy in 2 SBRT fractions. LF cumulative incidence (CI) at 2-years was 25.4% (95% CI 20.9%-30%). EGFR positivity (p&lt;0.0001), PD-L1≥50% (p=0.013) and treatment with IO within 1 month of SBRT (p=0.004) predicted for LC on multivariable analysis (MVA). The 2-year LF rate in EGFR-positive vs. negative patients were 17.7% vs. 28.8%, and in those PD-L1 ≥50% vs PD-L1&lt;50% were 7.8% vs. 38.1%. CI of VCF at 2-years were 8.8% (95% CI 6.1-12.0%). Prior SBRT to the same segment (P&lt;0.0001) and baseline VCF (p&lt;0.0001) were predictors on MVA. CONCLUSION: We identify predictability of EGFR mutation, PD-L1 ≥50% and peri-SBRT IO on LC following spine SBRT in NSCLC.
PERCEPTION AND KNOWLEDGE OF BRAIN TUMOR BANKING AMONG CANADIAN NEUROSURGEONS
Authors: Ranger Adrianna , Megyesi Joseph , Zhang Qi 
Published: July 2023

Abstract
Brain tumor banking provides an important resource for understanding the underlying pathophysiology of brain tumors. It requires a multidisciplinary team, including neurosurgeons who must recognize the importance of these banks and actively contribute. The perceptions and involvement of neurosurgeons regarding Canadian brain tumor banking remains to be studied.
OBJECTIVE: This study aims to 1) assess current Canadian tumor tissue banking practices 2) determine the perception of neurosurgeons towards brain tumor tissue banks, and 3) uncover obstacles to tissue sample access. METHODS: A 26 question survey was conducted using Qualtrics and distributed to 178 Canadian neurosurgeons. Questions pertained to respondent demographics, tissue samples being banked, funding, and collaboration. RESULTS: 35 neurosurgeons completed the survey (19.66%). The majority of respondents treated adult populations (65.71%) and practiced in Ontario (57.14%). Most centers banked a variety of primary and metastatic brain tumors. 25.00% of respondents stated that their center collaborates with others. Personal communication was the most frequently stated method (58.33%) used to raise awareness of tumor banks. Funding was the most commonly mentioned obstacle to successful banking (70.37%). Banks are funded through research grants (30.76%), departmental support (30.76%), government funding (11.54%) and donations (26.92%). CONCLUSIONS: This study investigated neurosurgeons’ perceptions of brain tumor banking and the state of Canadian tumor banking. Despite numerous centers banking a variety of brain tumors, collaboration between institutes was limited. The greatest perceived obstacle is funding. Canadian brain banking may benefit from improved communication, collaboration, and funding.
CLINICAL APPLICATION OF SATURATION TRANSFER MRI FOR DIFFERENTIATING TUMOUR PROGRESSION FROM RADIATION NECROSIS IN BRAIN METASTASES
Authors: Chan Rachel W , Lam Wilfred W , Murray Leedan , Chen Hanbo , Zhang Beibei , Theriault Aimee , Endre Ruby , Moon Sangkyu , Liebig Patrick , Djayakarsana Daniel , Mehrabian Hatef , Myrehaug Sten , Tseng Chia-Lin , Detsky Jay , Maralani Pejman J , Sahgal Arjun , Soliman Hany , Stanisz Greg J 
Published: July 2023

Abstract
Stereotactic radiosurgery for the treatment of brain metastases delivers a high dose of radiation with excellent local control, but increases the likelihood of radiation necrosis. As shown in our previous work, saturation transfer MRI, consisting of quantitative magnetization transfer (qMT) and chemical exchange saturation transfer (CEST), is a promising technique for distinguishing radiation necrosis (RN) from tumour progression (TP) in brain metastases. A 3D qMT/CEST acquisition was recently implemented and over 100 patients have been scanned to date. The purpose of this work is to assess the ability of advanced MRI parameters, including qMT and CEST metrics, which are sensitive to macromolecules and metabolism. The specific metrics that were explored included the amide and NOE contributions of the magnetization transfer ratio (MTR), the MTR asymmetry, the apparent exchange-dependent relaxation (AREX), the qMT semi-solid pool fraction and the T1 and T2 relaxation times. For a subset of the patients, dynamic susceptibility contrast (DSC) perfusion images were acquired. Examples of confirmed tumour progression and radiation necrosis cases will be presented, comparing the structural images (pre- and post-contrast T1-weighted and FLAIR images) with parameter maps from qMT and CEST and also the relative cerebral blood flow (rCBF) from DSC perfusion imaging. Interim cohort results will be presented. Approaches for standardizing the parameters across multiple MRI vendors are also explored.
EXPLORING THE ROLE OF GAT1 AND GABA IN TEMOZOLOMIDE TREATED GLIOMA
Authors: Poole Alisha , Lun Xueqing , Dufour Antoine , Senger Donna , Robbins Stephen 
Published: July 2023

Abstract
Approximately 3000 Canadians a year are diagnosed with the most aggressive and fatal form of brain cancer called glioma. Even with surgical resection, chemotherapy, and radiotherapy these patients have an average survival of less than 20 months. Research in the past has primarily focused on identifying and targeting specific genetic mutations in the tumor. However, it is apparent that the environment surrounding the tumor can influence tumor growth, tumor spread into the brain, and drug resistance. The brain presents many challenges to glioma treatment, one of which is the unique environment in which gliomas grow, which contributes to poor patient outcomes. The interaction between tumor cells, surrounding normal brain tissue, and immune cells supports the aggressiveness of glioma. Using a model of chemosensitive and chemoresistant tumors, we have identified an increase in the GABA transporter GAT1 in the chemosensitive tumor treated with the standard chemotherapy temozolomide. GAT1 is primarily expressed on neurons, but has also been shown to be expressed on astrocytes and immune cells such as macrophages. Our lab has identified that macrophages tend to concentrate in the same region as GAT1 expressing cells within the tumor environment. In addition, multiple papers have shown that an increase in GABA promotes a glioma-promoting immune microenvironment. Thus, we believe that treatment with temozolomide causes an increase in environmental GAT1 expression, resulting in a reuptake of GABA, and promoting a glioma-inhibitory macrophage phenotype. We believe that understanding how the glioma-inhibitory macrophage phenotype occurs will help improve patient outcomes.
HER2-LOW BREAST CANCER BRAIN METASTASES: INCIDENCE AND TREATMENT IMPLICATIONS
Authors: Chehade Rania , Nofech-Mozes Sharon , Plotkin Anna , Moravan Veronika , Jerzak Katarzyna J 
Published: July 2023

Abstract
Brain metastases (BrM) are a major cause of morbidity and mortality among women with breast cancer (BC). Central nervous system (CNS)-penetrating systemic therapies for patients with HER2-negative BrM are lacking; given CNS activity of trastuzumab deruxtecan, efficacy for patients with HER2-low BrM is of interest.
METHODS: A retrospective study of two cohorts of consecutive patients who underwent surgery for BC BrM at Sunnybrook Health Sciences Centre were identified. BrM subtype was assessed based on 2018 ASCO/CAP guidelines. HER2-zero was defined as immunohistochemistry (IHC) 0; HER2-low was defined as IHC 1+ or 2+ and fluorescence in situ hybridization (FISH) negative status. HER2-positive was defined as IHC 3+ or IHC 2+ with positive FISH. We also assessed the prognostic association between extent of HER2 expression and i) brain-specific progression free survival (bsPFS), as well as ii) overall survival (OS). RESULTS: Out of 137 patients with resected BrM, tissue for HER2 assessment was available in 74.5% (n=102) of cases. In this cohort, the median age at BrM diagnosis was 53.5 (range, 32- 85). 68.6% (n=70) had extracranial disease. 53% (n=54) of the BrM were HER2-positive; 29.4% (n=30) were HER2-low and 17.6% (n=18) had HER2-zero status. Among BrM that were triple negative based on ASCO/CAP guidelines, 14 out of 22 cases (63.6%) were re-classified as being HER2-low. 15/25 (60%) BrM that were hormone receptor positive/HER2 negative (HR+/HER2-) based on ASCO/CAP guidelines were re-classified as being HER2-low. There was no significant association between the extent of HER2 expression (HER2-zero, HER2-low versus HER2-positive status) in BrM and either bsPFS or OS. CONCLUSION: Among patients with surgically resected BrM, a high proportion of those with metastatic TNBC and HR+/HER2-negative disease have “HER2-low” BrM with potential to benefit from HER2-targeted therapy.
JAK/STAT PATHWAY COOPERATES WITH CIC FUSIONS TO DRIVE CIC-REARRANGED SARCOMAS
Authors: Kaloti R K , Bunda S B , Zadeh G Z 
Published: July 2023

Abstract
CIC-rearranged sarcoma is a rare disease driven by a specific fusion protein involving the CIC gene. Native CIC protein is a transcriptional repressor of the (RTK)/Ras/ERK signaling pathway, which is one of the most tumorigenic pathways in cancer. The most common rearrangement is with the double homeobox 4 (DUX4) transcription factor (CIC-DUX4), and others, such as CIC-NUTM1 fusions, have been identified in a subset of pediatric primitive neuroectodermal tumors. However, the molecular mechanisms by which CIC fusions induce tumorigenesis remains unknown. Hypothesis: Our preliminary data shows that CIC- DUX4/NUTM1 fusions activate JAK (cytokine receptors) and its downstream effector STAT1/3(transcription factors). We hypothesize that the JAK/STAT1/3 signal transduction pathway cooperates with CIC-fusions to induce the expression of oncogenic transcription factors ETV1/4/5 and drive these sarcomas.
METHODS AND RESULTS: JAK1 is a potential target for CIC-fusions- We show high levels of JAK1/STAT1/3 activation in CIC-fusion patient-derived sarcoma cell lines (NCC-SCC-89/C) as compared to other sarcoma cell lines without the fusion. JAK1 inhibition using Solicitinub and Ruxolitinib reduced phosphorylation of STAT1/3 as well as protein and mRNA expression of transcriptional oncogenic factors ETV1/4/5 and cell proliferation. JAK1/STAT1/3 inhibition in patient-derived CIC-DUX4 xenograft models- To evaluate the pre-clinical effect of targeting the JAK1/STAT1/3 pathway, the CIC-DUX4 cell line was grafted into NSG mice. Ruxolitinib treatment significantly reduced tumor volume, STAT1 activation, and oncogenic transcriptional factors ETV1/4/5. CONCLUSION: We show that the JAK1/STAT1/3 pathway plays a critical role in cooperating with CIC-fusions to drive CIC-rearranged sarcomas providing insight into potential therapeutic avenues for these aggressive tumors.
MOLECULAR PROFILING TO UNDERSTAND TREATMENT RESISTANCE AND RESPONSE IN GLIOBLASTOMA
Authors: Nikolopoulos Marina , Wu Megan , Bahcheli Alexander , Kellett Sorcha , Erickson Anders , Myrehaug Sten , Sahgal Arjun , Spears Melanie , Bayani Jane , Das Sunit 
Published: July 2023

Abstract
Patients with glioblastoma experience a wide variation in response to standard treatment, with nearly 30% experiencing tumour progression during treatment, and nearly 7% surviving more than 5 years. CEST-MRI is sensitive to treatment-induced changes in tumour metabolism and can be used to evaluate treatment response, allowing for the differentiation between early and late progressors before treatment initiation.
OBJECTIVE: The purpose of this study is to establish genomic and transcriptomic profiles of early and late progressors in patients with glioblastoma who have undergone CEST-MRI. METHODS: Patients (n=25) were imaged with CEST-MRI at multiple time points throughout standard chemoradiation treatment. DNA and RNA were co-extracted from 25 fresh-frozen matched normal and tumour pairs and processed for whole genome sequencing and gene expression analysis using Nanostring. RESULTS: Early progressors (n = 12) and late progressors (n =13) had significant differences in OS and PFS (log rank &lt;0.0001) as well as in gene expression and pathway deregulation. Genes significantly expressed in early progressors compared to late progressors include CCNA1 (p =0.000557), IGFBP3 (p = 0.000602), ASS1 (p = 0.000698), and ID1 (p= 0.000993), which were also prognostic of PFS and OS in a Cox regression model. CONCLUSION: Upon validation in a larger cohort, this data may serve as a radiogenomic biomarker to assess treatment response within early phases of treatment and adapt the treatment plan to individual biology.