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Item Cardiac Safety of TGF-β Receptor I Kinase Inhibitor LY2157299 Monohydrate in Cancer Patients in a First-in-Human Dose Study(Springer US, 2015-10) Kovacs, Richard J.; Maldonado, Giuliana; Azaro, Analia; Fernández, Maria S.; Romero, Federico L.; Sepulveda-Sánchez, Juan M.; Corretti, Mary; Carducci, Michael; Dolan, Melda; Gueorguieva, Ivelina; Cleverly, Ann L.; Pillay, N. Sokalingum; Baselga, Jose; Lahn, Michael M.; Department of Medicine, IU School of MedicineTransforming growth factor-beta (TGF-β) signaling plays an important role in the fetal development of cardiovascular organs and in the repair mechanisms of the heart. Hence, inhibitors of the TGF-β signaling pathway require a careful identification of a safe therapeutic window and a comprehensive monitoring of the cardiovascular system. Seventy-nine cancer patients (67 glioma and 12 solid tumor) enrolled in a first-in-human dose study and received the TGF-β inhibitor LY2157299 monohydrate (LY2157299) as monotherapy (n = 53) or in combination with lomustine (n = 26). All patients were monitored using 2D echocardiography/color and Spectral Doppler (2D Echo with Doppler) every 2 months, monthly electrocardiograms, thorax computer tomography scans every 6 months, and monthly serum brain natriuretic peptide (BNP), troponin I, cystatin C, high-sensitivity C-reactive protein (hs-CRP). Administration of LY2157299 was not associated with medically relevant cardiovascular toxicities, including patients treated ≥6 months (n = 13). There were no increases of troponin I, BNP, or hs-CRP or reduction in cystatin C levels, which may have been considered as signs of cardiovascular injury. Blood pressure was generally stable during treatment. Imaging with echocardiography/Doppler showed an increase in mitral and tricuspid valve regurgitation by two grades of severity in only one patient with no concurrent clinical symptoms of cardiovascular injury. Overall, this comprehensive cardiovascular monitoring for the TGF-β inhibitor LY2157299 did not detect medically relevant cardiac toxicity and hence supports the evaluation of LY2157299 in future clinical trials.Item Cribside Neurosonography: Real-Time Sonography for Intracranial Investigation of the Neonate(American Society of Neuroradiology, 1981) Edwards, Mary K.; Brown, David L.; Muller, Jans; Grossman, Charles B.; Chua, Gonzalo T.; Radiology and Imaging Sciences, School of MedicineA prospective study was made of 94 real-time sonographic sector scans of 56 neonates in a 6 month period. The examinations were performed using the anterior fontanelle as an acoustic window. In 17 cases, computed tomography (CT) head scans were available for comparison. In no case did the CT and sonographic examination disagree as to the size of the lateral ventricles. Abnormalities detected by sonography include ventriculomegaly, intracerebral hematomas, a congenital glioma, and several cystic lesions. Sonographic sector scanning produces excellent, detailed images of dilated lateral and third ventricles, uses no ionizing radiation, is less expensive than CT, and can be performed in the isolette, minimizing the risk of hypoxia and hypothermia. At Methodist Hospital Graduate Medical Center, sonography has replaced CT as the initial method of investigation of ventricular size. CT plays a complementary role in the evaluation of the posterior fossa, intracranial hemorrhage, and mass lesions.Item Differential Lipid Profiles of Normal Human Brain Matter and Gliomas by Positive and Negative Mode Desorption Electrospray Ionization – Mass Spectrometry Imaging.(PLOS, 2016) Jarmusch, Alan K.; Alfaro, Clint M.; Pirro, Valentina; Hattab, Eyas M.; Cohen-Gadol, Aaron A.; Cooks, R. Graham; Department of Neurological Surgery, IU School of MedicineDesorption electrospray ionization—mass spectrometry (DESI-MS) imaging was used to analyze unmodified human brain tissue sections from 39 subjects sequentially in the positive and negative ionization modes. Acquisition of both MS polarities allowed more complete analysis of the human brain tumor lipidome as some phospholipids ionize preferentially in the positive and others in the negative ion mode. Normal brain parenchyma, comprised of grey matter and white matter, was differentiated from glioma using positive and negative ion mode DESI-MS lipid profiles with the aid of principal component analysis along with linear discriminant analysis. Principal component–linear discriminant analyses of the positive mode lipid profiles was able to distinguish grey matter, white matter, and glioma with an average sensitivity of 93.2% and specificity of 96.6%, while the negative mode lipid profiles had an average sensitivity of 94.1% and specificity of 97.4%. The positive and negative mode lipid profiles provided complementary information. Principal component–linear discriminant analysis of the combined positive and negative mode lipid profiles, via data fusion, resulted in approximately the same average sensitivity (94.7%) and specificity (97.6%) of the positive and negative modes when used individually. However, they complemented each other by improving the sensitivity and specificity of all classes (grey matter, white matter, and glioma) beyond 90% when used in combination. Further principal component analysis using the fused data resulted in the subgrouping of glioma into two groups associated with grey and white matter, respectively, a separation not apparent in the principal component analysis scores plots of the separate positive and negative mode data. The interrelationship of tumor cell percentage and the lipid profiles is discussed, and how such a measure could be used to measure residual tumor at surgical margins.Item In vitro effect of chlorambucil on human glioma cell lines (SF767 and U87-MG), and human microvascular endothelial cell (HMVEC) and endothelial progenitor cells (ECFCs), in the context of plasma chlorambucil concentrations in tumor-bearing dogs(PLOS, 2018-09-07) Reese, Michael J.; Knapp, Deborah W.; Anderson, Kimberly M.; Mund, Julie A.; Case, Jamie; Jones, David R.; Packer, Rebecca A.; Medicine, School of MedicineThe objective of this study was to investigate a possible mechanism of action of metronomic chlorambucil on glioma by studying the in vitro cytotoxicity and anti-angiogenic effects on glioma and endothelial cells, respectively. The in vitro LD50 and IC50 of chlorambucil were determined using human SF767 and U87-MG glioma cell lines, human microvascular endothelial cells (HMVECs) and human endothelial colony forming cells (ECFCs). Results were analyzed in the context of chlorambucil concentrations measured in the plasma of tumor-bearing dogs receiving 4 mg m-2 metronomic chlorambucil. The LD50 and IC50 of chlorambucil were 270 μM and 114 μM for SF767, and 390 μM and 96 μM for U87-MG, respectively. The IC50 of chlorambucil was 0.53 μM and 145 μM for the HMVECs and ECFCs, respectively. In pharmacokinetic studies, the mean plasma Cmax of chlorambucil was 0.06 μM. Results suggest that metronomic chlorambucil in dogs does not achieve plasma concentrations high enough to cause direct cytotoxic or growth inhibitory effects on either glioma or endothelial cells.Item miR-1908 as a novel prognosis marker of glioma via promoting malignant phenotype and modulating SPRY4/RAF1 axis(Spandidos Publications, 2017-11) Chai, Zhi; Fan, Huijie; Li, Yanyan; Song, Lijuan; Jin, Xiaoming; Yu, Jiezhong; Li, Yanhua; Ma, Cungen; Zhou, Ran; Medicine, School of MedicineMicroRNAs (miRNAs) are reported to be involved in the development of glioma. However, study on miRNAs in glioma is limited. The present study aimed to identify miRNAs which can act as potential novel prognostic markers for glioma and analyze its possible mechanism. We show that miR-1908 correlates with shorter survival time of glioma patients via promoting cell proliferation, invasion, anti-apoptosis and regulating SPRY4/RAF1 axis. Analysis of GEO and TCGA database found that miR-1908 was significantly upregulated in glioma tissues, and strongly associated with shorter survival time of glioma patients. Further Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that miR-1908 is mainly involved in regulating cell proliferation, invasion and apoptosis. To further confirm the above results, in vitro, glioma U251 cells were transfected with miR-1908 mimics or inhibitor, and upregulated miR-1908 promoted U251 cell proliferation, and enhanced the ability of invasion by transwell assay. In addition, upregulated miR-1908 also enhanced anti-apoptosis ability of U251 cells through decreasing pro-apoptosis protein Bax expression. Since miRNAs regulate numerous biological processes by targeting broad set of messenger RNAs, validated target genes of miR-1908 in glioma were analyzed by Targetscan and miRTarBase databases. Among them SPRY4 was significantly decreased in glioma tissues and associated with short survival time, which was selected as the key target gene of miR-1908. Moreover, protein-protein interaction (PPI) showed that SPRY4 could interacted with pro-oncogene RAF1 and negatively correlated with RAF1 expression. Consistent with above analysis, in vitro, western blot analysis identified that miR-1908 upregulated significantly decreased SPRY4 expression and increased RAF1 expression. Hence, miR-1908 was correlated with poor prognosis of glioma via promoting cell proliferation, invasion, anti-apoptosis and regulating SPRF4/RAF1 axis. Our results elucidated the tumor promoting role of miR-1908 and established miR-1908 as a potential novel prognostic marker for glioma.Item Molecular Classification of Gliomas is Associated with Seizure Control: A Retrospective Analysis(Springer, 2021) Easwaran, Teresa P.; Lancki, Nicola; Henriquez, Mario; Vortmeyer, Alexander O.; Barbaro, Nicholas M.; Scholtens, Denise M.; Ahmed, Atique U.; Dey, Mahua; Pathology and Laboratory Medicine, School of MedicineClassically, histologic grading of gliomas has been used to predict seizure association, with low-grade gliomas associated with an increased incidence of seizures compared to high-grade gliomas. In 2016, WHO reclassified gliomas based on histology and molecular characteristics. We sought to determine whether molecular classification of gliomas is associated with preoperative seizure presentation and/or post-operative seizure control across multiple glioma subtypes. All gliomas operated at our institution from 2007 to 2017 were identified based on ICD 9 and 10 billing codes and were retrospectively assessed for molecular classification of the IDH1 mutation, and 1p/19q codeletion. Logistic regression models were performed to assess associations of seizures at presentation as well as post-operative seizures with IDH status and the new WHO integrated classification. Our study included 376 patients: 82 IDH mutant and 294 IDH wildtype. The presence of IDH mutation was associated with seizures at presentation [OR 3.135 (1.818-5.404), p < 0.001]. IDH-mutant glioblastomas presented with seizures less often than other IDH-mutant glioma subtypes grade II and III [OR 0.104 (0.032-0.340), p < 0.001]. IDH-mutant tumors were associated with worse post-operative seizure outcomes, demonstrated by Engel Class [OR 2.666 (1.592-4.464), p < 0.001]. IDH mutation in gliomas is associated with an increased risk of seizure development and worse post-operative seizure control, in all grades except for GBM.Item MR1 overexpression correlates with poor clinical prognosis in glioma patients(Oxford University Press, 2021-02-20) Kubica, Phillip; Lara-Velazquez, Montserrat; Bam, Marpe; Siraj, Seema; Ong, Irene; Liu, Peng; Priya, Raj; Salamat, Shahriar; Brutkiewicz, Randy R.; Dey, Mahua; Microbiology and Immunology, School of MedicineBackground: Glioblastoma is the most common adult primary brain tumor with near-universal fatality. Major histocompatibility complex (MHC) class I molecules are important mediators of CD8 activation and can be downregulated by cancer cells to escape immune surveillance. MR1 is a nonclassical MHC-I-like molecule responsible for the activation of a subset of T cells. Although high levels of MR1 expression should enhance cancer cell recognition, various tumors demonstrate MR1 overexpression with unknown implications. Here, we study the role of MR1 in glioma. Methods: Using multi-omics data from the Cancer Genome Atlas (TCGA), we studied MR1 expression patterns and its impact on survival for various solid tumors. In glioma specifically, we validated MR1 expression by histology, elucidate transcriptomic profiles of MR1 high versus low gliomas. To understand MR1 expression, we analyzed the methylation status of the MR1 gene and MR1 gene-related transcription factor (TF) expression. Results: MR1 is overexpressed in all grades of glioma and many other solid cancers. However, only in glioma, MR1 overexpression correlated with poor overall survival and demonstrated global dysregulation of many immune-related genes in an MR1-dependent manner. MR1 overexpression correlated with decreased MR1 gene methylation and upregulation of predicted MR1 promoter binding TFs, implying MR1 gene methylation might regulate MR1 expression in glioma. Conclusions: Our in silico analysis shows that MR1 expression is a predictor of clinical outcome in glioma patients and is potentially regulated at the epigenetic level, resulting in immune-related genes dysregulation. These findings need to be validated using independent in vitro and in vivo functional studies.Item Neuroinflammation in Autoimmune Disease and Primary Brain Tumors: The Quest for Striking the Right Balance(Frontiers Media, 2021-08-13) Mitchell, Dana; Shireman, Jack; Potchanant, Elizabeth A. Sierra; Lara-Velazquez, Montserrat; Dey, Mahua; Pediatrics, School of MedicineAccording to classical dogma, the central nervous system (CNS) is defined as an immune privileged space. The basis of this theory was rooted in an incomplete understanding of the CNS microenvironment, however, recent advances such as the identification of resident dendritic cells (DC) in the brain and the presence of CNS lymphatics have deepened our understanding of the neuro-immune axis and revolutionized the field of neuroimmunology. It is now understood that many pathological conditions induce an immune response in the CNS, and that in many ways, the CNS is an immunologically distinct organ. Hyperactivity of neuro-immune axis can lead to primary neuroinflammatory diseases such as multiple sclerosis and antibody-mediated encephalitis, whereas immunosuppressive mechanisms promote the development and survival of primary brain tumors. On the therapeutic front, attempts are being made to target CNS pathologies using various forms of immunotherapy. One of the most actively investigated areas of CNS immunotherapy is for the treatment of glioblastoma (GBM), the most common primary brain tumor in adults. In this review, we provide an up to date overview of the neuro-immune axis in steady state and discuss the mechanisms underlying neuroinflammation in autoimmune neuroinflammatory disease as well as in the development and progression of brain tumors. In addition, we detail the current understanding of the interactions that characterize the primary brain tumor microenvironment and the implications of the neuro-immune axis on the development of successful therapeutic strategies for the treatment of CNS malignancies.Item Pineal Region Gliomas: A Systematic Review of Clinical Features and Treatment Outcomes(International Institute of Anticancer Research, 2022) Bin Alamer, Othman; Palmisciano, Paolo; Rowe, Scott E.; Gupta, Aditya Dutta; Haider, Maryam; Alduhaymi, Mohammed; Cohen-Gadol, Aaron A.; Yu, Kenny; El-Ahmadieh, Tarek Y.; Haider, Ali S.; Neurological Surgery, School of MedicineBackground/aim: To review the current literature on pineal region gliomas, summarizing the clinical characteristics and treatment outcomes. Materials and methods: PubMed, Scopus, and Cochrane databases were used to identify relevant articles. Comprehensive clinical characteristic review and survival analysis were conducted. Results: Twelve studies describing 81 patients were included. The median age was 39 years (male=54.3%). Fifty patients (61.7%) had obstructive hydrocephalus requiring cerebrospinal fluid diversion with either ventriculoperitoneal shunt (VPS) (40.0%) or endoscopic third ventriculostomy (ETV) (24.0%). Patients who underwent VPS had significant survival benefits compared to ETV (p<0.05). All patients in our review underwent surgery, and gross-total resection (≥98%) was achieved in 34.6%. The supracerebellar infratentorial approach was the most employed surgical approach (62.3%). Chemotherapy was administered in 32.1% of cases, and radiotherapy in 40.7%. The median overall survival (OS) was 12 months, and the overall one-year survival rate was 60%. Conclusion: This study could not establish a correlation between the extent of tumor resection and positive treatment outcomes. However, among cases with hydrocephalus, patients who underwent VPS placement had better survival as compared to ETV.Item Surgical Neuro-Oncology: Management of Glioma(Elsevier, 2022) Mitchell, Dana; Shireman, Jack M.; Dey, Mahua; Pediatrics, School of MedicineGliomas are the most common intrinsic brain tumor in adults. Although maximal tumor resection improves survival, this must be balanced with preservation of neurologic function. Technological advancements have greatly expanded our ability to safely maximize tumor resection and design innovative therapeutic trials that take advantage of intracavitary delivery of therapeutic agents after resection. In this article, we review the role of surgical intervention for both low-grade and high-grade gliomas and the innovations that are driving and expanding the role of surgery in this therapeutically challenging group of malignancies.