Neurology Commons^™

Brain Metastasis Dna Methylomes, A Novel Resource For The Identification Of Biological And Clinical Features., Matthew P Salomon, Javier I J Orozco, James S Wilmott, Parvinder Hothi, Ayla O Manughian-Peter, C Cobbs, Richard A Scolyer, Dave S B Hoon, Diego M Marzese

Articles, Abstracts, and Reports

Brain metastases (BM) are one the most lethal and poorly managed clinical complications in cancer patients. These secondary tumors represent the most common intracranial neoplasm in adults, most frequently originating from lung cancer, breast cancer, and cutaneous melanoma. In primary brain tumors, such as gliomas, recent advances in DNA methylation profiling have allowed for a comprehensive molecular classification. Such data provide prognostic information, in addition to helping predict patient response to specific systemic therapies. However, epigenetic alterations of metastatic brain tumors with specific biological and translational relevance still require much further exploration. Using the widely employed Illumina Infinium HumanMethylation 450K …

Epigenetic Profiling For The Molecular Classification Of Metastatic Brain Tumors., Javier I Orozco, Theo A Knijnenburg, Ayla O Manughian-Peter, Matthew P Salomon, Garni Barkhoudarian, John R Jalas, James S Wilmott, Parvinder Hothi, Xiaowen Wang, Yuki Takasumi, Michael E Buckland, John F Thompson, Georgina V Long, Charles S Cobbs, Ilya Shmulevich, Daniel F Kelly, Richard A Scolyer, Dave S B Hoon, Diego M Marzese

Articles, Abstracts, and Reports

Optimal treatment of brain metastases is often hindered by limitations in diagnostic capabilities. To meet this challenge, here we profile DNA methylomes of the three most frequent types of brain metastases: melanoma, breast, and lung cancers (n = 96). Using supervised machine learning and integration of DNA methylomes from normal, primary, and metastatic tumor specimens (n = 1860), we unravel epigenetic signatures specific to each type of metastatic brain tumor and constructed a three-step DNA methylation-based classifier (BrainMETH) that categorizes brain metastases according to the tissue of origin and therapeutically relevant subtypes. BrainMETH predictions are supported by routine histopathologic evaluation. …

Intratumoral Delivery Of Mdna55, An Interleukin-4 Receptor Targeted Immunotherapy, By Mri-Guided Convective Delivery For The Treatment Of Recurrent Glioblastoma, Achal Achrol, Manish Aghi, Krystof Bankiewicz, Martin Bexon, Sotirios Bisdas, Steven Brem, Andrew Brenner, Nicholas Butowski, Melissa Coello, Seunggu Jude Han, Santosh Kesari, Fahar Merchant, Dina Randazzo, Diana Roettger, Michael Vogelbaum, Frank Vrionis, Miroslaw Zabek, John Sampson

Books, Presentations, Posters, Etc.

No abstract provided.

Conference Proceedings: Aurora Scientific Day 2018

Journal of Patient-Centered Research and Reviews

This journal supplement includes selected abstracts from among the more than 50 presented at the 44th annual Aurora Scientific Day research symposium. Held May 25, 2018, in Milwaukee, Wisconsin, Aurora Scientific Day provides a forum for original research conducted by faculty, fellows, residents, and other allied health professionals affiliated with Aurora Health Care, an integrated health system with hospitals and clinics in Wisconsin and Illinois.

Dual Inhibition Of Bcl-2/Bcl-Xl And Xpo1 Is Synthetically Lethal In Glioblastoma Model Systems, Enyuan Shang, Yiru Zhang, Chang Shu, Chiaki Tsuge Ishida, Elena Bianchetti, Mike-Andrew Westhoff, Georg Karpel-Massler, Markus D. Siegelin

Publications and Research

XPO1 has recently emerged as a viable treatment target for solid malignancies, including glioblastoma (GBM), the most common primary malignant brain tumor in adults. However, given that tumors become commonly resistant to single treatments, the identification of combination therapies is critical. Therefore, we tested the hypothesis that inhibition of anti-apoptotic Bcl-2 family members and XPO1 are synthetically lethal. To this purpose, two clinically validated drug compounds, the BH3-mimetic, ABT263, and the XPO1 inhibitor, Selinexor, were used in preclinical GBM model systems. Our results show that inhibition of XPO1 reduces cellular viability in glioblastoma cell cultures. Moreover, addition of ABT263 significantly …

Prothrombin Complex Concentrates Or Recombinant Factor Viia Are More Effective Than Fresh-Frozen Plasma At Lowering Inr In Patients With Liver Disease, Abel J. Ignatius

Clinical Research in Practice: The Journal of Team Hippocrates

A critical appraisal and clinical application of Kwon JO, MacLaren R. Comparison of fresh-frozen plasma, four-factor prothrombin complex concentrates, and recombinant factor VIIa to facilitate procedures in critically ill patients with coagulopathy from liver disease: a retrospective cohort study. Pharmacotherapy. 2016;36(10):1047-1054. doi: 10.1002/phar.1827

Procarbazine, Ccnu And Vincristine (Pcv) Versus Temozolomide Chemotherapy For Patients With Low-Grade Glioma: A Systematic Review., Karim Hafazalla, Arjun Sahgal, Blessing Jaja, James R Perry, Sunit Das

Student Papers, Posters & Projects

Low-grade gliomas (LGG) encompass a heterogeneous group of tumors that are clinically, histologically and molecularly diverse. Treatment decisions for patients with LGG are directed toward improving upon the natural history while limiting treatment-associated toxiceffects. Recent evidence has documented a utility for adjuvant chemotherapy with procarbazine, CCNU (lomustine), and vincristine (PCV) or temozolomide (TMZ). We sought to determine the comparative utility of PCV and TMZ for patients with LGG, particularly in context of molecular subtype. A literature search of PubMed was conducted to identify studies reporting patient response to PCV, TMZ, or a combination of chemotherapy and radiation therapy (RT). Eligibility …

Review Of Karyotypic Data From Low Grade Glial Brain Tumors, Specifically Pilocytic Astrocytomas, And Correlation Of Genetic Aberrations With Tumor Recurrence., Linda D. Cooley, Scott C. Smith, Lisa Warren, Melissa Gener, Kevin Ginn, John Herriges

Posters

Abstract: Brain tumors are the most common solid tumor of childhood. Approximately 50% of pediatric CNS tumors are low grade gliomas (WHO grade I or II) and Pilocytic astrocytoma (PA) is the most common accounting for 33% of all gliomas in children 0-14 years and ~18% of all childhood brain tumors. Prognosis with this slow-growing tumor is excellent; 10 year overall survival of ~95%. However, event free survival averages ~50%. Patient age and extent of tumor resection are key prognostic factors; tumor location and size impact resection and outcome. Histopathological features indicate PA is a benign tumor and rarely are …

Targeting Twist1 Through Loss Of Function Inhibits Tumorigenicity Of Human Glioblastoma., Andrei M Mikheev, Svetlana A Mikheeva, Liza J Severs, Cory C Funk, Lei Huang, José L Mcfaline-Figueroa, Jeanette Schwensen, Cole Trapnell, Nathan D Price, Stephen Wong, Robert C Rostomily

Articles, Abstracts, and Reports

TWIST1 (TW) is a bHLH transcription factor (TF) and master regulator of the epithelial-to-mesenchymal transition (EMT). In vitro, TW promotes mesenchymal change, invasion, and self-renewal in glioblastoma (GBM) cells. However, the potential therapeutic relevance of TW has not been established through loss-of-function studies in human GBM cell xenograft models. The effects of TW loss of function (gene editing and knockdown) on inhibition of tumorigenicity of U87MG and GBM4 glioma stem cells were tested in orthotopic xenograft models and conditional knockdown in established flank xenograft tumors. RNAseq and the analysis of tumors investigated putative TW-associated mechanisms. Multiple bioinformatic tools revealed significant …

Cdk5 Inhibition Resolves Pka/Camp-Independent Activation Of Creb1 Signaling In Glioma Stem Cells, Subhas Mukherjee, Carol Tucker-Burden, Emily Kaissi, Austin Newsam, Hithardhi Duggireddy, Monica Chau, Changming Zhang, Bhakti Diwedi, Manali Rupji, Sandra Seby, Jeanne Kowalski, Jun Kong, Renee Read, Daniel J. Brat

Neurology Faculty Publications

Cancer stem cells promote neoplastic growth, in part by deregulating asymmetric cell division and enhancing self-renewal. To uncover mechanisms and potential therapeutic targets in glioma stem cell (GSC) self-renewal, we performed a genetic suppressor screen for kinases to reverse the tumor phenotype of our Drosophila brain tumor model and identified dCdk5 as a critical regulator. CDK5, the human ortholog of dCdk5 (79% identity), is aberrantly activated in GBMs and tightly aligned with both chromosome 7 gains and stem cell markers affecting tumor-propagation. Our investigation revealed that pharmaceutical inhibition of CDK5 prevents GSC self-renewal in vitro and in xenografted tumors, at …

Long-Term Visual Outcomes In Optic Nerve Sheath Meningiomas Following Fractionated Stereotactic Radiotherapy, Sana Dastgheyb, Christian Fernandez, Md, Maria Werner-Wasik, Md, Voichita Bar-Ad, Md, David Andrews Md, James Evans, Md, Kevin Judy, Md, Sara Lally, Md, Carol Shields, Md, Arman Mashayekhi, Md, Wenyin Shi, Md, Phd, Christopher Farrell, Md

Sigma Xi Student Research Day

Introduction

Radiation therapy is often used for tumors of the optic nerve. The challenge with irradiating tumors surrounding structures associated with the eye is the risk of exposing the optic nerve, or other structures important to maintaining vision to potentially damaging radiation.

Fractionated stereotactic radiotherapy (FSRT) is commonly used for the treatment of optic nerve sheath meningiomas (ONSMs) for vision preservation. However, long term visual data in the literature is limited. We investigated visual outcomes in 27 patients with ONSMs after FSRT.

Stochastic Modeling Of Radiation-Induced Dendritic Damage On In Silico Mouse Hippocampal Neurons, Eliedonna Cacao, Vipan K. Parihar, Charles L. Limoli, Francis A. Cucinotta

Health Physics & Diagnostic Sciences Faculty Publications

Cognitive dysfunction associated with radiotherapy for cancer treatment has been correlated to several factors, one of which is changes to the dendritic morphology of neuronal cells. Alterations in dendritic geometry and branching patterns are often accompanied by deficits that impact learning and memory. The purpose of this study is to develop a novel predictive model of neuronal dendritic damages caused by exposure to low linear energy transfer (LET) radiation, such as X-rays, gamma-rays and high-energy protons. We established in silico representations of mouse hippocampal dentate granule cell layer (GCL) and CA1 pyramidal neurons, which are frequently examined in radiation-induced cognitive …

Emerging Cellular Therapies For Glioblastoma Multiforme., Paul J Choi, R Shane Tubbs, Rod J Oskouian

Articles, Abstracts, and Reports

Glioblastoma multiforme (GBM) is the most common type of malignant primary brain cancer in adults. It is composed of highly malignant cells that display metastatic and angiogenic characteristics, making it resistant to current first-line chemotherapy with temozolomide, an alkylating agent. Despite many years of research, GBM remains poorly responsive to multiple available therapies, giving GBM patients, who receive the conventional combination of chemoradiotherapies and surgical resection, a dismal prognosis. There is growing evidence that the conventional systemic chemotherapeutic agents for GBM are ineffective in improving the disease progression. We aim to explore the emerging cellular therapies which may play a …

14th Annual Parkview Research Symposium, Michael J. Mirro, Neil Sharma, Tammy Toscos, Roy Robertson Md, Micah Smith Md, Jason Voorhies Md

Presentations and Events

14th Annual Parkview Research Symposium: Innovative Interventions in Healthcare

Objectives

* Discuss latest innovative interventions in informatics, oncology, cardiology, orthopedids and neurosurgery.

* Develop a strategy for efficient diagnosis and treatment planning using the latest innovative techniques and research findings in informatics, oncology, cardiology, orthopedics and neurosurgery.

Ependymomas Overexpress Chemoresistance And Dna Repair-Related Proteins., Sherise D Ferguson, Shouhao Zhou, Joanne Xiu, Yuuri Hashimoto, Nader Sanai, Lyndon Kim, Santosh Kesari, John De Groot, David Spetzler, Amy B Heimberger

Articles, Abstracts, and Reports

Background: After surgery and radiation, treatment options for ependymoma are few making recurrence a challenging issue. Specifically, the efficacy of chemotherapy at recurrence is limited. We performed molecular profiling on a cohort of ependymoma cases in order to uncover therapeutic targets and to elucidate the molecular mechanisms contributing to treatment resistance.

Results: This ependymoma cohort showed minimal alterations in gene amplifications and mutations but had high expression rates of DNA synthesis and repair enzymes such as RRM1 (47%), ERCC1 (48%), TOPO1 (62%) and class III β-tublin (TUBB3) (57%), which are also all associated with chemoresistance. This cohort also had high …