Vol. 10 | Issue 3 - Neuroscience Outlook

VOL. 10 | ISSUE 3

NEUROSCIENCE OUTLOOK

NEWS AND RESEARCH FROM THE DEPARTMENTS OF NEUROLOGY AND NEUROSURGERY AT GEORGIA REGENTS NEUROSCIENCE CENTER

GLIOBLASTOMA: EXPLORING NOVEL THERAPIES From gene sequencing to targeted therapies

FROM THE CHAIRMEN

DEPARTMENT NEWS

Cargill H. Alleyne Jr., M.D., and David C. Hess, M.D.

We are delighted to present another issue of Neuroscience Outlook, the newsletter of the departments of Neurology and Neurosurgery.

In the Department News section of this issue, we feature the evolving multidisciplinary adult neuro-oncology program at GRU Cancer Center led by Olivier Rixe, M.D., Ph.D., our medical neuro-oncologist, and highlight the critical role of the nurse navigator. Dr. Rixe came to GRU Cancer Center in April 2012 from the University of Cincinnati and has done a tremendous job with the program. In the Research Spotlight, we explore promising new therapeutic options for glioblastoma multiforme and in the Clinical Spotlight, we highlight our Multiple Sclerosis Center.

We also list the accomplishments of the faculty and the residents in the Faculty Update and Resident Update sections. The presentations and publications of our departments are also listed. We hope you enjoy this issue.

Cargill H. Alleyne Jr., M.D. Professor and Marshall Allen Distinguished Chair of Neurosurgery calleyne@gru.edu

David C. Hess, M.D. Professor and Presidential Distinguished Chair of Neurology dhess@gru.edu

NEUROSCIENCE OUTLOOK A publication of the Georgia Regents University Departments of Neurology and Neurosurgery Editor-in-chief: Cargill H. Alleyne Jr., M.D. Editor: Phil Malkinson Illustrations: Colby Polonsky, M.S. Contributors: Olivier Rixe, M.D., Ph.D., Michelle De Jesus, M.D., Suzanne Smith, M.D., Rebecca Rahn, P.A.-C Alison Diamond, RN, BSN

2

NEUROSCIENCE OUTLOOK ď ˝ Volume 10 | Issue 3

The multidisciplinary Adult Neuro-Oncology Program develops optimal individualized treatment plans that use advanced technology and procedures to treat complex tumors.

From Basic Science to Compassionate Care

The multidisciplinary Adult Neuro-Oncology Program at GRU Cancer Center offers diagnosis and treatment recommendations The recent launch of the neuro-oncology program at GRU Cancer Center offers hope, compassion, expertise, and advanced technologies to patients from across the region and the U.S. Our academic program is fully open for collaborations with other centers, physician practice groups, or individual practitioners.

The program is closely affiliated with the departments of Neurosurgery, Neurology, Neuroradiology, and Neuropathology, and the Cancer Center at GRU. Through our multidisciplinary clinic, patients have the benefit of tumor boards and clinics with our team of surgical, medical, and radiation oncologists, including our genetic counselor, social worker, nutritionist, and nurse navigator, who are all present in one place at the same time to develop optimal individualized treatment plans.

Our multidisciplinary team of experts uses advanced technology and procedures to treat complex tumors of the central nervous system, as well as neurologic complications of cancer and its treatments. A Web-based tumor board is accessible twice a month by affiliated centers in Georgia (Rome, Albany, Dublin) or non-affiliated partners. We deliver recommendations for diagnosis and treatment, but also perform a screening for potential enrollment in our clinical trials.

The program has a specific emphasis on: 1. CLINICAL TRIALS AND EARLY DRUG DEVELOPMENT IN NEURO-ONCOLOGY Our goal is to design innovative clinical trials for patients with brain tumors who have failed conventional therapy and test new therapeutic hypotheses based on our three scientific missions: immune modulation, angiogenesis, and cell signaling and biomarkers. The program, in collaboration with the Experimental Therapeutics Program at the Cancer Center, is opening clinical trials for primary brain tumors and brain metastases. For example, recent trials have been initiated to evaluate the role of front-line vaccines in newly diagnosed GBM, or immune modulators in combinations with bevacizumab, radiation, or chemotherapy for recurrent GBM (see p. 8 in this issue).

2. BASIC AND TRANSLATIONAL RESEARCH Our research program focuses on the molecular mechanisms underlying brain tumors that have the highest potential to translate into clinically relevant therapies. Our core facilities have the ability to explore the entire genome of the

brain tumors using next-generation sequencing technology. Current evaluations are underway to explore the regulation of the EGFR gene in GBM, and to detect circulating blood markers (Detection of EGFRvIII mutant DNA in the peripheral blood of brain tumor patients. J. Neurooncol. 2013 Jul 23). Our innovative immunology program has identified new pathways (such as IDO or Indoleamine 2,3-dioxygenase) that will be evaluated in a clinical intervention in a GBM trial activated for fall 2013.

3. COMPASSIONATE CARE Our clinical practice is patient- and family-centered.

Dedicated resources have been allocated to offer the strongest support for our brain tumor patients and their families. A patient navigator (see p. 4 in this issue) helps the patients through the different multimodal steps of their therapy and during the healing phase of their recovery period. An integrative medicine program will be launched in fall 2013 with a specific focus on a mind-body approach. It will include meditation, acupuncture, yoga, reiki, music therapy, hypnosis, aromatherapy, healing touch, and other supportive-care methods to enhance the efficacy of conventional therapies and reduce their toxicities.

The GRU Cancer Center Neuro-Oncology team includes: A multi-disciplinary clinic with:

8 neurosurgeons Cargill Alleyne: calleyne@gru.edu Haroon Choudhri: hchoudhri@gru.edu Cole Giller: cgiller@gru.edu Ian Heger: iheger@gru.edu S. Dion Macomson: smacomso@gru.edu Scott Rahimi: srahimi@gru.edu Jonathan Tuttle: jtuttle@gru.edu John Vender: jvender@gru.edu 1 adult neuro-oncologist Olivier Rixe: orixe@gru.edu 2 neuropathologists Amyn Rojiani: arojiani@gru.edu Suash Sharma: susharma@gru.edu 3 neuroradiologists Ramon Figuero: rfigueroaortiz@gru.edu Scott Forseen: sforseen@gru.edu Bruce Gilbert: bgilbert@gru.edu 1 neurologist/epilepsy specialist Debra Moore-Hill: dmoorehill@gru.edu 1 radiation oncologist Feng-Ming Kong: fkong @gru.edu

1 nurse navigator Alison Diamond: adiamond@gru.edu

1 skull base ENT surgeon Arturo Solares: csolares@gru.edu

2 skull base neurosurgeons Cargill Alleyne: calleyne@gru.edu John Vender: jvender@gru.edu 1 genetic counselor Mallory Hire: mhire@gru.edu

1 dietician Randalynn Hajek: rhajek@gru.edu

Tumor Board, bi-weekly (Contact: Alison Diamond at adiamond@ gru.edu or 706-721-4422) Gamma-Knife Unit (gammaknife@ gru.edu) Clinical Research Unit (pbourbo@gru.edu) Basic Research Program (with 12 principal investigators) Dr. Rixe and Dr. Alleyne attend a tumor board session.

Volume 10 | Issue 3 gru.edu/neuro

3

Ian Heger, M.D., (Department of Neurosurgery) was selected as a Castle Connolly’s “Top Doctor” in the region.

FACULTY & STAFF UPDATES Cargill H. Alleyne Jr., M.D., (Department of Neurosurgery) chaired the Neurology/ Neurosurgery section of the National Medical Association at its annual meeting in Toronto in July.

He moderated the Clarence Greene Stroke symposium at the same meeting. He also completed his term as president of the Georgia Neurosurgical Society at its annual meeting, in Sea Island, Ga., in May 2013 and moderated a panel discussion, “Management of complex vascular lesions,” at the same meeting. In addition, he was cited in Augusta magazine as one of the Best Doctors in America and he was listed by the America Consumer Research Council as one of America’s Top Surgeons.

James E. Carroll, M.D., (Department of Neurology) was cited by Augusta magazine as one of the Best Doctors in America.

Haroon F. Choudhri, M.D., (Department of Neurosurgery) was selected as a Castle Connolly’s “Top Doctor” in the region.

Krishnan M. Dhandapani, Ph.D., (Department of Neurosurgery) was awarded an NIH/NINDS R03 grant entitled “NLRP3 inflammasome and TBI” (R03NS084228, $150,000 from 6/1/13–5/31/15). He also served on several study sections, including the Brain Injury and Neurovascular Pathologies (BINP) study section (NIH), the Special Emphasis Panel on Sports Related TBI and SCI (NIH), and the Neurobiology C study section (VA).

Cole A. Giller, M.D., Ph.D., M.B.A., (Department of Neurosurgery) was cited by Augusta magazine as one of the Best Doctors in America.

David C. Hess, M.D., (Department of Neurology) was awarded an NIH/NINDS R21 grant entitled “Remote ischemic preconditioning in acute ischemic stroke” (R21 NS081143, $275,000 direct costs, 10% effort from 4/1/13–3/30/15).

He also served on the editorial board of Stroke, Experimental and Translational Stroke, and Stroke Interventionalist, and was appointed Vice Chair of the Scientific Sessions Committee of the American Heart/Stroke Association. In addition, he was cited in Augusta magazine as one of the Best Doctors in America and was selected as one of Castle Connolly’s America’s Top Doctors.

Melanie King, Ph.D., (advisor K. Dhandapani, Department of Neurosurgery) successfully defended her Ph.D. thesis, “TNF-alpha signaling and intracerebral hemorrhage.”

Sergei A. Kirov, Ph.D., (Department of Neurosurgery) was awarded an American Heart Association Grant-in-Aid entitled “Brain injury depolarizations’ impact on the integrity of synaptic circuitry” (13GRNT16570006, 2-year direct cost: $150,000 from 2013–2015). He was also awarded an NIH/ NINDS R56 grant entitled, “Synaptic Circuitry in Stroke” (R56NS083858, 1-year direct cost $250,000 from 2013–2014).

DEPARTMENT NEWS

Nurse Navigator in Neuro-Oncology hired Individualized assistance facilitates timely access to medical and psychosocial care

4

In 2012, the Neuro-Oncology program acquired its first nurse navigator. The nurse navigator service at GRU Cancer Center refers to individualized assistance offered to patients and families to help them overcome health care system barriers and facilitate timely access to quality medical and psychosocial care (Comprehensive Cancer Control, 2009). In NeuroOncology, this assistance often starts at diagnosis and runs through all phases of the cancer care experience.

Allowing patients to be introduced to the nurse navigator early in their diagnosis is a best practice.

This will often alleviate misunderstandings patients may have, or keep track of those patients often lost to follow-up. The Neuro-Oncology navigator is the point person of the Neuro-Oncology care team.

Introducing the nurse navigator to the patient at

NEUROSCIENCE OUTLOOK  Volume 10 | Issue 3

Alison Diamond, RN, BSN, Neuro-Oncology & Experimental Therapeutics nurse navigator, guides cancer patients through the treatment process.

the time of diagnosis provides the patient with a resource to turn to when the patient has questions about their treatment options.

The role of the nurse navigator is complex and evolving. Our navigator program at GRU is still in its infancy. Nurse navigation is young in the field of medicine; it was only 1989 when Dr. Harold Freeman implemented the first patient navigation

Yong D. Park, M.D., (Department of Neurology) was the Chair of Scientific Programs of the 25th Annual Scientific Meeting & Reunion of Severance Alumni Association of North America, Yonsei University College of Medicine at Westin, Seattle, in August 2013.

Michael H. Rivner, M.D., (Department of Neurology) was cited by Augusta magazine as one of the Best Doctors in America.

Elizabeth A. Sekul, M.D., (Department of Neurology) was cited by Augusta magazine as one of the Best Doctors in America.

in America.

Kapil D. Sethi, MBBS, (Department of Neurology) was cited by Augusta magazine as one of the Best Doctors

John Vender, M.D., (Department of Neurosurgery) was listed as one of America’s Top Surgeons by the Consumer Research Council of America.

He was also cited by Augusta magazine as one of the Best Doctors in America.

RESIDENT UPDATES RESIDENT UPDATES Farewell:

Douglas G. Hughes, M.D., was honored at the annual neurosurgery graduation ceremony in June.

Dr. Hughes is currently in private practice in Reno, Nev. Samer Kassar, M.D., completed his neurology fellowship in June and is currently in private practice in Chicago.

Saima Khurram, M.D., completed her neurology fellowship in June.

She is currently

program. He recognized the need to decrease health care inequalities and delays to follow-up cancer care in Harlem Hospital, New York. The preliminary studies are showing that nurse navigation does improve patient satisfaction and even more so with early intervention.1,2 Health care decisions cannot be adequately made unless the patient is fully educated and aware of all the options. Improved communication allows the health care provider the ability to do their job without question and the patient has the confidence to know they have an additional resource in their nurse navigator with whom they can communicate.

Alison Diamond, RN, BSN (adiamond@gru.edu) References: 1. Comprehensive Cancer Control (2009). Cancer patient navigation program toolkit.

Retrieved from Kansas Comprehensive Cancer Control & Prevention website: www.cancerkansas.org 2. Shockney, L.D. (2010). Evolution of patient navigation. Clinical Journal of Oncology Nursing, 14(4), 405-407.

doing a Clinical Neurophysiology fellowship at GRU. Kent Posey, M.D., completed his neurology residency in June. Dr. Posey is currently completing a Clinical Neurophysiology fellowship at Georgia Regents University.

Dagmara Pychynski, M.D., completed her neurology residency in June.

Dr. Pychynski is currently completing a Clinical Neurophysiology fellowship at Georgia Regents University.

Welcome:

This July we welcomed our new PGY-1 neurosurgery resident Khoi Nguyen, M.D. Dr. Nguyen graduated from our own Medical College of Georgia at Georgia Regents University.

Five new PGY-2 neurology residents were also welcomed.

They were Puneet Dabas (St Petersburg Pavlov State Medical University, Russia), Shaun Shaker (St. George’s University, Grenada), Leila Darki (Ghazvin University of Medical Sciences, Iran), Andrew Erian (Ross University School of Medicine, Dominica), and Nitzmari MelendezVazquez (Child Neurology Resident from Ponce School of Medicine, Puerto-Rico).

Professor Fountas (seated on left) is pictured with Drs. Joseph Smith (seated on right), Cole Giller (standing on left), and Cargill Alleyne.

Visiting professor

Transitions

The neurosurgery department was delighted to host Professor Kostas N. Fountas, M.D., for a Grand Rounds presentation entitled “Extra-Operative Cortical Mapping for Language.”

Dr. Fountas is head of the Department of Neurosurgery at University of Thessaly School of Medicine in Larissa, Greece.

Dr. Fountas earned his medical degree from the National and Capodistrian University of Athens, Greece. He completed his neurosurgical training at the Medical Center of Central Georgia and a stereotactic-functional fellowship with Dr. Joseph Smith at the Medical College of Georgia, GRU.

Brooke Vaught, longtime business manager in the Neurology and Neurosurgery departments, has resigned her position to spend more time with her family. We wish her the best of luck in the future.

Volume 10 | Issue 3 gru.edu/neuro

5

CLINICAL SPOTLIGHT

Multiple sclerosis:

Slowing disease progression The Augusta Multiple Sclerosis Center’s multidisciplinary approach provides comprehensive care for MS patients

By Rebecca Rahn, P.A.-C, and Suzanne Smith, M.D.

6

Multiple sclerosis (MS) is a progressive neurologic disease with unpredictable, relapsing symptoms ranging from blindness to numbness to paralysis. The diagnosis is overwhelming and yet, for patients at the Augusta Multiple Sclerosis Center at Georgia Regents Health System, it is a part of

NEUROSCIENCE OUTLOOK  Volume 10 | Issue 3

day-to-day life. Angela is one such patient. One summer, while at the beach with her family, she noticed tingling in her legs. She assumed that her legs were sunburnt, but instead of improving with time, the symptoms progressively worsened. Over the course of a week, she developed lower extremity

weakness leading eventually to paralysis. Rather than relaxing on a beach, she was undergoing a variety of tests in a hospital, including MRIs, visual evoked potentials, and a lumbar puncture. She was diagnosed with MS and was referred to the Augusta MS Center for management.

The main goal of the Augusta MS Center is to improve the quality of life for people living with MS, utilizing a multidisciplinary approach to provide access to cutting-edge treatments and comprehensive care. Although there is no cure for MS, many medications are used to slow the progression. The decision process for sequencing disease-modifying medications (DMTs) has become far more complicated as newer medications have been brought to market; however, first-line treatment for most patients is still injectable therapy—either interferon beta or glatiramer acetate. Angela started with interferon: She was provided with injection training at her home and she was able to learn to give the injections herself.

For her symptoms of LE weakness, Angela was treated with IV methylprednisolone acutely. When administered by nurses who specialize in MS and are also chemotherapy-certified, a steroid infusion is not so scary to the patient. Angela was able to come into the clinic for the infusions and go home each day to be with her family. While many patients return to baseline functioning after a course of IV steroids, Angela continued to have some residual weakness in her legs. Collaboration with outpatient rehabilitation allowed her to slowly regain her strength. As a result of the weakness, Angela had been unable to drive and was nervous to get behind the wheel. Through a grant from the National MS Society, she was able to participate in a research study with the MS Center and Georgia Regents University’s Driving Simulation Lab, which gave her the confidence to drive again.

A routine depression screening during one of her visits confirmed that she was having difficulty adjusting to the diagnosis. In a program funded by the MS Foundation, she had free counseling sessions with the psychologists at the MS Center and learned necessary coping mechanisms. She seemed to do well for several months and life normalized.

After about a year, Angela started to develop increasing LE spasticity. She was treated with oral muscle relaxers, but the spasticity progressed, making her dependent on a cane for assistance ambulating. She decided to pursue treatment with intrathecal baclofen and was referred to neurosurgery for her test dose and pump

implantation. While adjustments are part of the process, Angela’s spasticity is likely to decrease.

Repeat MRIs demonstrated that Angela had a new demyelinating lesion and it was necessary to change her DMT. She was counseled about the available options, including glatiramer, natalizumab, teriflunomide, fingolimod, and dimethyl fumarate. She preferred to try an oral agent because of injection site reactions from interferon. She had a history of bradycardia and was considering having additional children, so fingolimod and teriflunomide were not ideal choices for her. Ultimately, her disease-modifying therapy was changed to dimethyl fumarate, which was FDA-approved for treating relapsing forms of MS in April 2013. Although the mechanism of action is unknown, dimethyl fumarate is an oral

agent, which is believed to activate the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway that is involved in the cellular response to oxidative stress. A future goal is to identify biomarkers that can help to ascertain the best medication for an individual, but until that time, dosing, mechanism of action, adverse effects, and efficacy drive medication decision-making. Angela’s journey is not complete and time will tell how she responds to dimethyl fumarate. Regardless of the disease course, through the Augusta MS Center, she will continue to have access to the multidisciplinary care she needs.

Volume 10 | Issue 3 gru.edu/neuro

7

RESEARCH SPOTLIGHT

Glioblastoma multiforme: Exploring new therapeutic avenues Recent advances reveal a wealth of information about the pathophysiology of GBM By Olivier Rixe, M.D., Ph.D. and Michelle De Jesus, M.D.

CDX-110 is a vaccine directed against EGFRvIII mutated tumors. The 13 amino acid peptide induces a specific cellular and antibody-specific response. Patients are selected based on their EGFR tumor status (30 percent of patients carry the deleted gene) after initial gross total resection.

8

1. HIGH EXPECTATIONS FROM IMMUNE THERAPY Vaccine therapies Despite advances in our understanding of the molecular biology of glioblastoma multiforme (GBM), the prognosis of this high-grade glioma remains poor. Median survival rates range from 12–15 months. GBMs almost universally recur despite conventional therapies, including maximal surgical resection, radiation, and chemotherapy.

Recent advances in research techniques have given rise to a wealth of new information regarding the pathophysiology of GBM and the four distinct molecular subgroups involved with the aberrant signaling pathways, namely EGFR, NF1, and PDGFRA/IDH1, which drive the tumor phenotype. The Cancer Genome Atlas Network recently proposed a new molecular classification of GBM based on these markers as follows: 1) Classical subgroup, which has an overexpression of EGFR, 2) the Mesenchymal subgroup, which involves lower

NEUROSCIENCE OUTLOOK ď ˝ Volume 10 | Issue 3

expression of NF1, and 3) Proneural, which has both alterations of PDGFRA and point mutations in IDH1 (Verhaak et al., Cancer Cell 2010). The overall prognosis and response to various types of therapy, such as dose-dense chemotherapy, vary by subtype.

This is a very promising approach to classification because it can provide a solid framework for the design of future clinical trials, and it highlights the urgent need for sensitive, highly reproducible, lowcost personalized biomarkers to accurately monitor residual and recurrent tumors and enhance the clinical management of GBM patients.

In addition to this classification and recent other landmark papers (Frattini et al., Nature Genetics 2013), there is a strong interest in exploring somatic mutations, which occur exclusively with GBM, which would eventually lead to the identification of a GBMspecific biomarker. One mutation is the EGFRvIII deletion. Approximately 33 percent of all high-grade gliomas express EGFRvIII, and it is a bona fide tumorspecific antigen with potent oncogenic properties.

It results from an in-frame deletion of 801 bp spanning exons 2 to 7 of the coding region of EGFR and leads to ligand-independent tyrosine kinase activity that activates persistent downstream phosphatidylinositol 3-kinase (PI3-K) pathways. Comparing their twoyear survival rate, virtually no EGFRvIII-positive patients survive past their second year versus about 15 percent of those patients who are EGFRvIIInegative. Currently, considerable effort is being put into the development of anti-EGFRvIII agents.

An antibody drug conjugate (AMG-595) is currently in phase 1 testing and is specifically designed to deliver a toxin into EGFRvIII-positive GBM cells, based on robust preclinical data.

We are currently conducting a phase 3 study at GRU testing an anti-EGFRvIII vaccine called CDX-110. This 13-amino acid peptide, administered subcutaneously, has demonstrated an outstanding activity in phase 2 studies, with a 24-month overall median survival compared to 15 months in the historical controls. In this front-line phase 3 study, 374 EGFRvIII-positive patients will receive the standard Stupp regimen (chemoradiation with temodar, after gross total

resection), and will be randomized (vaccine versus placebo, GRU PI: O. Rixe). This study can provide further evidence for the role of immune therapy in this tumor type, in combination with a standard therapy, and open a new paradigm for the therapeutic management of this subpopulation of patients.

Disrupting the immune tolerance in GBM Key cellular and molecular immune system mediators in the context of brain tumors have been identified, including TGF-ß, cytotoxic T cells, Tregs, CTLA4, PD-1/PD-L1, and IDO. New and promising immunotherapeutic drugs, as well as combinatorial strategies, which focus on the simultaneous inhibition of immunosuppressive checkpoints in both immune and brain tumor cells, will open new avenues for the treatment of high-grade gliomas.

In an investigator-initiated study conducted at GRU Cancer Center (PI: O. Rixe), we will evaluate in a phase I/II trial the role of indoximod in combination with temodar, bevacizumab, or stereotactic radiation in recurrent (temozolomide-resistant) glioma patients. Indoximod was developed to inhibit the indoleamine 2, 3 dioxygenase (IDO) enzymatic pathway, which is important in the natural regulation of immune responses, as previously identified at GRU by Davis Munn et al. Indoximod has very good oral bioavailability and favorable pharmacokinetics with once or twice daily dosing. In addition, the drug was well-tolerated in preclinical animal studies, with a significant anti-tumor effect. The overall goal of this study is to provide a foundation for future studies to make Indoximod part of the first-line therapy, in conjunction with radiation and temozolomide, or in combination with vaccine therapies, for newly diagnosed glioblastoma patients.

2. REVISITING OUR STRATEGY ON ANTI-ANGIOGENICS Large randomized studies evaluating the role of bevacizumab, a VEGF inhibitor, compared to standard therapy in newly diagnosed glioblastoma multiforme have been recently reported and did not meet their primary endpoints. In the RTOG study, bevacizumab (compared to a placebo) added to upfront standard of care (radiation plus temozolomide) failed to significantly extend progression-free survival and overall survival. A total of 637 newly diagnosed patients with GBM were randomized after initial surgery. After a median follow-up period of more than 20 months, median overall survival was 15.7 months with

bevacizumab and 16.1 months with standard therapy. Interestingly, a biomarker study, based on 234 patients enrolled in this trial, aimed to identify predictive markers for bevacizumab activity. A nine-gene signature performed at baseline identified a “favorable” profile with a highly significant higher survival after the use of bevacizumab (20.3 months) compared to those with an unfavorable profile (10.4 months, p<.0001). In an identical study conducted in Europe (AVAglio study), similar results have been observed with the absence of survival benefit (17 months in each arm). However, in this study the benefit on progression-free survival was significantly higher in the bevacizumab arm.

Finally, a German randomized phase 2 study conducted on 182 patients (Glarius study) with MGMT unmethylated glioblastoma compared bevacizumab plus irinotecan or temozolomide, all given with radiation therapy followed by maintenance therapy. At six months, progression-free survival was significantly higher with bevacizumab/ irinotecan (9.74 versus 5.99 months), with a minimal impact on overall survival (16.6 vs. 14.8 months).

These extensive but disappointing data do not currently support the routine use of bevacizumab as part of the upfront therapy with newly diagnosed GBM, despite a strong rational for its use in these VEGF-largely angiogenesis-dependent tumors, and a significant activity in recurrent disease. There is a clear need to identify robust predictive markers for bevacizumab activity. In a recent publication, the use of DCE-MRI to evaluate the microvessel tumor perfusion rate has been correlated with a better clinical outcome, but this preliminary study needs to be evaluated on a larger population size (Sorensen et al., Cancer Res. 2011).

Finally, we should attempt to explore the next generation of new agents that inhibit anti-VEGFassociated invasiveness. Celingitide, an anti-avb5 integrins, failed to demonstrate a clinical benefit in a recent phase 3 trial. At GRU Cancer Center, we are currently investigating the role of Nov C-ter, a non-VEGF antiangiogenic agent that targets two alternative pro-angiogenic pathways—apelin and adrenomedulin. Based on its promising preclinical antitumor activity in GBM, we are planning to conduct a first-in-human phase 1 study in patients with recurrent GBM.

Olivier Rixe, M.D., Ph.D. conducts research on vaccines, immunotherapeutic drugs, and anti-angiogenesis approaches to enhance clinical management of GBM patients.

Volume 10 | Issue 3 gru.edu/neuro

9

PUBLICATIONS & PRESENTATIONS

May–August 2013 PUBLICATIONS Farook JM, Shields J, Tawfik A, Markand S, Sen T, Smith SB, Brann DW, Dhandapani KM, Sen N Induction of GADD34 attenuates Akt activation and induces cell death following traumatic brain injury.

Cell Death and Disease 4:e75, 2013

King MD, Alleyne CH, Dhandapani KM TNF-alpha receptor antagonist, R-7050, improves neurological outcomes following intracerebral hemorrhage in mice.

Neurosci Letters 542:9296, 2013

Khan MM, Dhandapani KM, Zhang QG, Brann DW Estrogen regulation of spine density and excitatory synapses in rat prefrontal and somatosensory cerebral cortex.

Steroids 78:614-623, 2013

The percutaneously placed ventriculocholecystic (gallbladder) shunt is a cerebrospinal fluid diversion alternative. The technique of placing the distal catheter into the gallbladder using a percutaneous technique can be performed in patients with excessive intra-abdominal scarring. Additional tubing can be placed into the gallbladder to accommodate growth.

Bruno A, Close B, Switzer JA, Hess DC, Gross H, Nichols FT III, Akinwuntan AE Simplified modified Rankin Scale questionnaire correlates with stroke severity.

Clin Rehabil 27:724-7, 2013

Bruno A, Lanning KM, Gross H, Hess DC, Nichols FT III, Switzer JA Timeliness of intravenous thrombolysis via telestroke in Georgia.

Stroke 44:2620-2622, 2013 [doi: 10.1161/ strokeaha.113.001898] Hess DC, Sila CA, Furlan AJ, Wechsler LR, Switzer JA, Mays RW A double-blind placebocontrolled clinical evaluation of MultiStem for the treatment of ischemic stroke.

Int J Stroke. 2013 May 22. [doi: 10.1111/ijs.12065, Epub ahead of print] Wechsler LR, Tsao JW, Levine SR, SwainEng RJ, Adams RJ, Demaerschalk BM, Hess DC, Moro E, Schwamm LH, Steffensen S, Stern BJ, Zuckerman SJ, Bhattacharya P, Davis LE, Yurkiewicz IR, Alphonso AL American Academy of Neurology Telemedicine Work Group. Teleneurology applications: Report of the Telemedicine Work Group of the American Academy of Neurology.

Neurology 80:6706, 2013 [doi: 10.1212/

Names in blue indicate faculty members in the Georgia Regents University Neurosurgery or Neurology department.

10

NEUROSCIENCE OUTLOOK  Volume 10 | Issue 3

WNL.0b013e3182823361.

Epub Feb 12, 2013] Hess DC, Audebert HJ The history and future of telestroke.

Nat Rev Neurol 9:34050, 2013 [doi: 10.1038/ nrneurol.2013.86. Epub 2013 May 7] Shakir BA, Heger IM Percutaneous ventriculocholecystic shunt as cerebrospinal fluid diversion alternative: a technical report.

Contemporary Neurosurgery, August 2013 Shakir BA, Woodall MN, Choudhri HF Anterior cervical instrumentation, Kim DK, Vaccaro AR, Dickman C, Cho D, Lee S, and Kim I, eds.

Surgical Anatomy and Techniques to the Spine. 2nd edition Switzer JA, Forseen SE, Bruno A, Hess DC Serendipitous recanalization of basilar artery occlusion.

J Stroke Cerebrovasc Dis. 2013 [doi:10.1016/j. jstrokecerebrovasdis.

2013.06.019] Woodall MN, Nguyen K, Alleyne CH, Macomson SD Bilateral transverse sinus stenosis causing intracranial hypertension.

BMJ Case Reports, [doi: 10.1136/bcr-2013010513, August 2013]

PRESENTATIONS Alleyne CH Vascular malformations.

National Medical Association Meeting, Toronto, Canada, July 2013

Alleyne CH, Viers A, Allen M A brief history of neurosurgery in Augusta and at Georgia Regents University.

Georgia Neurosurgical Society Meeting, Sea Island, Ga., May 2013

Shields JS, Dhandapani KM Activation of microglial toll-like receptor-4 induces aquaporin-4 expression in astrocytes.

2013 National Neurotrauma Society Annual Meeting, Nashville, Tenn., August 2013 (poster)

Kirov SA Window into the injured brain; single neurons and astrocytes during osmotic and ischemic stress.

University of Helsinki Neuroscience Center Seminar Series, Helsinki, Finland, May 2013 Kirov SA Evolution of neuronal and astroglial disruption in brain trauma.

Neuroprotection against spreading depolarization.

Second International Symposium on In Vivo Microscopy, Helsinki, Finland, May 2013 Shakir B, Wang D, Rahimi S, Alleyne CH Cranioplasty after ‘Dura Sandwich’ technique during craniectomy versus single layer dura protection.

Georgia Neurosurgical Society Meeting, Sea Island, Ga., May 2013 Woodall MN, Tuttle J Resolution of retroodontoid pannus following occipital cervical fusion.

Georgia Neurosurgical Society Spring Meeting, Sea Island, Ga., May 2013

Dr. Kirov’s lab defines the immediate stroke and associated cytotoxic edema injury at the cellular level by using in vivo 2-photon microscopy. This state-of-the-art technique provides a dramatic window several hundred microns deep into the cortex to view in real time the damage and repair to neurons, astrocytes, and blood vessels. The new results show, in a natural setting unparalleled by any other venue, the highly dynamic process of ischemic penumbral recruitment into the infarct core.

Woodall MN, Tuttle J Resolution of retroodontoid pannus following occipital cervical fusion.

15th Annual Orthopedic Surgery Spine Conference, Augusta, Ga., May 2013 Alleyne CH, Sharma S Pituitary adenoma neuronal choristoma (PANCH): report of an unusual case.

American Association of Neuropathology Meeting, June 2013 Kirov SA Window into the injured brain: Neurons and astrocytes in early stroke and traumatic brain injury.

4th Annual Conference of Centre of Excellence for Integrated Approaches in Chemistry and Biology of Proteins (CIPKeBiP) & Superresolution

Kirov SA Neuronal and glial cell volume dynamics during spreading depolarization.

10th International Congress on Cell Volume Regulation: Novel Therapeutic Targets & Pharmacological Approaches, Moscow, August 2013

Microscopy, Institute of Pathological Physiology, Ljubljana, Republic of Slovenia, June 2013 Bhaumik D, Shields J, Alleyne C, Dhandapani K Curcumin analogue identification in improved anti-cancer effects on human glioblastoma cells.

2013 STAR presentation, Augusta, Ga., July 2013 (poster)

Volume 10 | Issue 3 gru.edu/neuro

11

Georgia Regents University 1120 15th St., AD 1114 Augusta, GA 30912

NON-PROFIT US POSTAGE

PAID

GEORGIA REGENTS UNIVERSITY

GRU-005

September–December 2013

CONFERENCE SCHEDULES

Neurosurgery 10–11 am Sept. 6

Anatomy

Sept. 5

Dr. David Hess

11 am–noon

Business Giller

Sept. 12

Dr. Tom Swift

noon–1 pm

Case Conference

Sept. 19

Dr. Suzanne Strickland

Sept. 26

Dr. Robert Sorrentino

10–11 am Sept. 13

Sept. 27

Neuro 101, June Yowtak

noon–1 pm

Case Conference Functional Giller

noon–1 pm

Case Conference

10–11 am

Resident Meeting

11 am–noon

Journal Club

noon–1 pm

M&M Business Giller

noon–1 pm

Case Conference

Oct. 25

Nov. 15

Oct. 31 Nov. 7

All conferences are held from 8–9 am

Case Presentation

Dr. Debra Moore-hill Dr. Michael Rivner Dr. Yong Park

Nov. 14

Dr. Tom Swift

Nov. 21

Dr. Jeff Switzer

Case Presentation

Nov. 28

Thanksgiving Holiday

Dec. 5

Dr. Suzanne Smith

Dec. 12

Dr. Tom Swift

Case Presentation

Dec. 19

Christmas Holiday

Radiology

Dec. 26

Christmas Holiday

11 am–noon

Functional Giller

noon–1 pm

Case Conference

10–11 am

Resident Meeting

11 am–noon

Journal Club

noon–1 pm

M&M Anatomy

11 am–noon

Business Giller

noon–1 pm

Case Conference Oral Board Review

11 am–noon

Neuro 101, Neil Woodall

noon–1 pm

Case Conference

10–11 am

Resident Meeting

11 am–noon

Journal Club

noon–1 pm

M&M Anatomy

11 am–noon

Business Giller

noon–1 pm

Case Conference

10–11 am Dec. 13

Dr. Subhashini Ramesh

Case Conference

10–11 am Dec. 6

Dr. Tom Swift

Oct. 17

noon–1 pm

10–11 am Nov. 8

Oct. 10 Oct. 24

Oral Board Review

11 am–noon

Neuro 101, David Wang

noon–1 pm

Case Conference

New Diagnostic Methods for Atrial Fibrillation

Dr. John Morgan

Neuro 101, Basheer Shakir

10–11 am Nov. 1

Oral Board Review

Oct. 3

Case Presentation

11 am–noon 10–11 am

Oct. 18

Anatomy

11 am–noon 10–11 am

Oct. 11

Radiology

11 am–noon

10–11 am Oct. 4

Oral Board Review

11 am–noon 10–11 am

Sept. 20

Neurology

Meetings North American Spine Society Oct. 9–12, New Orleans, La. American Neurological Association Oct. 13–15, New Orleans, La. Congress of Neurological Surgeons Oct. 19–23, San Francisco, Calif.

American Academy of Neurology Fall Session Oct. 25–27, Las Vegas, Nev.

American Board of Neurological Surgery (Orals) Nov. 12–15, Houston, Texas AANS/CNS Section on Pediatric Neurological Surgery Dec. 3–6, Toronto, Canada Georgia Neurosurgical Society Dec. 7–8, Greensboro, Ga.

Research Update in Neuroscience for Neurosurgeons Oct. 26–Nov. 2, Woods Hole, Mass.

As a regional referral center for the Southeastern U.S., the Georgia Regents Neuroscience Center of Excellence includes the area’s largest, most diverse team of adult and pediatric neurologists and neurosurgeons, including renowned experts in Parkinson’s disease, stroke, ALS, MS, functional and cerebrovascular neurosurgery, and complex spine surgery. To make an online referral, visit gru.edu/referral.