TUMORS AANS/CNS SECTION ON TENTH BIENNIAL SATELLITE TUMOR SYMPOSIUM PROGRAM BOOK

Transcription

AANS/CNS SECTION ON
TUMORS
TENTH BIENNIAL SATELLITE TUMOR SYMPOSIUM
PROGRAM BOOK
APRIL 26–27, 2013
Hilton New Orleans Riverside
New Orleans, LA
This Program Book is sponsored by
Arbor Pharmaceuticals.
Jointly Sponsored by the AANS
JOIN THE AANS/CNS SECTION ON TUMORS
IN NEW ORLEANS
Dear Colleagues,
It is a great pleasure to welcome you to the 2013 Biennial Satellite Tumor Symposium of the AANS/CNS Section on
Tumors. This year is particularly special as it marks the 10th Anniversary of the inception of this flagship Tumor Section
meeting.
The primary goal of the meeting is to present and discuss the most recent advances in clinical, translational, and basic
science neuro-oncology research. Therefore, we have focused the meeting on peer reviewed oral and poster presentations
selected from over 200 abstracts submitted by your colleagues. We have tried to provide ample time for discussion of the
novel work that is presented.
We also look forward to exciting keynote lectures by Eric Holland, MD, PhD, on “Molecular Targeting of Gliomas Using
Mouse Models” and by Linda Liau, MD, PhD on “Imaging Paradigms to Characterize Tumor Genetics.” Both these lectures
should provide critical updates on the paradigm shifting work of these two neurosurgical leaders. We thank Drs. Holland
and Liau for their participation in the meeting.
In addition, we have organized a comprehensive seminar on the “Multi-disciplinary Management of Meningiomas.”
Co-sponsored by the Society of Neuro-Oncology (SNO), this seminar will explore all aspects of meningiomas, including
pathology and molecular genetics, animal models, imaging, surgery, radiotherapy, stereotactic radiosurgery, medical
therapies, quality of life and clinical trial opportunities. This symposium represents the continued effort of the Section on
Tumors to partner with our neuro-oncology colleagues in SNO. We hope this will be the first of many events co-sponsored
by the Section and SNO.
We also invite everyone to attend the evening seminars to be held on Friday night. The first will focus on the “Latest
Advances in Immunotherapy,” and the second will discuss “Surgical Adjunct to Optimize Tumor Resection.” These
seminars will provide opportunities to meet with panels of experts in their respective fields.
To celebrate the occasion of the 10th Anniversary of the Satellite Symposium, we have organized a reception on Saturday
evening. We invite everyone to attend this reception to help us celebrate this important milestone, to learn about the
history of this meeting, and to honor our Charles B. Wilson Awardee.
On behalf of the Executive Committee of the AANS/CNS Section on Tumors, we thank you for participating in this 10th
Biennial Satellite Tumor Symposium. We acknowledge the generous support of our corporate sponsors without whom
this meeting would not be possible. We especially thank the staff at the AANS, particularly Rhonda Foss, who did
yeoman’s work, while also making sure the organizing of this meeting was an enjoyable and fun experience.
Sincerely,
Frederick F. Lang Jr., MD, FAANS
Chair, AANS/CNS Section on Tumors
Nader Sanai, MD
Scientific Program Co-Chair,
AANS/CNS Section on Tumors
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Isaac Yang, MD
Scientific Program Co-Chair,
AANS/CNS Section on Tumors
TABLE OF CONTENTS
Joint Sponsorship Disclaimer
The material presented at the AANS/CNS Section on
Tumors 10th Biennial Satellite Tumor Symposium has
been made available by the AANS/CNS Section on
Tumors and the AANS for educational purposes only.
The material is not intended to represent the only, nor
necessarily the best, method or procedure appropriate
for the medical situation discussed, but rather it is
intended to present an approach, view, statement or
opinion of the faculty, which may be helpful to others who
face similar situations.
Continuing Medical Education Credit......................... 3
Disclaimer................................................................... 3
Learning Objectives.................................................... 3
Officers and Standing Committees of the
AANS/CNS Section on Tumors................................... 4
Keynote Speakers....................................................... 5
Hotel Floor Plans........................................................ 6
Neither the content (whether written or oral) of any
course, seminar or other presentation in the program,
nor the use of specific product in conjunction therewith,
nor the exhibition of any materials by any parties
coincident with the program, should be construed
as indicating endorsement or approval of the views
presented, the products used, or the materials
exhibited by the AANS/CNS Section on Tumors and
jointly sponsored by the AANS, or its Committees,
Commissions, or Affiliates.
Exhibit Hall Floor Plan................................................ 7
Commercial Support.................................................8
Exhibitor Listing.......................................................... 8
Program Schedule.................................................... 10
Disclosures............................................................... 14
Scientific Program.................................................... 17
Oral Presentation Abstracts
Scientific Program.................................................... 32
Electronic Poster Abstracts
Neither the AANS nor the AANS/CNS Section on Tumors
makes any statements, representations or warranties
(whether written or oral) regarding the Food and Drug
Administration (FDA) status of any product used or
referred to in conjunction with any course, seminar or
other presentation being made available as part of the
AANS/CNS Section on Tumors 10th Biennial Satellite
Tumor Symposium. Faculty members shall have sole
responsibility to inform attendees of the FDA status of
each product that is used in conjunction with any course,
seminar or presentation and whether such use of the
product is in compliance with FDA regulations.
Learning Objectives:
Upon completion of the CME activity, participants should
be able to:
n
n
n
U
pdate the audience on new neurosurgical techniques
for brain tumors.
R
eview recent knowledge gained from neuro-oncology
clinical trials.
E
valuate progress in the adjuvant therapy of brain tumors.
Claim CME Credit the Easy Way
Meeting attendees will self-report CME credit for the
programs they attend by going online to MyAANS.org.
PLEASE HAVE YOUR USERNAME [e-mail address] AND
PASSWORD HANDY during and after the meeting for
convenient completion and submission. Once logged in,
click on “Self Reporting” on the left and choose
AANS/CNS Section on Tumors 10th Biennial Satellite
Tumor Symposium.
Continuing Medical Education Credit
This activity has been planned and implemented in
accordance with the Essential Areas and policies of the
Accreditation Council of Continuing Medical Education
through the joint sponsorship of the AANS and AANS/CNS
Section on Tumors. The AANS is accredited by the ACCME
to provide continuing medical education for physicians.
Designation Statement
The AANS designates this live activity for a maximum of
13 AMA PRA Category 1 CreditsTM. Physicians should claim
only the credit commensurate with the extent of their
participation in the activity.
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AANS/CNS TENTH BIENNIAL SATELLITE TUMOR
SYMPOSIUM CONFERENCE COMMITTEE
Scientific Committee
Scientific Advisory Committee
Nader Sanai, MD, Scientific Co-Chair
Isaac Yang, MD, Scientific Co-Chair
Frederick F. Lang, Jr., MD, FAANS
Andrew Thomas Parsa, MD, PhD, FAANS
Michael A. Vogelbaum, MD, PhD, FAANS,
Society of Neuro-Oncology Representative
Michael Lim, MD, FAANS
Jonathan Harris Sherman, MD
Gordon Ho-Wan Li, MD
Gabriel Zada, MD
William T. Curry Jr., MD, FAANS
Theodore H. Schwartz, MD, FAANS
Ricardo Jorge Komotar, MD
James Bradley Elder, MD
OFFICERS OF THE AANS/CNS SECTION ON TUMORS
Chair.......................................................... Frederick F. Lang Jr., MD, FAANS
Past-Chair. ...................................................... Jeffrey N. Bruce, MD, FAANS
Secretary-Treasurer. .......................Frederick G. Barker II, MD, FAANS
Advisory Board................................... Gene H. Barnett, MD, MBA, FAANS
Mitchel S. Berger, MD, FAANS
Ennia Antonio Chiocca, MD, PhD, FAANS
William T. Couldwell, MD, PhD, FAANS
Roberta P. Glick, MD, FAANS
James M. Markert Jr., MD, FAANS
Joseph M. Piepmeier, MD, FAANS
Mark L. Rosenblum, MD, FAANS
James T. Rutka, MD, PhD, FAANS
Raymond Sawaya, MD, FAANS
Ronald E. Warnick, MD, FAANS
Journal of Neuro-Oncology. .............. Linda M. Liau, MD, PhD, FAANS
Medical Neuro-Oncology. .......................................... Susan M. Chang, MD
Matrix........................................... Ennio Chiocca, MD, PhD, FAANS (Chair)
Membership......................................................................... Allen E. Waziri, MD
Newsletter................................................... Jonas M. Sheehan, MD, FAANS
NeuroPoint Alliance..................... Mark E. Linskey, MD, FAANS (Chair)
Nominating...................................................... Jeffrey N. Bruce, MD, FAANS
Pediatrics............................................................. George I. Jallo, MD, FAANS
Programs................................................ Daniel P. Cahill, MD, PhD, FAANS
Christopher M. McPherson, MD, FAANS
Viviane S. Tabar, MD, FAANS
Michael A. Vogelbaum, MD, PhD, FAANS
Radiosurgery.................................... Jason P. Sheehan, MD, PhD, FAANS
Research. ...................................... Howard L. Weiner, MD, FAANS (ABTA)
William T. Curry Jr., MD, FAANS (BrainLAB)
Skull Base................................................... Nicholas B. Levine, MD, FAANS
Spine. .......................................................... Laurence D. Rhines, MD, FAANS
SANS MOC.......................................................................... Sarah C. Fouke, MD
Washington...................................................... Andrew E. Sloan, MD, FAANS
Young Neurosurgeons.........................................................Brian Nahed, MD
Committee Chairs
Awards...................................... Andrew Thomas Parsa, MD, PhD, FAANS
Bylaws......................................................Isabelle M. Germano, MD, FAANS
Clinical Trials. ................................................... Manish K. Aghi, MD, FAANS
John A. Boockvar, MD, FAANS
Constantinos G. Hadjipanayis, MD, PhD, FAANS
CCI...........................................................Aaron A. Cohen-Gadol, MD, FAANS
Brian T. Ragel, MD, FAANS
Guidelines...................................................Steven N. Kalkanis, MD, FAANS
Timothy C. Ryken, MD, FAANS
Jeffrey J. Olson, MD, FAANS
History.......................................................Anthony D’Ambrosio, MD, FAANS
Information Technology.................................. Jason A. Heth, MD, FAANS
International.................... Daniel Monte-Serrat Prevedello, MD (Chair)
Randy L. Jensen, MD, PhD, FAANS (Chair)
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KEYNOTE SPEAKERS
ERIC C. HOLLAND, MD, PHD
Dr. Holland is a board-certified neurosurgeon who specializes in the treatment of patients
with gliomas — the most common malignant brain tumor in adults — and metastatic brain
tumors. He is an attending physician in the Departments of Neurosurgery, and Neurology
as well as a laboratory head in the Sloan-Kettering Institute's Cancer Biology and Genetics
Program. He is also Vice Chair for Translational Research in the Department of Surgery.
In the laboratory, his research team is seeking to understand the molecular mechanisms
underlying the development of central nervous system tumors and developing models of these
cancers in mice. Dr. Holland, along with his colleagues, have developed mouse models of
many subtypes of gliomas, including the first truly lifelike model of glioblastoma — the most
lethal brain tumor in people. These animal models are essential for making the transition
from a scientific concept to understanding the behavior of a human tumor. Over the years, Dr. Holland has received several
awards, including the American Brain Tumor Association Research Award, the Bittner, Bressler, Farber Award, Searle
Scholar Award, Seroussi, the Steck Award and the Voynick Awards. In addition, he is a member of the National Academies’
Institute of Medicine.
LINDA M. LIAU, MD, PHD, FAANS
Dr. Linda M. Liau is Professor and Vice Chair of Academic Affairs in the Department of
Neurosurgery at the David Geffen School of Medicine at UCLA, and Director of the UCLA
Brain Tumor Program. She received her B.S. degree in Biochemistry and B.A. degree in
Political Science, both with honors, from Brown University. She then received her M.D. degree
from Stanford University and a Ph.D. degree in Molecular Neuroscience from UCLA. After
completing her residency and fellowship training in neurosurgery and neurosurgical oncology
at UCLA, she joined the faculty at the UCLA School of Medicine as an Assistant Professor
in 1997, and is now a tenured Professor of Neurosurgery at UCLA. She is currently a boardcertified neurosurgeon with both an active research laboratory and a busy clinical practice in
the field of brain tumors and neurosurgical oncology. She is currently ranked as one of the top 1% of neurosurgeons in the
country by U.S. News Top Doctors.
Dr. Liau currently serves on the Scientific Advisory Council of the National Brain Tumor Society, as well as the Scientific/
Medical Advisory Boards of the Musella Foundation for Brain Tumor Research, the Brad Kaminsky Foundation for Brain
Tumors, the Miles for Hope Foundation, and Voices Against Brain Cancer. She has been the Principal Investigator on
several NIH R01 research grants over the past 15 years, and is the mentor for several NIH training grants (R25, K01, K12,
T32) for neurosurgical residents, fellows, and postdoctoral researchers in her laboratory. Her research interests include
translational experimental therapeutics of cell-based therapies for brain tumors and characterization of molecular
targets involved in brain tumor pathogenesis and progression. She is the principal investigator on various clinical trials of
brain cancer vaccines and immunotherapy for patients with brain tumors and has published extensively in the field. She
has authored over 100 peer-reviewed research articles, along with several book chapters and a textbook entitled Brain
Tumor Immunotherapy. She is on the editorial boards of several scientific/medical journals and is the current Editor-inChief of the Journal of Neuro-Oncology.
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HILTON NEW ORLEANS RIVERSIDE FLOOR PLAN
Second Floor
Third Floor
6
EXHIBIT FLOOR PLAN
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COMMERCIAL SUPPORT
The AANS/CNS Section on Tumors wishes to thank the following companies for their generous support
of this year’s meeting.
GOLD SUPPORT LEVEL
SILVER SUPPORT LEVEL
NEUROSURGICAL
Rethinking Possibilities, Reshaping Lives
EXHIBITOR LISTING
Agenus
3 Forbes Road
Lexington, MA 02421
Phone: (781) 674-4711
Fax: (781) 674-4200
www.agenusbio.com
Booth #302
Brainlab
600 W. Van Buren, Suite 510
Chicago, IL 60607
Phone: (312) 257-0118
Fax: (708) 409-1619
www.brainlab.com
Booth #304
Agenus is a biotechnology company focused on developing cancer
immunotherapies, which includes Prohage G Series Vaccines
currently being tested in clinical trials of newly diagnosed and
recurrent GBM. Prophage Series contain HSPPC-96, which
comprises heat shock protein, gp96, and associated peptides that
are purified from the patients’ own tumor tissue.
Brainlab develops, manufactures and markets software-driven
medical technology, enabling access to improved, more efficient,
less-invasive patient treatments.
Arbor Pharmaceuticals, Inc.
980 Hammond Drive
Building Two, Suite 1250
Atlanta, GA 30328
Phone: (866) 516-4950
Fax: (678) 334-2433
www.arborpharma.com
Booth #100
Brainlab technology currently powers treatments in the fields of
neurosurgery, radiation oncology, orthopedics, ENT, CMF, spine,
and trauma.
Core products revolve around less-invasive image guided surgery
technology, more accurate and effective radiation therapy, and
integration through planning and collaboration systems that bring
patient data and physicians together.
Privately held since its formation in Munich, Germany in 1989,
Brainlab has more than 5,000 systems installed in about 80
countries. Brainlab employs 1,070 people in 17 offices worldwide,
including 280 Research & Development engineers, who form a
crucial part of the product development team.
Arbor Pharmaceuticals, a specialty pharmaceutical company
headquartered in Atlanta, GA, is pleased to announce the recent
acquisition of the U.S. rights for GLIADEL® Wafer (polifeprosan 20
with carmustine implant) from Eisai Inc. Gliadel® is manufactured
by Eisai Inc. for Arbor Pharmaceuticals, LLC. Gliadel® is a
registered trademark of Eisai Inc.
Learn more at www.brainlab.com.
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Elekta
400 Perimeter Center Terrace, Suite 50
Atlanta, GA 30346
Phone: (770) 670-2592
Fax: (770) 448-6338
www.elekta.com
Booth #202
NeuroBlate System®, a neurosurgical ablation device providing
controlled therapy for difficult-to-treat brain tumors. Monteris also
offers the AXiiiS® Stereotactic Miniframe; a single use platform
for image-guided, stereotactic brain biopsy; and the AtamA® Head
Coil and Stabilization System form MRI-guided neurosurgical
procedures requiring head fixation.
Elekta pioneers significant innovations and clinical solutions
for treating cancer and brain disorders. The company develops
advanced tools and treatment planning systems for radiation
therapy, radiosurgery and brachytherapy, as well as workflow
enhancing software systems. Through its products and services,
Elekta aims to improve, prolong and save patient lives.
Novocure
195 Commerce Way
Portsmouth, NH 03801
www.novocure.com
Booth #104
Novocure is an oncology company pioneering a novel treatment
modality for solid tumors called NovoTTF™ Therapy. In patients
with recurrent glioblastoma, treatment with NovoTTF Therapy
has been shown to provide patients with efficacy outcomes
comparable to chemotherapy with fewer side effects and a
better quality of life. NovoTTF Therapy is delivered by a portable,
non-invasive medical device designed for continuous use by
the patient. For full prescribing information please visit www.
novottftherapy.com.
Integra LifeSciences
311 Enterprise Drive
Plainsboro, NJ 08536
Phone: (609) 275-0500
Fax: (609) 275-5363
www.integralife.com
Booth #102
Integra LifeSciences, a world leader in medical devices, is
dedicated to limiting uncertainty for surgeons, so they can
concentrate on providing the best patient care. Integra offers a
vast portfolio of implants, devices, instruments and systems used
in neurosurgery and neuro critical care.
Osteomed
3885 Arapaho Rd
Addison, TX 75001-4314
Phone: (800) 456-7779
Fax: (972) 677-4731
www.osteomed.com
Booth #206
Medtronic
6743 Southpoint Drive N
Jacksonville, FL 32216
Phone: (800) 876-3133
Fax: (901) 332-3920
www.medtronic.com
Booth #208
OsteoMed is a leading global innovator, developer, manufacturer
and marketer of specialty medical devices, surgical implants and
powered surgical instruments.
Stryker
750 Trade Centre Way, Suite 200
Portage, MI 49002
Phone: (800) 962-6558
Fax: (269) 324-5484
www.stryker.com
Booth #204
Medtronic is the global leader in medical technology – alleviating
pain, restoring health and extending life for millions of people
around the world. During the past year, Medtronic provided
medical professionals with products and therapies to improve
the lives of nearly six million patients. Today, every five seconds
another person, somewhere in the world, is alive or living a fuller
life as a result of a Medtronic product or therapy.
Since the beginning, Stryker has taken pride in developing
innovative equipment and technology that helps medical
professionals perform their jobs better and more efficiently. Our
products include joint replacements, trauma, spine and micro
implant systems, biologics, powered surgical instruments,
surgical navigation systems, endoscopic products, patient
handling and emergency medical equipment.
Monteris Medical Inc.
16305 36th Avenue N, Suite 200
Plymouth, MN 55446
Phone: (763) 253-4710
Fax: (763) 746-0084
www.monteris.com
Booth #300
Formed in 1999, Monteris Medical is a privately held medical device
company dedicated to the development of innovative MRI guided,
laser-based brain cancer treatments. Monteris Medical markets
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PROGRAM SCHEDULE
Friday, April 26, 2013
2:14–2:24 PM
Rapid, Label Free Detection of Microscopic Brain Tumor
BoundPerrs with Coherent Raman Scattering Microscopy
Presenting Author: Daniel Orringer, MD
10:00 AM–7:00 PM
Registration
Hilton Exhibition Center Foyer, Second Floor
3:00–6:30 PM
Exhibit Hall Open
E-Poster Abstract Viewing
Hilton Exhibition Center Hall B&C, Second Floor
2:25–2:35 PM
Improving Functional Preservation in Acoustic
Neuroma Surgery
Presenting Author: Hirofumi Nakatomi
1:00-3:20 PM General Session I
Hilton Exhibition Center Hall A, Second Floor
Supported by an Educational Grant Provided by OsteoMed
2:36–2:46 PM
Morbidity of Repeat Transsphenoidal Surgery Assessed in
Over 1000 Operations
Presenting Author: Arman Jahangiri
2:47–2:57 PM
Comparative Integrated Analysis of Brain Tumor Initiating
Cells and Their Parent Tumors
Presenting Author: Candice Poon, MD
NEUROSURGICAL
1:00–1:10 PM
Opening Remarks
Nader Sanai, MD
2:58–3:08 PM
MicroRNA 100 Targets the ‘Silencing Mediator for Retinoid
Receptors’ (SMRT) Gene, Reduces Tumor Proliferation,
and Improves Survival in Glioblastoma
Presenting Author: John S. Kuo, MD, PhD, FAANS
1:10–1:40 PM
Keynote Address I
Molecular Targeting of Gliomas
Eric C. Holland, MD, PhD
3:09–3:19 PM
Prediction of Outcomes After Surgical Resection of
Glioblastoma Using Contrast Enhancing and FLAIR
Residual Tumor Volume
Presenting Author; Matthew M. Grabowski
Selected Abstract Presentations
Moderators: Nader Sanai, MD; Isaac Yang, MD
1:41–1:51 PM
Epileptic Seizures in Adult Diffuse Low Grade Gliomas.
A Multicentre Study of 1544 Cases
Presenting Author: Johan Pallud, MD
3:20–3:40 PM
Beverage Break in Exhibit Hall
1:52–2:02 PM
Periostin Induces Glioblastoma MRI T2/FLAIR Signal,
Cellular Invasion, and Angiogenesis
Presenting Author: Pascal Zinn, MD, PhD
3:00–7:00 PM
Exhibit Hall Open
2:02–2:12 PM
Surgery for Primary Supratentorial Brain Tumors in
the United States, 2000 to 2009: The Effect of Provider
Caseload on Complication Rates
Presenting Author: Victoria Trinh
3:40–6:00 PM
General Session II
NEUROSURGICAL
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3:40–4:10 PM
Keynote Address II
Imaging Paradigms to Characterize Tumor Genetics
Linda M. Liau, MD, PhD, FAANS
5:38–5:48 PM
Delay of GBM Adjuvant Therapy Does Not Decrease Overall
and Progression Free Survival: A Retrospective Analysis
Presenting Author: Matthew Z. Sun
6:00–7:00 PM
Opening Reception in Exhibit Hall
4:10–4:20 PM
miR 124 Systemically Enhances Antitumor Clearance
by Inhibiting STAT3 Signaling and Reversing Glioma
Associated Immune Suppression
Presenting Author: Amy B. Heimberger, MD, FAANS
7:00–8:00 PM Evening Symposium I–Immunotherapy for the Treatment
of Glioma Patients
Belle Chasse, Third Floor
Isaac Yang, MD
Michael Lim, MD, FAANS
Ian Parney, MD, PhD
This Evening Symposium is Supported by an Educational
Grant Provided by Agenus
4:21–4:31 PM
Intracranial Therapy of Glioblastoma by CED With a Novel
Bispecific Ligand Directed Diphtheria Toxin Targeting EGF
and uPA Receptors
Presenting Author: Yan Michael Li, MD
4:32–4:42 PM
MRI Based High Resolution Maps for Guiding Surgical
Procedures in Brain Tumor Patients
Presenting Author: Yael Mardor, MD
7:00–8:00 PM
Evening Symposium II–Surgical Adjuncts To Optimize Tumor
Resection: Applying Advanced Imaging And Navigation
Techniques To Maximize Resection And Minimize Morbidity
Melrose, Third Floor
Alessandro Olivi, MD, FAANS
Michael Edward Sughrue, MD
This Evening Symposium is Supported by an Educational
Grant Provided by Brainlab
4:43–4:53 PM
Post Transcriptional Regulation of O6 Methylguanine DNA
Methyltransferase (MGMT) by miR 603: A Step Toward
Personalized Glioblastoma Treatment
Presenting Author: Clark C. Chen, MD, PhD, FAANS
4:54–5:04 PM
Distinct Roles for Histone Methyltransferase Ezh2
in Epigenetically Promoting Adult Neural Stem Cell
Proliferation and Differentiation
Presenting Author: Ryan Salinas
Saturday, April 27, 2013
7:00 AM–6:00 PM
Registration
Hilton Exhibition Center Foyer, Second Floor
5:05–5:15 PM
High Field Intraoperative MRI and Endoscopy Provide
Complementary Extent of Transsphenoidal Resection
Improvements for Pituitary Adenoma
Presenting Author: Ralph Dacey Jr., MD
7:00–8:00 AM Continental Breakfast served in Exhibit Hall
5:16–5:26 PM
Tumor Derived Vasculogenesis in von Hippel Lindau
Syndrome Associated CNS Hemangioblastoma
Presenting Author: Jason Michael Frerich
7:00 AM–4:00 PM
Exhibit Hall Open
5:27–5:37 PM
Advanced MRI is Accurate and Cost Effective for Predicting
Recurrent Glioma versus Treatment Related Necrosis
Presenting Author: Jackson D. Hamilton, Jr.
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7:45 AM–9:00 AM
General Session III
9:00–9:10 AM
Introductory Remarks
9:00–10:10 AM
Meningioma Session I
NEUROSURGICAL
7:45–7:55 AM
Opening Remarks
Issac Young, MD
9:10–9:30 AM
Pathology and Molecular Genetics of Meningiomas
Arie Perry, MD
9:30–9:50 AM
Mouse Models of Meningiomas
Michel Kalamarides, MD, PhD
7:55–8:05 AM
Radiographic Predictors of Functional Recovery in Adult
Posterior Fossa Ependymomas
Presenting Author: Zaman Mirzadeh, MD
9:50–10:10 AM
Imaging
8:06–8:16 AM
Continuous Dynamic Mapping of Corticospinal Tract during
Surgery of Motor Eloquent Brain Tumors: Prospective Study
Presenting Author: Andreas Raabe
10:10–10:30 AM
10:30 AM-12:35 PM
Meningioma Session II
8:17–8:27 AM
Radical Resection Plus Radiation Therapy for Central
Nervous System Hemangiopericytoma
Presenting Author: Adam M. Sonabend Wothalter, MD
10:30–10:50 AM
Surgery for Meningiomas
Frederick G. Barker II, MD, FAANS
8:28–8:38 AM
SapC DOPS Nanovesicles Selectively Target Externalized
Phosphatidylserine and Identify Metastatic Brain Tumors
Presenting Author: Xiaoyang Qi
10:50–11:10 AM
Fractionated Radiation Therapy of Meningiomas
Leland Rogers, MD
8:39–8:49 AM
Utilizing PVI Z CCL21 Vault Nanoparticles as a Novel AntiTumor Therapy for Glioblastoma
Presenting Author: Isaac Yang, MD
11:10–11:30 AM
Radiosurgery of Meningiomas
Jason P. Sheehan, MD, PhD, FAANS
Moderators: Patrick Wen, MD; William T. Curry, Jr, MD, FAANS
8:50–9:00 AM
Importance of Extent of Resection in the Treatment of
GBM: How Much is Enough?
Presenting Author: Lauren Elana Rotman
11:30–11:40 AM
A Molecular Predictor of Meningioma Recurrence
Presenting Author: Erik P. Sulman
9:00 AM–5:00 PM
Symposium on Multidisciplinary Management of
Meningiomas
Co-Sponsored by Society for Neuro-Oncology
11:41–11:51 AM
The Novel Neoplasia Genes, TRAF7 and KLF4, Along with
SMO and AKT1, Define Clinically Distinct Meningiomas
Presenting Author: Murat Gunel, MD, FAANS
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11:52 AM–12:02 PM
Genomic and Transcriptomic Analysis Reveals an
Oncogenic Functional Module in Meningiomas
Presenting Author: Gabriel Zada, MD
3:15-3:25 PM
Autologous Vaccine Therapy to Control Invasive Canine
Meningioma
Presenting Author: Grace Elizabeth Pluhar
12:03–12:13 PM
Trends in Centralization of Meningioma Surgery in the
United States, 1988–2010: A Population Based Study
Presenting Author: Frederick G. Barker II, MD, FAANS
3:26-3:36 PM
Expression of CD163 Prevents Apoptosis Through the
Production of Granulocyte Colony Stimulating Factor in
Meningioma
Presenting Author: Hiroshi Nishihara
12:14–12:24 PM
Preclinical Studies of Intratumoral Cellular
Immunotherapy for Recurrent Meningiomas with
Alloresponsive Cytotoxic T Lymphocytes
Presenting Author: Richard George Everson, MD
3:37-3:47 PM
Increased [68Ga] DOTATOC Uptake in PET Imaging
Discriminates Meningioma and Tumor Free Tissue
Presenting Author: Jörg Christian Tonn, MD
12:25–12:35 PM
mTOR Inhibition as a Reasonable Strategy for
Meningioma Treatment
Presenting Author: Christian Mawrin
3:48-3:58 PM
Imaging and Clinical Factors Predictive of Atypical
Meningiomas
Presenting Author: Le (Lucy) He, MD
12:35–1:35 PM Lunch in Exhibit Hall
3:59–4:09 PM
Development of Atypical and Anaplastic Meningioma Cell
Resources: Results From Three Years
Experience at UCSF
Presenting Author: Charles David James
1:35–4:20 PM Meningioma Session III
4:10-4:20 PM
Progression of Atypical Meningiomas Irrespective of
Adjunctive Radiation
Presenting Author: Heather M. Kistka
1:35–1:55 PM
Medical Therapies of Meningiomas
Patrick Wen, MD
4:20–5:00 PM
Meningioma Session IV
Moderator: Michael A. Vogelbaum, MD, PhD, FAANS
1:55–2:15 PM
New Therapeutic Targets of Meningiomas
Rameen Beroukhim, MD, PhD
2:15–2:35 PM
Quality of Life of Patients with Meningiomas
Susan M. Chang, MD
4:20–5:00 PM
Point to Counter Point
Should Radiation Be Used for Newly Diagnosed or
Recurrent WHO Grade II Meningiomas?
Yes: Ricardo Jorge Komotar, MD
No: Franco de Monte, MD
2:35-2:55 PM
Clinical Trial Opportunities in Meningioma
Thomas J. Kaley, MD
5:00-7:00 PM
10th Biennial Satellite Tumor Symposium Celebration
Versailles Ballroom, Third Floor
This reception is supported by
2:55-3:15 PM
Moderators: Leland Roger, MD; James Bradley Elder, MD
13
DISCLOSURES
The AANS controls the content and production of the CME activity and attempts to ensure the presentation of balanced
objective information. In accordance with the Standards for Commerical Support established by the Accreditation Council
for Continuing Medical Education, speakers, paper presenters/authors and staff (and the significant others of those
mentioned) are asked to disclose any relationship they or their co-authors have with commercial companies which may be
related to the content of their lecture.
DISCLOSURES REPORTED
Rameen Beroukhim, MD, PhD
Novartis, Consultants
J. Bryan Iorgulescu
Aesculap, Inc., Consultants
AstraZeneca, Stock Shareholder (Directly purchased)
Randy Lynn Jensen, MD, PhD, FAANS
Medtronic, Consultants
Li Bie, Grant/Research Support Vivian Capilla-Gonzalez
NIH, Grant/Research Support
Pharmokinesis, Honorarium
Osteomed, Consultants
Susan M. Chang, MD
Novartis, Grant/Research Support
Medtronic, Consultants Schering, Grants/Research Support
Linda M. Liau, MD, PhD, FAANS
Northwest Biotherapeutics, Inc., Grant/Research Support
William T. Curry, Jr., MD, FAANS
Stryker CMF, Consultants
NIH, Grants/Research Support
Yael Mardor, MD
Zach, Guez, Last, Daniels and Mardor are authors on a
pending patent titled ‘vessel function maps’
Franco De Monte, MD, FAANS, FACS
Medtronic, Consultants, Honorarium
Murat Gunel, MD, FAANS
NIH, Grant/Research Support
Christian Mawrin
Pfizer Inc., Grant/Research Support, Other Financial or
Material Support
Gregory M. Kiez and Mehmet Kutman Foundation,
Grants/Research Support
Jackson D. Hamilton, Jr.
JDH—Travel expenses (‹$3000) were paid by
Anatom-e information systems for travel expenses
associated with a speaking engagement. Honorarium
LAH is owner of Anatom-e Information Systems, whose
program was used during some of the analysis. Other
Financial or Material Support
14
Ziaoyang Qu, PhD
Inventor on the patent (SapC-DOPS)
Merck, Consultants
Development and Commercialization has been licensed to
Bexion Pharmaceuticals, LLC
Pharmaco-kinesis, Consultants
Patrick Wen, MD
Novartis Consultants, Grant/Research Support, Honorarium
Inventor of Scientific Research in the Pre-clinical Stage for
Bexion Pharmaceuticals
Genentech, Consultants, Grants/Research Support,
Honorarium
Bexion Pharmaceuticals does not offer any marketable
treatments or drugs
Merck, Grants/Research Support, Honorarium
Theodore H. Schwartz, MD, FAANS
Wellcome Trust, Grant/Research Support
Pfizer, Grants/Research Support
Sanofi-Aventis, Grants/Research Support
Integra,Consultants
Fumio Yamaguchi, MD, PhD
Ministry of Education, Culture, Sport, Science, and
Technology, Japan (MEXT), Grant/Research Support
Visionsense, Honorarium
Andrew E. Sloan, MD, FAANS
Genentech, Consultants,
Other Financial or Material Support
Zaitun Zakaria
Consultants
Roche Pharmaceuticals, Inc, Consultants
Corinna C. Zygourakis, MD
Meningioma Mommas
Surgical Theatre, Consultants
Lentigen Inc., Grants/Research Support, Other Financial or
Material Support
Ruth Halperin Endowed Chair in Meningioma Research
(McDermott), Grant/Research Support
Erik P. Sulman
GlaxoSmithKline, Consultants
Reza and Georgianna Khatib Endowed Chair in Skull Base
Tumor Surgery (Parsa), Grants/Research Support
Jorg-Christian Tonn, MD
Merck Serono, Consultants, Honorarium
Roche, Consultants, Honorarium
2013
15
NON-DISCLOSURE INFORMATION
Speakers, paper presenters/authors and staff (and the significant others of those mentioned) who have reported they do
not have any relationships with commercial companies:
Amjad Anaizi, MD
Charles David James
Walter Rachinger
Patricia Anderson
Michel Kalamarides, MD, PhD
Shervin Rahimpour
Khaled M. A. Aziz, MD, PhD, FAANS
Farrukh Karimov, MD
Maryam Rahman, MD
El Mustapha Bahassi
Yasutaka Kato
Alexander Ramos
Frederick G. Barker II, MD, FAANS
Robert Givens Kellogg, MD
Leland Rogers, MD
Ernest Barthelemy
Kartik Kesavabhotla
Lara K. Ronan
Maria Blagia
Heather M. Kistka
Lauren Elana Rotman
Christian Andrew Bowers, MD
John S. Kuo, MD, PhD, FAANS
Ryan Salinas
Clark C. Chen, MD, PhD, FAANS
Nader Sanai, MD
Felipe Goncalves de Carvalho, MD
Christine Lauro
Christopher Ian Sanders Taylor, MD
Philip C. de Witt Hamer, MD
Gordon Ho-Wan Li, MD
Kenneth Schott
Yan Michael Li, MD
Lucia Schwyzer, MD
Sam Eljamel, MD, FRCS
Mohammad Arif Malik, MBBS, FCPS
Jason P. Sheehan, MD, PhD, FAANS
Richard George Everson, MD
Emmanuel Mandonnet
Leslie Smith
Javier Figueroa
Salvador Manrique, MD
Adam M. Sonabend Wothalter, MD
Elena Fomchenko
John M. McGregor, MD
T. Barrett Sullivan
Rhonda F. Foss
Zaman Mirzadeh, MD
Matthew Z. Sun
Jason Michael Frerich
Jennifer Moliterno Gunel, MD
Peter Sylvester
Matthew M. Grabowski
Jeffrey Murray
Yuzo Terakawa
Sanjeet Singh Grewal
Hirofumi Nakatomi
Nam D. Tran, MD
Puneet Gulati, MD
Hiroshi Nishihara
Victoria Trinh
William C. Gump, MD
Verrad Kwasi Nyame, MD
Stephanie Elizabeth Weiss, MD
John Franklin Hamilton, MD, PhD,
FAANS
Joseph Orinya Obande, MD
Anna Magdalena Wilk
Carl Irwin Odom
Jing Wu
Le (Lucy) He, MD
Sacit Bulent Omay, MD
Chunzhang Yang
Amy B. Heimberger, MD, FAANS
Mark E. Oppenlander, MD
Isaac Yang, MD
Tadashi Higuchi
Daniel Orringer, MD
Gabriel Zada, MD
Allen L Ho
Quinn T. Ostrom
Zaitum ZaKaria
Eric C. Holland, MD, PhD
Johan Pallud, MD
Pascal Zinn, MD, PhD
Peleg Moshe Horowitz, MD
Abdel Nasser Hosein
Andrew Thomas Parsa, MD, PhD,
FAANS
Anwar Hossain
Arie Perry, MD
Namath Hussain, MD
Grace Elizabeth Pluhar
Michael Edward Ivan, MD
Candice Poon, MD
Arman Jahangiri
Andreas Raabe
16
2013 AANS/CNS SECTION ON TUMORS
SCIENTIFIC PROGRAM ORAL PRESENTATION ABSTRACTS
1. A Molecular Predictor Of Meningioma Recurrence
2. Advanced MRI Is Accurate And Cost Effective For Predicting
Recurrent Glioma Versus Treatment Related Necrosis
Erik P. Sulman; Lindsey Goodman, BS; Khalida Wani, PhD;
Albert Lai, MD, PhD; Franco DeMonte, MD; Kenneth Aldape, MD
(Houston, TX)
Jackson D. Hamilton, Jr.; Edward Jackson, PhD; Norman Leeds,
MD; Leena Ketonen, MD, PhD; David Schellingerhout, MD;
Jessica Jones; LaToi Tatum; Ping Hou, PhD; David Evans; Michelle
Underwood; Jerell Jones; Brandy Reed; Stacy Hash; Joseph
Steele, MD; Heidi Albright; Ashok Kumar, MD (Houston, TX)
Introduction: More than 20% of patients with meningioma
suffer from tumor recurrence, leading to aggressive surgical
and radiotherapeutic interventions that add to patient morbidity.
Neither grade nor extent of surgical resection/Simpson grade
fully account for recurrence risk. Adjuvant radiation may decrease
this risk in some patients but comes with increase toxicity. We
hypothesized that tumors at risk for recurrence would exhibit a
unique gene expression signature that could be used to assign
patients to adjuvant treatment.
Introduction: Treatment related brain necrosis (TRN) mimics
recurrent high grade glial tumor but can often be managed non
surgically.
Methods: Glioma patients radiated ‹6 months prior with a new
enhancing lesion were prospectively imaged to determine
recurrent glioma versus TRN. The protocol began in 2009, adding
dynamic contrast enhanced and susceptibility contrast perfusion,
diffusion tensor and multivoxel spectroscopy to conventional
imaging. In 2011, multiple refinements occurred based on review
of earlier results. Radiologist reports were considered accurate
if within a point of pathology reports on a scale from pure tumor
(1) to pure treatment effects (5). The cost of all care (surgery,
chemotherapy, etc.) for patients beginning from imaging through
90 days was tabulated from baseline and after refinements, with
inflation adjustment and outliers censored. Fisher exact test
compared group differences.
Methods: We performed expression profiling (Affymetrix HG
U133Plus2.0) on previously untreated tumors resected at first
diagnosis and correlated expression to clinicopathologic features
(age, WHO grade, Simpson grade, sex, tumor location) and
outcome [recurrence free (RFS) and overall survival (OS)].
Results: We evaluated 62 patients treated between 1991 2007.
Median age was 57y. Forty three were female, 19 male. Median
follow up was 3.9y with 8 deaths and 13 recurrences. WHO grading
was as follows: grade I, 30 (48%); grade II, 31 (50%); grade III,
1 (2%). 46 resections were coded as Simpson I or II. Adjuvant
radiation was given to 8 patients. Unsupervised clustering
identified two predominant molecular subtypes with 25% of
cases belonging to group 1 (meningioma recurrence risk group 1,
MRRG1) and 75% to group 2 (MRRG2). Analysis by grade revealed
that MRRG2 contained more higher grade tumors: 82% of grade
II and 100% of grade III tumors. All but 1 recurrence belonged
to MMRG2. Survival analysis revealed a 5yr RFS of 94% vs. 59%
for MRRG1 vs. MRRG2. The 5yr OS was 100% vs. 82% (p=NS). We
validated this signature using a published meningioma dataset
(GSE16581) and found a similar association between MRRG group
and recurrence with 100% of recurrent cases belonging to MRRG2
(p=0.0056).
Results: In the baseline group, 33 of 110 had biopsy/surgery
within 60 days of imaging and 11 had only treatment effects. After
the protocol was refined, 29 of 103 had biopsy/surgery and 1 had
only treatment effects (p=0.003). The radiology reports accuracy
increased from 72% (24/33) to 97% (28/29). The average total cost
for the 110 baseline imaged patients was $28,447 and for the 103
patient after the refinements $24,507, a savings of $3,900/patient.
Conclusions: Improved diagnostic accuracy may decrease
unnecessary surgical intervention for treatment effect and
reduce overall care costs. This required an experienced team
(technologists, physicists and neuroradiologists) with little
additional scanning/post processing time (‹1 hour more than
conventional imaging), justifying a prospective multicenter clinical
trial.
Conclusions: Our data suggest that gene signature can accurately
segregate patients at risk for recurrence. This accurate
classification would be a powerful tool for assigning patients for
appropriate adjuvant therapy.
17
3. Autologous Vaccine Therapy To Control Invasive Canine
Meningioma
4. Comparative Integrated Analysis Of Brain Tumor Initiating
Cells And Their Parent Tumors
Grace Elizabeth Pluhar; Matthew Hunt, MD; Brian Andersen, BS;
John Ohlfest, PhD (St. Paul, MN)
Candice Poon, MD; Wei Wu, PhD; Carly Pontifex; Mohammad Al
Najjar; H. Luchman; Charles Chesnelong; Samuel Weiss, PhD;
Jennifer Chan; J. Cairncross, MD, PhD; Michael Blough, PhD
(Calgary, Canada)
Introduction: Canine and human meningiomas have similar
neuroimaging characteristics, gross and histological appearance,
and expression of growth factors and cell surface receptors.
However the biological behavior of tumors in dogs is more
aggressive compared to human tumors. Median survival times
in dogs after standard surgical excision has been reported to be
6 7.5 months and the prevalence of grade II meningiomas (40%)
is high compared to humans. These characteristics make dogs
a more meaningful model of high grade meningioma compared
to mice for testing new strategies. To that end, we assessed
safety and efficacy of tumor lysate vaccines to treat spontaneous
meningioma in pet dogs.
Introduction: Glioblastoma (GBM) is a uniformly fatal intra axial
neoplasm that carries a dismal prognosis. It is speculated that
brain tumor initiating cell (BTIC) cultures derived from resected
GBM better captures its molecular heterogeneity and clinical
features than traditional cell lines. As the effect of cell culture
stresses on genomic alterations in BTICs has yet to be elucidated,
we sought to inspect the genetic fidelity of BTICs compared to
their parent tumors (PTs) by performing a comparative genomic
and genetic analysis.
Methods: Using the Affymetrix 6.0 SNP array and the Illumina
HT12 beadarray, we acquired data on genome wide copy number
alterations (CNAs), loss of heterozygosity (LOH), and gene
expression patterns from 12 BTIC lines and their matched PTs.
Methods: Dogs had surgical resection followed by six vaccinations
with autologous tumor lysate and toll like receptor ligand
adjuvant. Toxicities were monitored by examinations and blood
tests, disease status by MRI, and immune response in peripheral
blood mononuclear cells (PBMC) by ELISpot and flow cytometry
and in sera by Western blot.
Results: Although BTICs acquired more amplifications and
deletions than their PTs, statistical significance was not achieved.
However, the magnitude of amplifications with and without LOH
in coding regions of the genome were significantly different.
Expression analysis revealed that differentially expressed genes in
BTICs were chiefly involved with metabolism, while an integrated
analysis demonstrated chromosomal alterations in BTICs were
most commonly associated with chromosome 7 amplifications, a
location connected to putative oncogenes.
Results: Gross total resection was achieved 17 of 19 cases; grade
I (11), grade II (5), grade III (3). Adverse effects were rare, primarily
pain and erythema at injection sites. Median survival time = 401
days (5 dead with NED; 1 alive 921 days) with CpG treated dogs,
865 days (2 euthanized @ 343 and 733 days) with imiquimod (n=6).
Median survival is 155 days in a new trial with triziquimod (n=7);
2 dogs euthanized @130 and 200 days (NED) and 1 recurrence
after 290 days. CD8+ T cells were increased post vaccination in
two dogs. Polyclonal antibodies to tumor specific antigens were
detected in all dogs and also triggered antibody dependent cell
mediated cytotoxicity against autogolous and allogeneic cells.
Conclusions: BTICs maintain their ancestor’s core
genome structure, with many changes appearing to be
"passenger" alterations.However, statistically significant
changes did occur in the form of enhancement of existing
genomic modifications. Notably, novel recurring genomic
alterations were not observed in BTICs.
Conclusions: Immunotherapy using autologous tumor lysate/
TLR agonists elicits antibody and T cell responses and increases
survival compared to reported survival in dogs treated by surgery
alone. Since dogs tend to have more aggressive disease, this may
be a treatment for humans with meningiomas that have failed
other standard therapies or those at high risk of recurrence.
5. Continuous Dynamic Mapping Of Corticospinal Tract During
Surgery Of Motor Eloquent Brain Tumors: Prospective Study
Andreas Raabe; Juergen Beck, MD, PhD; Philippe Schucht, MD;
Kathleen Seidel, MD (Koenigstein, Germany)
Introduction: We recently reported that the subcortical mapping
motor threshold (MT) where irreversible DCS MEP changes
and motor deficits regularly occur is lower (&lt;2mA)
than previously thought. However, mapping at MTs of 1 5mA is
hampered by insufficient temporal and spatial coverage of the
surgical site with conventional monopolar fingerstick mapping
probe (MFMP). A new continuous and dynamic mapping technique
is described.
18
Methods: We prospectively studied 41 patients with tumor surgery
adjacent to the CST with simultaneous subcortical monopolar
motor mapping (train of five stimuli). Continuous and dynamic
(spatial coverage) mapping was achieved by integrating the
stimulation probe at the tip of a new suction device. MTs obtained
with the new device and MFMP at the same site were analyzed.
Motor function was assessed one day after surgery, at discharge,
and after 3 months.
additional adjuvant chemotherapy, delay was also significant
but only when categorized into quartiles(p=0.042). Unexpectedly,
delay was associated improved PFS(HR: 2nd quartile:0.515; 3rd
quartile:0.608; 4th quartile:0.732).
Conclusions: We demonstrated that delay to adjuvant therapy is
not associated with decrease in either PFS or OS. This suggests
that, when necessary, delay of adjuvant therapy may not negatively
affect patient prognosis.
Results: A 1:1 correlation of motor MTs for stimulation sites
simultaneously mapped with the suction device and MFMP was
found (74 stimulation points, r = 0.996, p&lt;0.001). All
procedures were technically successful. Lowest individual MTs
were: >5mA, n=12; 4 5mA, n=13; 1 3mA, n=16 patients. At 3
months, one patient had a persisting postoperative motor deficit
(2.4%). Surgeons using continuous dynamic mapping unanimously
reported a higher confidence regarding the exact location and safe
distance from the CST compared to the MFMP.
7. Development Of Atypical And Anaplastic Meningioma Cell
Resources: Results From Three Years Experience At UCSF
Charles David James; Rintaro Hashizume, MD, PhD; Yu Jen
Lu, MD, PhD; Arie Perry, MD; Andrew Parsa, MD, PhD; Michael
McDermott, MD (San Francisco, CA)
Introduction: The primary objective of this study is to assess
the feasibility of establishing xenografts from surgical cases
diagnosed as atypical or anaplastic menigioma. The long
term purpose of this study is to develop preclinical models for
therapeutic testing.
Conclusions: Continuous dynamic mapping is a feasible technique
for localizing the exact site and distance to the CST. It may
increase the safety of motor eloquent tumor surgery by providing
better temporal and spatial coverage compared to mapping with
the fingerstick probe.
Methods: Tumor specimens, classified as atypical WHO grade
II (n = 9) or anaplastic WHO grade III meningioma (n = 10) were
collected over a three year period from surgical cases at UCSF.
Athymic mice were engrafted directly with 50 100 mm3 of tumor
tissue in the subcutaneous space. Remaining tissue from surgical
resection was minced in serum free media, then mechanically
disrupted by repetitive pipetting to generate cell suspensions from
which we attempted to establish cell cultures.
6. Delay Of GBM Adjuvant Therapy Does Not Decrease Overall
And Progression Free Survival: A Retrospective Analysis
Matthew Z. Sun; Orin Bloch, MD; Aaron Clark, MD, PhD; Michael
Ivan, MD; Michael Safaee, BS; Taemin Oh, BA; Andrew Parsa, MD,
PhD (San Francisco, CA)
Results: Twelve of 19 cell cultures have proven sustainable (7
atypical and 5 anaplastic). Athymic mice, receiving subcutaneous
implantation of patient surgical specimen, and that have been
monitored for as long as one year for indication of subcutaneous
tumor growth, have yielded transplantable tumor tissue, for
successful serial propagation in 5 of 12 instances (42%: two
atypical and three anaplastic); 7 mice receiving subcutaneous
injection of patient surgical specimen remain under observation
for the growth of tumor that can be serially propagated. Four
of the tumorigenic meningiomas have been modified with a
luciferase reporter, to enable in vivo bioluminescence imaging of
tumor growth and response to therapy.
Introduction: The effect of delaying concurrent chemotherapy
and radiotherapy after GBM surgery remains unclear. Current
literature on the subject lacks modern cohorts in the Stupp
protocol era.
Methods: We retrospectively analyzed GBM patients in the Stupp
protocol era (2005 2011). Delay to adjuvant therapy after surgery
was reclassified into 3 categorical variables:1) Binary(>28 or
&;lt;28 days), 2)Quartiles (1st, 2nd, 3rd, or 4th quartile in time),
and 3) bi weekly(<2, 2 4, 4 6, 6 8, or >8 weeks). Survival
analysis was performed by constructing Kaplan Meier curves
assessed by logrank test, and by multivariate Cox proportional
hazards models.
Conclusions: Our results demonstrate the feasibility of
establishing a meningioma xenograft panel that can be used
to test experimental therapies for treating patients whose
meningiomas are not surgically curable.
Results: There were 352 patients; median age was 59.88. Median
delay, follow up, progression free survival(PFS), and overall
survival(OS) were 28, 292, 172, and 356 days, respectively. Kaplan
Meier Analysis showed no statistically significant differences with
either OS or PFS when delay was analyzed as binary, quartile, or
bi weekly categorical variables. Unexpectedly, those in the longest
quartile had better PFS compared to the shortest quartile(p=0.04).
Cox proportional hazards model incorporating delay, age,
concurrent chemotherapy, additional adjuvant chemotherapy, and
KPS revealed that only age and additional adjuvant chemotherapy
remained significant for OS(age,p=0.003,HR:1.023; additional
chemotherapy,p=0.04,HR:0.659). For PFS, in addition to age and
19
8. Distinct Roles For Histone Methyltransferase Ezh2 In
Epigenetically Promoting Adult Neural Stem Cell Proliferation
And Differentiation
Methods: On data obtained on 1544 adult patients with
supratentorial hemispheric diffuse low grade gliomas from
multicentre French cooperative study groups, we addressed the
relationships among seizures and clinical, imaging, pathological,
molecular, treatment related parameters and outcomes.
Ryan Salinas; William Hwang, PhD; Daniel Lim, MD, PhD (San
Francisco, CA)
Results: 89.8% of patients had seizures at diagnosis. Male gender,
long time to diagnosis, temporal and parietal locations, and
tumor close to functional areas were independent predictors of a
history of seizures at diagnosis. Tumor volume, growth velocity,
cortical location, histological subtype or molecular markers did
not affect seizure occurrence probability. Long history of seizures
and insular location were independent predictors of uncontrolled
seizures at diagnosis, while history of seizures at diagnosis,
tumor parietal and insular locations were independent predictors
of uncontrolled seizures after oncological treatment. Subtotal
and total surgical resections were independent predictors of
seizure control after oncological treatment. History of seizures at
diagnosis was associated with longer survival without malignant
transformation and with longer overall survival.
Introduction: The molecular mechanisms underlying the stem
cell nature of glioblastoma are poorly understood. Aberrant
overexpression of EZH2, a histone methyltransferase normally
required to maintain stem cell populations in other tissues, likely
contributes to this oncogenic transformation. Understanding
EZH2 genomic targets in subventricular zone neural stem cells
(SVZ NSCs), where many brain tumors potentially arise, would
advance our understanding of oncogenesis and identify novel
therapeutic targets.
Methods: SVZ NSCs with conditional Ezh2 deletion were analyzed
in vitro and in vivo. Neurosphere formation assays, chromatin
immunoprecipitation (ChIP), reverse transcriptase quantitative
PCR, immunocytochemistry, and immunohistochemistry (IHC)
were used to identify molecular targets of Ezh2. Lentiviral Olig2
overexpression and Olig2 shRNA knockdown assessed Ezh2
mediated neuronal differentiation.
Results: Ezh2 deletion in vitro greatly impairs both proliferation
and neurogenesis. ChIP and mRNA analysis indicate EZH2
specifically binds and represses the tumor suppressor Ink4a/Arf
locus in SVZ NSCs. Co deletion of Ink4a/Arf restored proliferation,
but not neurogenesis. Co deleted cells had increased expression
of basic helix loop helix transcription factor, OLIG2. ChIP analysis
identified Olig2 as a direct and functional target of EZH2. Transient
overexpression of Olig2 profoundly inhibited neurogenesis and
intriguingly, knockdown of Olig2 enhanced neurogenesis in Ezh2
deleted but not WT NSCs. IHC revealed Ezh2 deletion greatly
impairs SVZ neurogenesis in vivo.
Conclusions: Ezh2 epigenetically represses Ink4a/Arf in SVZ
NSCs, potentially contributing to SVZ NSC derived oncogenesis.
However, Ezh2 mediated repression of Olig2, commonly expressed
in gliomas, is required for neuronal progression. Rather than
solely maintaining self renewal and anaplasticity, Ezh2 has a dual
role in epigenetically regulating both self renewal and progressive
lineage restriction in SVZ NSCs.
9. Epileptic Seizures In Adult Diffuse Low Grade Gliomas. A
Multicentre Study of 1544 Cases.
Johan Pallud, MD; Etienne Audureau, MD; Nader Sanai; Marie
Blonski; Luc Bauchet; Denys Fontaine; Emmanuel Mandonnet;
Jacques Guytotat; Philippe Peruzzi; François Xavier Roux; Luc
Taillandier; Gilles Huberfeld; Laurent Capelle; Hugues Duffau
(Paris, France)
Introduction: The natural history of seizures, the predictors of
seizure control and their prognostic significance have not been
clearly defined in diffuse low grade gliomas, although seizures
are known to be the most frequent symptom in glioma and deeply
impact quality of life.
Conclusions: Epileptic seizures occurrence depends on specific
tumor characteristics and independently affect glioma prognosis.
Patients with a history of seizures and those with a complete
surgical resection have better outcomes. Thus, in addition to the
oncological benefit, early and maximal surgical resection could
help in achieving seizure control of patients harboring a diffuse
low grade glioma.
10. Expression Of CD163 Prevents Apoptosis Through The
Production Of Granulocyte Colony Stimulating Factor In
Meningioma
Hiroshi Nishihara; Hiromi Kanno, MD, PhD; Lei Wang, PhD; Hiroyuki
Kobayashi, MD, PhD; Sunsuke Terasaka, MD, PhD; Kiyohiro Houkin,
MD, PhD; Shinya Tanaka, MD, PhD (Sapporo, Japan)
Introduction: CD163 is a 130 kDa transmembrane protein
expressed in human monocytes and macrophages, while the
aberrant expression of CD163 in breast and colorectal cancer
associated with patients poor prognosis was reported. Here we
analyzed the expression of CD163 in meningioma, a common
intracranial tumor, and its molecular mechanism in association
with meningioma progression.
Methods: First, we performed immunohistochemical analysis
using 50 human meningioma specimens. Next, we established
CD163 overexpressing human meningioma cell lines and
investigated its roles on tumor progression in vitro and in vivo.
Results: Immunohistochemically, 26 out of 50 human meningioma
specimens (52.0%) were positive for CD163 in tumor cells,
including benign Grade I (48.5%) and Grade II (71.4%) cases.
Furthermore, CD163 expression was correlated with histological
atypical parameters which directly predict the prognosis of
meningioma patients. CD163 overexpressing meningioma cells
showed significant suppression of apoptosis and accelerated
tumor growth in nude mice. In addition, unexpected splenomegaly
affiliated with the xenograft predicted to us the tumor derived
20
12. High Field Intraoperative MRI And Endoscopy Provide
Complementary Extent Of Transsphenoidal Resection
Improvements For Pituitary Adenoma
granulocyte colony stimulating factor (G CSF) production, which
was confirmed by RT PCR and ELISA.
Conclusions: To our knowledge, this is the first report which
demonstrates CD163 expression in meningioma not only by
immunohistochemistry but also by RT PCR using primary culture
cells, and provides the novel molecular function of CD163 to
prevent apoptosis through the production of G CSF in meningioma.
Peter Sylvester; John Evans, BS; Feng Gao, PhD; Richard Chole,
MD; Anne Getz, MD; Bruce Haughey, MD; Ravindra Uppaluri, MD;
Keith Rich, MD; Gregory Zipfel, MD; Ralph Dacey, MD; Michael
Chicoine, MD (St. Louis, MO)
Introduction: Advanced operative techniques (AOTs; endonasal
approach, stereotactic neuronavigation, and endoscopy) and
intraoperative MRI (iMRI) are replacing traditional operative
techniques (TOTs) for pituitary adenoma resection. The study
objective was to evaluate the impact of AOTs and iMRI on extent of
resection (EOR).
11. Genomic And Transcriptomic Analysis Reveals An Oncogenic
Functional Module In Meningiomas
Gabriel Zada, MD; Xiao Chang; Lingling Shi; Fan Gao; Jonathan
Russin; Liyun Zeng; Shuhan He; Thomas Chen; Steven Giannotta;
Daniel Weisenberger; Kai Wang; William Mack (Los Angeles, CA)
Methods: Review of 184 iMRI and 298 conventional post operative
MRI only (coMRI) cases (mean follow up=17.3 and 39.6 months,
respectively), and the impact of AOTs. Case matching based on
propensity scores yielded 133 matched iMRI/coMRI pairs. The
EOR gross, near, or sub total resection (GTR, NTR, or STR) was
determined, and progression free survival (PFS) assessed.
Introduction: Meningiomas are among the most common
primary adult brain tumors. Although typically benign, roughly 3
5% display malignant pathological features. The key molecular
pathways involved in malignant transformation of meningiomas
remain to be determined.
Methods: A systematic analysis of genomic and transcriptomic
differences between benign, atypical, and malignant meningiomas
(n=19 total) was performed using DNA SNP array, DNA
methylation sequencing, and gene expression array in an effort
to provide insight into the tumor biology governing malignant
transformation.
Results: Patients who received no post operative radiation or
hormone suppression had an increased PFS if post operative
MRI revealed GTR or NTR versus STR (p=.049). Multivariate
analysis showed that surgeries performed with all AOTs resulted
in improved EOR compared to surgeries with TOTs (p=.041).
Surgeries performed with AOTs without endoscopy did not
show improved EOR compared to surgeries with TOTs (p=.932),
indicating an EOR benefit specific to endoscopy. Of 49 patients
with additional resection after iMRI, 14 improved to a higher level
of EOR (28.6%). Improvement in EOR post iMRI was equivalent for
cases performed with or without endoscopy (p=.674), indicating an
iMRI benefit distinct from endoscopy. The absolute risk reduction
and number needed to treat to improve EOR after iMRI usage were
6.8% and 14.8, respectively.
Results: At the genomic level, malignant and atypical
meningiomas had more chromosomal losses (average length
in malignant: 528 Mb, atypical: 203Mb, benign: 34Mb) than their
benign counterparts. Monosomic loss of chromosome 22 was
identified as one of the primary chromosomal level abnormalities
in all subsets of meningiomas, particularly in malignant samples.
At the transcriptomic level, a weighted gene co expression
network was constructed, 23 co expression modules were
identified. Gene functional enrichment analysis identified a
module with 356 genes that was highly related to tumorigenesis.
Four intramodular hub genes (GAB2, KLF2, ID1, CTF1) were
oncogenic and are related to leukemia. A meningioma related
gene (MN1), which is also associated with leukemia, was also
identified in this module and shown to demonstrate differential
expression between malignant and benign meningiomas.
Conclusions: For patients undergoing transsphenoidal surgery
for pituitary adenomas, increased EOR led to increased PFS.
Endoscopy and iMRI led to increased EOR compared to TOTs.
Conclusions: DNA copy number variation analysis confirmed
the high frequency of chromosome 22 monosomy and the
association between WHO grade and chromosomal abnormalities.
Transcriptome analysis identified several genes with highly
differential expression between the benign and malignant groups,
including a meningioma candidate gene, MN1. Genomic and
transcriptomic analysis of surgical meningioma samples provides
novel insight into the malignant transformation of meningiomas,
with implications regarding molecular heterogeneity.
21
13. Imaging And Clinical Factors Predictive Of Atypical
Meningiomas
14. Importance Of Extent Of Resection In The Treatment Of GBM:
How Much Is Enough?
Le (Lucy) He, MD; Megan Strother, MD; Roopa Vemireddy, MD;
Lola Chambless, MD (Nashville, TN)
Lauren Elana Rotman; Quinn Ostrom; Benjamin Kuhns, BS; Paul
Farah; Jaime Vengoechea, MD; Carleton Johnson; Lisa Rogers,
DO; Jill Barnholtz Sloan, PhD; Andrew Sloan, MD (Cleveland
Heights, OH)
Introduction: The World Health Organization (WHO) classifies
meningiomas as WHO I (88 94%), WHO II (5 7%) and WHO III (1
2%). Grade II meningiomas have an aggressive clinical course with
increased risk of post treatment recurrence. Distinguishing Grade
II meningiomas from Grade I meningiomas preoperatively could
affect surgical planning and improve treatment outcomes for
patients. In this study, we examined whether clinical and magnetic
resonance imaging (MRI) features could distinguish between
Grade I and Grade II meningiomas.
Introduction: Glioblastoma multiforme (GBM) is the most common
malignant brain tumor and contributes disproportionately to
mortality. Previous studies demonstrate that maximal extent
of resection (EOR) is associated with increased survival. This
prospective study assesses survival advantages of EOR in light of
advancements in postoperative therapy.
Methods: Clinical data and MRI imaging from 128 patients with
Grade I or II meningiomas was retrospectively evaluated and
correlated with histological grade to determine which features
were predictive of more aggressive meningiomas. Imaging factors
analyzed included peritumoral edema, presence of a draining vein,
tumor necrosis, and tumor location.
Methods: One hundred thirty four (134) newly diagnosed GBM
patients were identified as part of the Ohio Brain Tumor Study.
Tumor volume and eloquent location were determined based on
preoperative and postoperative (‹ 48 hours following surgery)
MRIs. Kaplan Meier and Cox Proportional Hazards models were
used to determine the relationship between EOR and other
prognostic factors on median survival (MS).
Results: The 128 meningioma patients studied included 94
females and 34 males. Mean age at the time of meningioma
diagnosis was 54.7 years (range 18 to 87 years). On histological
grading at surgical resection, 94 patients had WHO I tumors and
34 patients had WHO II tumors. Imaging features associated with
increased risk for atypical meningioma in univariate analysis
included tumor necrosis by imaging (p=0.025), increased
peritumoral edema (p=0.022) and convexity location (p=0.026).
Neither male sex nor patient age were significant. In multivariate
analysis, there was a trend towards increased risk of higher grade
in patients with peritumoral edema (p=0.072), but this finding did
not meet our criteria for statistical significance.
Results: Mean patient age was 64, median post operative
Karnofsky Performance Status (KPS) was 70. 65% underwent
standard radiation and temozolomide following surgery.
Median preoperative tumor volume was 34.68cm3 and median
postoperative tumor volume was 4.42cm3. Mean EOR was 84.8%
(range 26.8 100%). MS was 10.88 months from the date of surgery.
KPS, age, eloquent location, and postoperative concomitant
chemoradiation were significant predictors of survival. Significant
survival benefit was observed with as minimal EOR as 83% (p
‹ 0.001) in both unadjusted and adjusted models. However, MS
incrementally increased with EOR of ‹90%; ‹95% or ‹99% to 12.33,
13.48, 14.07 months respectively.
Conclusions: Grade II meningiomas, are highly aggressive tumors
that generally require early surgical resection and consideration
of adjuvant radiation. Observation of these cases, may lead to
the development of neurologic symptoms and may complicate
future resections. We have identified three factors that are
associated with increased risk of higher grade: convexity location,
peritumoral edema, and presence of tumor necrosis. Future
studies including larger numbers of patients may allow us to
build a useful multivariate model that clinicians can use to predict
meningioma grade accurately prior to treatment.
Conclusions: Though EOR ‹99% is associated with the greatest
survival benefit, significant survival advantage accrues with EOR
as low as 83% in patients undergoing surgery for newly diagnosed
GBM. This supports the survival advantage of debulking GBM
‹83% even when complete resection is not feasible or safe.
15. Improving Functional Preservation In Acoustic
Neuroma Surgery
Hirofumi Nakatomi; Hirofumi Nakatomi (Tokyo, Japan)
Introduction: To restore nerve functions during acoustic neuroma
(AN) surgery, we focused on minimizing the injury period and
maximizing the recuperation period.
Methods: Ninety consecutive patients underwent retrosigmoid
unilateral AN surgery, and postoperative hearing and facial
nerve function were evaluated. A novel application of continuous
direct brainstem evoked potentials (CDBEPs) that visualized and
tracked these neural functions was used to analyze the factors
affecting same grade functional preservation: auditory evoked
dorsal cochlear nucleus action potentials (AEDNAPs) for cochlear
nerve (CN) and continuous facial nerve root evoked muscle
action potentials (FREMAPs) for facial nerve (FN). Of the 90
patients, 23 underwent continuous direct AEDNAP and FREMAP
22
monitoring alone without intraoperative recuperation treatment
(the monitoring alone group), and 67underwent both types of
monitoring with intentional intraoperative extended recuperation
treatment (IERT) (the IERT strategy group). Whenever these
responses declined to 40% and 65% of initial responses,
respectively, intentional IERT was performed up to every 30 min
for AEDNAP and every 15 min for FREMAP until the determined
level was restored.
Conclusions: Increased [68Ga] DOTATOC uptake in PET allows
a spatially precise discrimination between SRII expressing
meningioma and tumorfree tissue, valuable both for surgery and
radiation planning.
Results: Logistic analysis revealed that the final AEDNAP/
FREMAP % and undertaking IERT were contributing factors for
same grade functional preservation. Patients in the IERT strategy
group had a significantly better functional preservation rate than
those in the monitoring alone group (the adjusted hazard ratio for
cochlear nerve same grade preservation in IERT strategy group
relative to monitoring alone group, 0.173 [95% confidence interval
(CI), 0.036 to 0.831], p =0.028 and the adjusted hazard ratio for
facial nerve same grade preservation, 0.103 [95%CI, 0.027 to
0.398], p <0.0001).
Yan Michael Li, MD; Daniel Vallera, PhD; Walter Hall, MD
(Syracuse, NY)
Conclusions: Visualizing neural function and rescuing reversible
injury by IERT with continuous AEDNAP and FREMAP improved
functional preservation in AN surgery.
16. Increased [68Ga] DOTATOC Uptake In PET Imaging
Discriminates Meningioma And Tumorfree Tissue
Walter Rachinger; Niklas Thon, MD; Alexander Haug, MD; Ulrich
Schüller, MD; Jörg Christian Tonn, MD (Munich, Germany)
Introduction: The somatostatin receptor II (SRII) analogue [68Ga]
DOTATOC has been used for positron emission tomography (PET)
imaging of meningiomas. However, no correlative analysis of
increased [68Ga] DOTATOC uptake, SRII expression and histology
has been published so far. This prospective study offers a spatially
precise histopathological analysis of SRII expression using
[68Ga] DOTATOC PET guided biopsies in primary and recurrent
meningioma patients.
Methods: Adult patients with suspected intracranial meningiomas
and without prior radiotherapy were included. PET analysis
included SUVmax within areas of biopsy inside and outside of
the tumor. Magnetic resonance imaging (MRI), [68Ga] DOTATOC
PET integrated into neuronavigation and intraoperative computed
tomography (iCT) were used for a neuronavigated tissue sampling
procedure. Histopathological analysis included SRII expression.
Results: 12 patients (8x de novo and 4x recurrent meningiomas;
median age 49 years) were included. Overall, 59 specimens were
collected. 48 samples displayed tumor, 11 samples showed
tumorfree scar tissue or dura. A SUVmax ‹2.3 was significantly
associated with meningioma tissue. Sensitivity, specificity and
positive predictive value of SUVmax ‹2.3 to detect meningioma
tissue was 95.8%, 81.8%, and 95.8%, respectively. SRII expression
was exclusively found in tumor specimens. Less than 25% SRII
positive tumor cells were found in 20, 25 50% positive cells in 10,
50 75% positive cells in 13, and more than 75% in 16 samples.
A significant correlation was found between SUVmax and
quantitative SRII expression (p=0.001). Results did not significantly
differ between primary and recurrent tumors.
17. Intracranial Therapy Of Glioblastoma By CED With A Novel
Bispecific Ligand Directed Diphtheria Toxin Targeting EGF And
uPA Receptors
Introduction: Recombinant protein toxins that specifically target
tumor cells appear to be a promising therapy for GBM. We aimed
to broaden the receptor recognition by immunotoxins (IT) to a
wider range of GBM by incorporating two totally unrelated ligands
uPA and EGF that recognize common GBM and neovascular
antigens and determinate whether this immunotoxin could inhibit
the growth of aggressive human GBM in our mouse intracranial
model via convection enhanced delivery (CED).
Methods: We tested this new recombinant bispecific cytotoxin,
called DTATEGF, against GBM lines using assays for cell
proliferation, cytotoxicity, and flow cytometry. We established
aggressive brain tumors intracranially (IC) in nude mice with U87
Luc and LN229 Luc glioma cells genetically marked with a firefly
luciferase reporter gene. DTATEGF was delivered intracranially to
treat mice with GBM via CED by a microosmotic pump.
Results: DTATEGF was highly potent and selective in killing
malignant glioblastoma cells lines, which is receptor specific
since cytotoxicity could be blocked with antibodies and
accompanied by increased apoptotic population. In vivo, DTATEGF
significantly inhibited the tumor growth volume of the IC GBM
shown by In Vivo Imaging System, compared to irrelevant control
IT (P‹ 0.01). The mice with IC GBM treated with DTATEGF delivered
by osmotic pump survived longer than the control animals
(P‹0.01). No obvious local and systemic toxicity was seen at a dose
of 1 µg via CED.
Conclusions: A new co targeting agent that simultaneously
recognizes EGFR and uPAR is more effective for anti glioblastoma
therapy due to simultaneously targeting glioblastoma cells and
the neovasculature. DTATEGF delivered by CED has effective
therapeutic advantages for glioblastoma and low toxicity in an
intracranial mouse model. Keywords: Glioblastoma, EGF, uPA,
Diphtheria toxin, Cytotoxin, Convection enhanced delivery.
23
18. Morbidity Of Repeat Transsphenoidal Surgery Assessed In
Over 1000 Operations
Arman Jahangiri; Arman Jahangiri; Jeffrey Wagner; Liane Miller,
BS; Mai Tran; Maxwell Tom, BS; Sandeep Kunwar, MD; Lewis
Blevins, MD; Manish Aghi, MD, PhD
Introduction: While transsphenoidal surgery has low morbidity,
the degree of morbidity increase during reoperation remains
unclear. We investigated morbidity of repeat transsphenoidal
surgery in 946 consecutive patients.
Methods: Five year retrospective review of the first 946 patients
treated at our center since being named a pituitary center of
expertise.
Results: Of 946 patients, 104 had reoperation(s) (93 second
operations, 9 third; 1 fourth; 1 fifth) a mean of 7 months
after the first operation (range 1 55 months), with diagnoses
including endocrine inactive (29%) or active (22%) adenomas,
craniopharyngioma (15%), and Rathke’s cleft cysts
(12%). Morbidity of reoperation versus initial surgery included
transient diabetes insipidus (DI;24%vs.5%; P‹0.001), postoperative
hyponatremia (14%vs.16%; P=0.6), CSF leak requiring repair
(10%vs.3%; P=0.1), meningitis (4%vs.2%; P=0.4), length of stay
(2.9 vs. 4.9 days; P=0.001), and new postoperative hypopituitarism
(18% vs. 13%; P=0.1). Three category analysis comparing first,
second, and third fifth operations revealed increased meningitis
(1.5%/4.3%/10%; P‹0.01), length of stay (2.9/4.3/6.9 days; P‹0.001)
and DI (5%/11%/80%; P‹0.0001). There was an insignificant trend
towards more frequent reoperations for CSF leaks (2%/6%/9%;
P=0.08), while new postoperative pituitary deficits did not occur
more frequently (18%/11%/20%; P=0.6). Morbidity for reoperation
was comparable amongst pathologies. No carotid artery injuries
occurred.
Conclusions: The benign nature of pituitary disease meant that
reoperations were rarely needed in these 946 patients undergoing
1153 operations. However, when needed, repeat transsphenoidal
had more frequent postoperative DI and meningitis and greater
length of stay, with morbidity increasing with each subsequent
operation. Our findings underscore the importance of repeat
transsphenoidal surgery being performed by experienced
neruosurgeons working with endocrinologists to reduce morbidity.
19. MRI Based High Resolution Maps For Guiding Surgical
Procedures In Brain Tumor Patients
Yael Mardor, MD; Zvi Cohen; David Guez; David Last; Dianne Daniels;
Chen Hoffmann; Dvora Nass; Alisa Talianski; Leor Zach; Roberto
Spiegelmann; Yuval Grober; Ouzi Nissim (Tel Hashomer, Israel)
Introduction: Conventional MRI is currently unable to differentiate
tumor from non tumoral tissues which show enhancement on
conventional T1 MRI (such as radionecrosis). We have applied
delayed contrast extravasation MRI for calculating high resolution
maps clearly differentiating tumor from non tumoral tissues.
Here we demonstrate the feasibility of applying these maps for
improved targeting of stereotactic biopsies.
Methods: 23 patients with primary/metastatic brain tumors
post chemoradiation/radiosurgery were scanned by delayed
contrast extravasation MRI prior to surgery. High resolution maps
were calculated and used for planning stereotactic biopsies.
Histological assessment was then compared with the pre
surgical maps.
Results: The maps showed two primary enhancement
populations: the slow population where contrast clearance from
the tissue was slower than contrast accumulation and the fast
population where clearance was faster than accumulation. In
all cases, biopsies obtained from regions of the fast population
consisted of morphologically active tumor while biopsies
obtained from regions of the slow population consisted of non
tumoral tissues. According to our maps, in this cohort of patients
48.4±1.9%;1.9% (on average) of the enhancing lesion volume on T1
MRI did not represent morphologically active tumor.
Conclusions: The fact that 50% of the enhancing volume on
T1 MRI represents non tumoral tissues emphasizes the need
for improved targeting of surgical procedures. The excellent
correlation between our pre surgical maps and histology
suggests that the maps may be applied for planning of diagnostic
stereotactic biopsies thus improving targeting to regions of
morphologically active tumor and for improved resection planning
especially in the case of close proximity to functionally eloquent
brain regions.
20. MicroRNA 100 Targets the 'Silencing Mediator For Retinoid
Receptors' (SMRT) Gene, Reduces Tumor Proliferation, And
Improves Survival In Glioblastoma
John S. Kuo, MD, PhD, FAANS; Bahauddeen Alrfaei, MS; Raghu
Vemuganti, PhD (Madison, WI)
Introduction: Improved therapeutic approaches are needed for
the most common primary adult brain cancer, glioblastoma (GBM)
because of the current dismal median survival of less than two years.
We identified and tested the differentially expressed microRNA 100
(MiR 100) as a candidate "tumor suppressor" in GBM.
Methods: Standard molecular biology methods were used. GBM
specimens were obtained with patient consent via IRB approved
protocols to establish cell lines.
Results: Quantitative PCR validated differential microRNA array
results showing high miR100 expression in normal cells and low
expression in multiple GBM lines. MiR100 overexpression via
transfection of 4 GBM lines with miR 100 precursor (U87, U251,
patient derived 22T and 33T) reduced proliferation on MTS assays
(average 50%+15; p ‹ 0.05). TUNEL assays showed that transient
transfection of 15 pmole of miR 100 per 500K GBM tumor cells
triggered apoptosis 70% more than scrambled control miR after
24 hrs (p ‹ 0.01). SMRT was identified as a candidate miR100
target in multiple miRNA databases, and validated with miR100
specific inhibition in a luciferase SMRT 3’UTR reporter assay. In
addition, a single dose of pre mir 100 (60 pmol) injected directly
into intracranial GBM xenografts significantly extended survival
30% more than mice injected with control scrambled miRNA (p ‹
0.01; n=8). GBM lines that stably overexpressed miR 100 two fold
24
22. Post Transcriptional Regulation Of O6 Methylguanine
DNA Methyltransferase (MGMT) By miR 603: A Step Toward
Personalized Glioblastoma Treatment
over similar control transfected GBM lines were created for in vivo
studies: 10x6 cells were implanted for tumor xenograft histology
and survival analysis. Significantly reduced Ki 67 proliferation
index was observed compared to control (mir 100 vector: 18 +14%
Ki 67+; empty vector: 100+11% Ki 67+; p ‹ 0.01). Two fold over
expression of miR 100 in vivo showed an average of 70% reduction
in Ki 67 proliferation index. Furthermore, miR 100 overexpressing
cells was associated with significantly smaller xenografts than
injection of sibling control GBM cells.
Clark C. Chen, MD, PhD; Valya Ramakrishnan, PhD; Deepa
Kushwaha, PhD; Kimberly Ng, MD; Diahnn Futalan; David Gonda,
MD; Tyler Steed, MD; Jann Sarkaria, MD; Bob Carter, MD, PhD (La
Jolla, CA)
Introduction: Approximately 10% of glioblastoma patients derive
long term benefit from temozlomide (TMZ). As such, there is a
critical need to develop predictive biomarkers to identify this
patient subset. Patients unlikely to benefit from TMZ should be
enrolled in novel therapeutic trials. The DNA repair enzyme O6
methylguanine DNA methyltransferase (MGMT) is the major
mechanism by which cells detoxify TMZ induced DNA damage.
The observation that the transcription of MGMT is suppressed
by methylation of its promoter has led one set of predictive
biomarkers. However, these biomarkers fail to assess the effect
of post transcriptional regulation by micro RNAs. This study aims
to identify critical MGMT regulating miRNAs that would help to
predict clinical response to TMZ.
Conclusions: These studies establish the tumor suppressor
activity of miR 100 in GBM, which may lead to further development
of miR 100 related cell mechanisms as novel GBM therapies.
21. Periostin Induces Glioblastoma MRI T2/FLAIR Signal,
Cellular Invasion, And Angiogenesis
Pascal Zinn, MD, PhD; Pascal Zinn, MD, PhD; Pratheesh Sathyan,
PhD; Frederick Lang, MD; Raymond Sawaya, MD; Rivka Colen,
MD; Sadhan M, PhD (Houston, TX)
Introduction: The search for an effective therapy of Glioblastoma
Multiforme (GBM) continues. Imaging Genomics, a newly emerged
field, links gene expression profiles with MRI phenotypes (Zinn
et al, 2011, 2012). MRI FLAIR was found to correlate with cellular
invasion in GBM, thus, whole genome quantitative imaging
analysis can reveal functional microRNA gene regulatory
networks as novel targets for cellular invasion in GBM.
Methods: Laboratory study.
Results: A biochemical screen transfecting 885 known miRNAs
into MGMT expressing T98 glioblastoma cells was performed
to identify those miRNAs suppressing MGMT expression.
Top candidates were confirmed using multiple adherent
and neurosphere glioblastoma lines. We found that miR 603
consistently down regulated both MGMT protein and mRNA
expression. Injection of miR 603 into murine glioblastoma
xenografts down regulated MGMT expression in vivo. Importantly,
antagomir introduction into cell lines that natively express high
levels of miR 603 restored MGMT expression and TMZ resistance.
MGMT mRNA preferentially affinity precipitated with biotinylated
miR 603 and the predicted miR 603 binding region in the MGMT
3’UTR was necessary for suppressing luciferase activity in a
luciferase 3’UTR assay. Finally, high expression of miR 603
correlated with low MGMT expression in clinical specimens and
clinical response to TMZ.
Methods: We performed radiogenomic mapping of MRI and
corresponding genomic data in 78 TCGA patients. The top
microRNA gene regulatory network was biologically validated
by luciferase reporter assays, gain and loss of function using tet
inducible lentiviral microRNA expression systems, as well as si/
shRNA, small molecule inhibitor/recombindant protein in vitro
experiments and in vivo orthotopic xenograft models. Small animal
7T MRI T2/FLAIR was used for imaging genomic validations.
Results: The top up regulated gene in high invasion MRI
phenotypes was PERIOSTIN (POSTN). The top down regulated
microRNA (miR 219) was validated to bind to POSTN. Glioblastoma
derived stem cells (GSCs) from high FLAIR GBM patients
correlated with levels of POSTN and increased invasion in vitro
and in orthotopic xenograft tumor models on histological sections
and MRI. Functionally, miR 219 overexpression reduced POSTN
protein levels, while recombinant POSTN, neutralizing antibody,
and shRNA experiments significantly altered cellular invasion
in vitro and in vivo. MRI T2/FLAIR signal highly correlated with
POSTN levels and the degree of cellular invasion in orthotopic
xenograft models. Furthermore, high POSTN and a high POSTN/
miR 219 signature resulted in decreased survival and shorter time
to progression.
Conclusions: miR 603 is a MGMT regulating miRNA and a
potential predictive biomarker for response to TMZ.
Conclusions: In this study, we validated a novel noninvasive
diagnostic method to screen for functional networks of cellular
invasion. POSTN inhibition can be a novel therapeutic approach
to target invasion in GBM. Furthermore, targeted individualized
molecular therapies can be based on diagnostic imaging
genomics and can be monitored through out the treatment period.
25
23. Preclinical Studies Of Intratumoral Cellular Immunotherapy
for Recurrent Meningiomas With Alloresponsive Cytotoxic T
Lymphocytes
24. Prediction Of Outcomes After Surgical Resection Of
Glioblastoma Using Contrast Enhancing And FLAIR Residual
Tumor Volume
Richard George Everson, MD; Horacio Soto, MS; Edward Ha, BS;
Kate Erickson, BS; Colin Malone, BS; Rudi Scharnweber, MD,
PhD; Emma Young, NP; Neil Martin, MD; Isaac Yang, MD; Bob
Shafa, MD; Marvin Bergsneider, MD; Robert Prins, PhD; Linda
Liau, MD, PhD; Carol Kruse, PhD (Los Angeles, CA)
Matthew M. Grabowski; Pablo Recinos, MD; Michael Vogelbaum,
MD, PhD (Cleveland, OH)
Introduction: Approximately one third of primary brain tumors
are meningiomas and a third of those will display aggressive
behavior, leading to recurrence. Since few experimental therapies
are available for this subset of patients, we explored a cellular
immunotherapeutic approach for the treatment of recurrent
atypical meningiomas.
Methods: We generated alloresponsive cytotoxic T lymphocytes
(alloCTL) against atypical meningioma surgical explants by mixed
lymphocyte tumor reactions (MLTRs). We measured alloCTL
viability, growth and anti meningioma cytotoxicity and evaluated to
what degree this antitumor activity was HLA specific.
Results: We found that nearly all low passage atypical
meningioma cells (P1 3 explant cultures of UC LH and UC
CB derived from surgically resected material) displayed high
levels of class I human leukocyte antigen (HLA), which could be
upregulated upon exposure to interferon gamma (IFN γ).
Thus, we prepared alloCTL with IFN γ incubated,
radiation inactivated (70 Gy) tumor cells using one way MLTRs,
which led to a 8 14 fold alloCTL expansion over a 25 33 day period
after their culture. At 2 weeks, the alloCTL cultures were ‹70%
CD3+ and 80 85% viable. They displayed cytotoxic function toward
the meningioma cells in 4 hr calcein AM cytotoxicity assays, i.e.,
specific lysis of 54% ± 2% SEM at a 30:1 effector to target
ratio; the cytotoxicity could be inhibited between 24 50% with anti
HLA A,B,C blockade, indicating alloCTL specificity for meningioma
cell HLA.
Conclusions: These preclinical data were used to support
the inclusion of patients with recurrent meningiomas to our
Phase I dose escalation clinical study (www.clinicaltrials.
gov, NCT 01144247), which is predicated upon high levels
of HLA expression by tumor cells that are not expressed on
normal neuroglia. Multiple intratumoral adoptive transfers
of alloCTL will be performed after they are made by one way
mixed lymphocyte reaction, where only patient lymphocytes are
needed to accomplish alloCTL generation. Thus, a personalized
immunotherapeutic approach is approved and open to enrollment
for patients with recurrent meningioma. Supported by NIH R01
CA125244 and the Joan S Holmes Memorial Research Fund.
Introduction: Currently, contrast enhancing tumor volume is used
to delineate tumor burden in patients with glioblastoma (GBM).
However, the enhancing tumor volume may underestimate the full
extent of tumor burden, as tumor infiltration into normal brain has
been observed in non enhancing areas, which are characteristically
hyperintense on T2 weighted sequences. The relationship of post
surgical FLAIR residual tumor volume (RTV) to clinical outcome is
not well understood. We hypothesized that contrast RTV and FLAIR
RTV may be individually predictive of survival.
Methods: We retrospectively analyzed patients who underwent
primary surgical resection of a supratentorial GBM followed by
standard radiation/chemotherapy. Patients were excluded if ‹18
years old, had preoperative chemotherapy/radiotherapy, other
intracranial malignancies, or were without post operative imaging
within 48 hours of surgery. A semi automated volumetric analysis
tool was used to quantitatively measure RTV using contrast
enhanced and FLAIR MRI. Clinical and outcome data were
compared to contrast RTV and FLAIR RTV.
Results: One hundred twenty eight patients met study entry
criteria. Median age was 60 years (range, 23-86), with a median
KPS score of 90 (range, 30-100) at diagnosis. Median overall
survival was 13.75 months (range, 1-84.2). After separately
adjusting each volume measurement for age and Karnofsky
performance score (KPS), both log contrast RTV (p=0.039) and
log FLAIR RTV (p=0.018) were individually predictive of overall
survival.
Conclusions: Individually, contrast RTV and FLAIR RTV may be
predictive of survival in patients with GBM, supporting the concept
that post operative evaluation of GBM resection should incorporate
both enhancing and non enhancing components of tumor.
25. Progression Of Atypical Meningiomas Irrespective Of
Adjunctive Radiation
Heather M. Kistka; Jessica Bassett, BS; Cheryl Kinnard, RN; Allen
Redmond, RN; Allen Sills, MD (Nashville, TN)
Introduction: Atypical meningiomas(AM) are rare tumors with a
heterogeneous natural history. Their varying growth rates and
resistance to conventional therapies render them challenging
to treat. This has led to dispute over the role of radiation in
treatment.
Methods: We retrospectively reviewed the medical records of 78
surgically treated AM at our institution from 2002 to 2011. Overall
survival(OS) and time to progression(TTP) were analyzed using
univariate and multivariate Cox regression analyses.
26
Results: There were an equal number of males and females with
a mean age of 52 years. Average follow up was 58 months (range
12 192). Gross total resection was achieved in 64(82%) patients.
Nineteen patients (24.4%) received adjuvant radiation. Seventeen
patients (21.8%) experienced disease recurrence/progression
following resection with a median TTP of 31.5 months. Univariate
analysis revealed female sex(p=0.006), age at diagnosis(p=0.023),
and preoperative tumor size(p=0.020) as predictors of increased
TTP. Neither extent of resection nor adjuvant radiation
significantly prolonged TTP(p=0.693 and p=0.374 respectively) or
OS(p=0.330 and p=0.084 respectively). Multivariate analysis did not
reveal any independent predictors of increased TTP or OS.
Conclusions: This series describes outcomes of CNS
hemangiopericytomas from a nationwide patient population. In
this study, overall survival benefit is only found when gross total
resection can be accomplished, and it is combined with radiation
therapy.
27. Radiographic Predictors Of Functional Recovery In Adult
Posterior Fossa Ependymomas
Zaman Mirzadeh, MD; Peter Nakaji, MD; Randall Porter, MD;
Robert Spetzler, MD; Nader Sanai, MD (Phoenix, AZ)
Introduction: Adult posterior fossa ependymomas have a relatively
favorable prognosis compared with other intraparenchymal brain
tumors. Following gross total resection and adjuvant radiation
therapy, 10 year survival rates now approach 83%, emphasizing
the importance of preserving neurological function. Here, we
identify predictors of functional outcome following microsurgical
resection.
Conclusions: A subset of AM in our analysis were prone to
progression irrespective of initial treatment. The use of adjuvant
radiotherapy did not significantly prolong TTP or OS in our sample.
As radiation introduces risk to patients without benefit, it should
not be used as a first line treatment. Given the uniquely aggressive
nature of a fraction of AM, further research should be aimed at
identifying factors that render those tumors more prone to growth.
Methods: We identified patients with newly diagnosed grade II
posterior fossa ependymomas surgically treated at the Barrow
Neurological Institute between 1996 and 2011. Pediatric patients
were excluded. Routine clinical and radiographic variables were
retrospectively collected, including volumetric extent of resection,
cystic changes, peritumoral T2 signal changes, progression free
survival, and overall survival.
26. Radical Resection Plus Radiation Therapy For Central
Nervous System Hemangiopericytoma
Adam M. Sonabend Wothalter, MD; Brad Zacharia, MD; Hannah
Goldstein, BS; Samuel Bruce, BS; Dawn Herschman, MD; Alfred
Neugut, MD; Jeffrey Bruce, MD (New York, NY)
Results: Forty five patients were identified with median follow
up of 72 months. Median progression free survival and overall
survival were 5.2 and 6.0 years, respectively. Greater extent of
resection and the adjuvant radiotherapy were both associated
with improved survival. In univariate analyses, tumor size
(p=0.016), cystic changes (p<0.001), and post operative T2
signal (p<0.001) predicted the rate of neurological recovery.
Interestingly, multivariate regression analysis identified cystic
changes (p=0.009) and post operative T2 signal (p=0.015)
as independent predictors of slower neurological recovery.
Specifically, patients with cystic changes and increased
peritumoral T2 signal recovered their baseline KPS by 1 year,
while those without these features improved by 6 weeks.
Introduction: Central nervous system (CNS)
hemangiopericytomas are relatively uncommon and are unique
among CNS tumors as they can originate or develop metastasis
outside the CNS. Most of the literature on this disease consists
of single institution case series collected over long periods
of time, and thus may reflect selection bias and might not be
representative of the outcomes of current treatment paradigms.
Methods: We queried the Surveillance Epidemiology and End
Results (SEER) database to investigate the clinical behavior and
prognostic factors for hemangiopericytomas originating within the
CNS during the years 2000 2009.
Results: We identified 227 patients with a diagnosis of CNS
hemangiopericytoma. Age, radiation therapy, and gross total
resection plus adjuvant radiation were significantly associated
with survival on univariate analysis. On the multivariable model,
age, location and adjuvant radiation therapy were significantly
associated with prolonged overall survival. Older patients had
a hazard ratio of 1.90 (95% CI: 1.28 2.83, p=0.001) of mortality
from hemangiopericytoma. Patients with supratentorial lesions
were found to have prolonged survival, with infratentorial tumors
associated with a hazard ratio of 2.89 (95% CI: 1.03 8.06, p=0.043).
The only treatment paradigm to confer a survival advantage was
gross total resection plus radiation therapy. Patients undergoing
this combination therapy were found to have significantly better
survival, with a hazard ratio of 0.031 (95% CI: 0.01 0.95, p=0.04).
Conclusions: Following microsurgical resection of posterior
fossa ependymomas, cystic changes and increased peritumoral
T2 signal are independent predictors of the rate of neurological
recovery. Further study should examine the biological correlates
underlying these radiographic features of adult posterior fossa
ependymomas.
27
28. Rapid, Label Free Detection Of Microscopic Brain Tumor
Boundaries With Coherent Raman Scattering Microscopy
Daniel Orringer, MD; Minbiao Ji, PhD; Christian Freudiger, PhD;
Shakti Ramkissoon, MD; Sandro Santagata, MD, PhD; Oren
Sagher, MD; Sunney Xie, PhD (Ann Arbor, MI)
Introduction: Surgery is an essential component in the treatment
of brain tumors. However, delineating tumor infiltrated tissue
from normal brain remains a challenge. Here we describe the use
of Coherent Raman scattering (CRS) microscopy for differentiating
healthy brain from tumor infiltrated brain based on histologic and
biochemical differences. Unlike traditional histopathology, CRS is
a label free technique that can be rapidly performed in situ.
Methods: All experiments were performed using an established
system for CRS microscopy. We started by comparing the ability
of CRS and H/E to differentiate tumor from normal brain in frozen
tissue sections from infiltrative human glioblastoma xenograft
models. To demonstrate the ability of CRS to detect tumor
infiltration in unprocessed tissue specimens we imaged fresh 2mm
thick tissue sections from normal and tumor bearing mice. Finally,
to simulate the in vivo use of CRS during surgery, we imaged
superficial human tumor xenografts implanted in SCID mice.
Results: In our experiments there was excellent correlation
between CRS and H/E based tumor detection (K=0.98, (95% CI
0.96 0.99). Frozen and fresh tissue CRS imaging demonstrated
both normal brain structures and and tumor infiltrated brain with
excellent clarity and accuracy. We also demonstrated, that tumor
detection with CRS is possible in vivo, revealing tumor margins
that are invisible under the standard operative conditions.
Methods: Using annexinV FITC labeling, we assessed the
correlation between phosphatidylserine expression and SapC
DOPS mediated death in human brain cancer and normal cells.
Fluorescently labeled nanovesicles [SapC DOPS CVM (CellVue
Maroon)] were used to test PS specific binding in vivo. To evaluate
selective targeting of metastatic brain tumors induced with the
luciferase expressing cell line MDA MB 231 luc D3H2LN, SapC
DOPS CVM were systemically injected and colocalization assessed
by luminescence/fluorescence in tumor bearing animals.
Results: PS expression in cultured tumor cells correlated
positively with SapC DOPS induced death. SapC DOPS CVM
binding to tumor regions was seen in brain tumor tissues from
patients. Selective targeting of brain tumor cells by SapC DOPS
was observed in astrocyte Gli36 co cultures, a model that better
resembles the in vivo tumor environment. Synergistic anticancer
effects were observed after co treatment of glioma cell lines
with SapC DOPS and chemotherapeutic drugs that promote
PS externalization. Providing strong evidence that SapC DOPS
targets PS, masking cell surface PS in U87EGFR Luc glioma cells
with lactadherin C2 or beta 2 glycoprotein 1 inhibited binding
by SapC DOPS CVM in vivo. Additionally, selective targeting of
brain metastatic tumors was evidenced by colocalization of
bioluminescent (MDA MB 231 luc D3H2LN) and fluorescent (SapC
DOPS CVM) signals using animal models.
Conclusions: These results support SapC DOPS as promising
diagnostic and therapeutic agents for primary and metastatic
brain tumors.
Conclusions: By providing the surgeons with rapid histologic
assessment of the operative field, CRS microscopy may ultimately
improve the safety and accuracy of tumor surgeries where tumor
boundaries are visually indistinct. FIGURE LEGEND: In vivo CRS
microscopy imaging in an acute cranial window preparation in
mice 24 days post implantation of human GBM xenografts. CRS
microscopy demonstrates a clear distinction between tumor
infiltrated areas (T) and non infiltrated brain (N) (a). Brightfield
microscopy demonstrates no gross differences within the same
FOV (b). High magnification views within the tumor (c), at the
tumor/brain interface (d), and within normal brain (e) demonstrate
the ability of SRS to image the architectural differences between
tumor and normal brain.
30. Surgery For Primary Supratentorial Brain Tumors In The
United States, 2000 To 2009: The Effect Of Provider Caseload On
Complication Rates
29. SapC DOPS Nanovesicles Selectively Target Externalized
Phosphatidylserine And Identify Metastatic Brain Tumors
Victor Blanco, PhD; Zhengtao Chu, MD, MS; Ashley Stevens, BA;
Ady Kendler, MD, PhD; Ronald Warnick, MD; Xiaoyang Qi, PhD
(Cincinnati, OH)
Results: Several complications of biopsy and craniotomy occurred
less frequently for high volume centers. Patients treated by high
volume surgeons (‹=20 cases/year) were 47% less likely to have
a postoperative neurological complication, including infarction
or hemorrhage (p=0.013). Patients treated in high volume
hospitals (‹= 75/year) were less likely to develop hematoma
(p‹0.001), hydrocephalus (p=0.006), and require placement of
a ventriculostomy (p=0.013). Patients treated by high volume
surgeons and hospitals were also less likely to experience renal
(p=0.005), pulmonary (p‹0.001), and infectious complications
(p‹0.001), including pneumonia (p=0.002). In the multivariate
analysis adjusting for age, sex, race, tumor grade, medical
Introduction: Though research into the pathogenesis of primary
and metastatic brain tumors has advanced, current therapies still
show limited efficacy. Saposin C dioleoylphosphatidylserine (SapC
DOPS) nanovesicles are a novel antitumor agent that selectively
target exposed phosphatidylserine (PS) on brain tumor cell
membrane surface and induces cell death. We evaluate SapC DOPS
in binding PS exposing cancer cells and its ability to target tumors.
Victoria Trinh; Jason Davies, MD, PhD; Mitchel Berger, MD (San
Francisco, CA)
Introduction: Prior studies have suggested a volume outcome
relationship for surgical resection or biopsy of primary brain
tumors. The authors present analysis of these procedures
between 2000 2009 to evaluate how procedural volume impacts
complication rates.
Methods: The authors performed a retrospective cohort study
using data from the Nationwide Inpatient Sample (NIS) for 62,514
admissions for biopsy or resection of supratentorial primary brain
tumors from 2000 to 2009.
28
comorbidity score, teaching status, weekend admission, and
year of admission, low volume hospital (‹=25 cases/year) was
significantly correlated with the presence of one or more of these
complications (OR 1.6, 95% CI 1.3 1.9). The presence of one or
more complications was significantly correlated with increased
mortality (OR 6.5, p‹0.001) and delayed functional return (OR 0.29,
p‹0.001). Median length of stay (LOS) was shortest at hospitals
with ‹=100 cases/year (p‹0.001), and for surgeons with ‹=20
cases/year (p‹0.001). In the multivariate analysis, treatment by
high volume hospitals and surgeons correlated with decreased
mortality (p‹0.001, p=0.01) and more frequent routine discharge
(p‹0.001, p=0.021).
chromosomal instability and malignancy, anatomical location,
histological appearance, gene expression and acetylation
pattern. The mutational profile of a meningioma can largely be
predicted based on its anatomical position, serving as the basis
for targeted therapeutics.
Conclusions: Consistent with the previous decade, the number
of high volume hospitals and surgeons performing craniotomies
and needle biopsies for primary brain tumor increased over the
study period. Analysis of outcomes demonstrate that high surgeon
and hospital volumes correlate with decreased risk of adverse
outcome and support a shift towards regionalization of care.
Introduction: Studies have suggested better outcome after
complex surgery at hospitals with larger treatment volume,
including meningioma craniotomy. We investigated whether
previously reported US national trends toward neurosurgical
centralization, as for intracranial aneurysm treatment, affected
meningioma craniotomy practice patterns from 1988 2010.
32. Trends In Centralization Of Meningioma Surgery In The
United States, 1988–2010: A Population Based Study
Frederick G. Barker II, MD, FAANS, FACS; Pamela Jones, MD;
William Curry, MD; Brian Nahed, MD; Daniel Cahill, MD, PhD
(Boston, MA)
Methods: Retrospective cohort study using the Nationwide
Inpatient Sample (HCUP, AHRQ, Rockville, MD), 1988 2010.
31. The Novel Neoplasia Genes, TRAF7 And KLF4, Along With
SMO And AKT1, Define Clinically Distinct Meningiomas
Murat Gunel, MD, FAANS; Victoria Clark; Zeynep Erson Omay,
PhD; Akdes Serin, PhD; Jennifer Günel, MD; Luis Kolb, MD; Ryan
Hebert, MD; Bulent Omay, MD; Eric Holland, MD, PhD; Kaya
Bilgüvar, MD; Joachim Baehring, MD; Philip Gutin, MD; Joseph
Piepmeier, MD; Alexander Vortmeyer, MD; Cameron Brennan,
MD; M. Pamir, MD; Türker Kilic, MD; Katsuhito Yasuno, PhD; _
Meningioma Genomics Group (New Haven, CT)
Introduction: The genetic architecture of meningiomas, other than
loss of NF2, is poorly understood. We aimed to comprehensively
characterize the genomics of meningiomas.
Methods: We performed genome wide genotyping, exome
sequencing, ChIP seq and gene expression analyses of 50 tumors,
followed by targeted resequencing of an independent cohort of 250
meningiomas. We correlated the genomic analyses with clinical
findings.
Results: Somatic mutations in just 5 genes, NF2, TRAF7, KLF4,
AKT1 and SMO, explain the genetic basis of majority of benign
meningiomas. Among the novel neoplasia genes, TRAF7, a pro
apoptotic E3 ubiquitin ligase, is mutated in one fourth of all
meningiomas. Mutations in TRAF7 co exist either with a recurrent
K409Q mutation in another novel neoplasia gene, KLF4, a
transcription factor known for its role in inducing pluripotency,
or with the recurrent E17K mutation in AKT1. Hedgehog pathway
activating SMO mutations are found in another 5%. These non
NF2 meningiomas are nearly always benign, show chromosomal
stability, include secretory and meningothelial histology, and
mostly originate from the anterior and medial skull base with SMO
mutants localizing to midline. In contrast, the vast majority of NF2
mutant tumors show genomic instability, localize to the cerebral
and cerebellar hemispheres and are more likely to be malignant.
Results: 31,921 adult craniotomy admissions to 1350 hospitals
were studied; median age 59yr; 70% female. In hospital mortality
was 1.8%, decreasing from 3.3% (1988 90) to 1.1% (2008 10).
Annual US meningioma craniotomy caseload increased from
4300/yr (‘88 90) to 10100/yr (‘01 10). The number of US hospitals
performing meningioma craniotomies remained largely stable:
1060 hospitals (1990), 1150 (2010). After multivariate adjustment
(age, sex, race, payer, surgery year and admission type), larger
hospital volume significantly predicted lower mortality both in
1988 2000 (OR 0.72 for tenfold larger volume, P=0.007) and in 2001
2010 (OR 0.64,P=0.001). Median hospital craniotomy volume (per
patient analysis) increased from 7 cases/hospital/year (‘88 90)
to 20 cases/hospital/yr (‘08 10). In 1988 90, 23% of meningioma
craniotomies were at hospitals with ‹4 cases/yr, compared with
9% (2008 10). In 1988 90, 5% of meningioma craniotomies were at
hospitals with 50+ cases/yr, compared to 38% (2008 10). Larger
hospitals grew fastest in a per hospital analysis: median hospital
volume increased from 3 cases/yr (1990) to 4/yr (2010), 90th
percentile volume from 10/yr (1990) to 23/yr (2010), and 98th
percentile volume from 23/yr (1990) to 58/yr (2010).
Conclusions: Higher hospital volume continues to predict lower
mortality after meningioma craniotomy. An increasing proportion
of meningioma craniotomies in the US are being performed at
high volume centers.
Conclusions: Our results clearly identify clinically relevant
meningioma subgroups, distinguishing them based on their
mutually exclusive distribution of mutations, distinct potential for
29
33. Tumor Derived Vasculogenesis In von Hippel Lindau
Syndrome Associated CNS Hemangioblastoma
34. Utilizing PVI Z CCL21 Vault Nanoparticles As A Novel
Anti Tumor Therapy For Glioblastoma
Jason Michael Frerich; Chunzhang Yang, PhD; Kristin Huntoon,
PhD; Marsha Merrill, PhD; Russell Lonser, MD; Zhengping
Zhuang, MD, PhD (Bethesda, MD)
Isaac Yang, MD; Winward Choy, BA; Heather Garcia, BS; Andy
Trang; Brittany Voth, BA; Nicole Cremer, BA; Linda Liau, MD,
PhD; Robert Prins, PhD; Jian Yang, PhD; Leonard Rome, PhD (Los
Angeles, CA)
Introduction: von Hippel Lindau disease (VHL) patients develop
a multitude of highly vascular tumors. It has been proposed
that the vascular nature of these tumors is the product of
reactive angiogenesis. Recent studies have shown that the
characteristic islands of erythrocytes in VHL associated CNS
hemangioblastomas develop from tumor cells. We hypothesized
that a subset of vascular structures within VHL associated lesions
are a result of tumor derived vasculogenesis.
Methods: Tumor endothelial markers within CNS
hemangioblastomas were visualized by immunofluorescence and
three dimensional immunohistochemistry. Additionally, identified
vascular elements from human vHL deficient murine xenografts
were micro dissected and analyzed for loss of heterozygosity, as
well as visualization by co localization immunofluorescence and
fluorescence in situ hybridization (FISH).
Results: Immunofluorescence showed small CD31 positive
vascular elements that did not express Factor VIII. Three
dimensional immunohistochemistry identified isolated islands of
CD31 expressing structures. Micro dissected vascular structures
demonstrated marked allelic imbalance after amplification
with VHL gene flanking primers, indicating a loss of VHL and a
somatic second hit deletion of the wild type allele. Co localization
by immunofluorescence for HLA and CD31 further confirmed
the presence of tumor derived vascular tissue. Moreover, FISH
analysis of CD31 positive endothelial cells confirmed consistent
loss of one copy of either chromosome 3 or VHL.
Conclusions: The hemangioblast cell was identified as the
embryologic progenitor cell for both endothelial cells and
erythrocytes. We established that some VHL associated tumor
cells differentiate into endothelial cells, confirming that
developmentally arrested vHL deficient hemangioblast cells are
responsible for VHL associated tumorogenesis, and maintain the
potential to develop into endothelial cells.
Introduction: While immunotherapy has demonstrated promise in
clinical studies, overcoming immunosuppression within the tumor
microenvironment remains a challenge. Naturally occurring
ribonucleoproteins known as vault nanoparticles have been found
capable of enclosing, protecting and delivering various antigens
and drugs. In this study, we assay a bioengineered PVI Z vault
containing CCL21, a potent lymphocyte chemoattractant, inducing
antitumor immunity in glioblastoma in vivo.
Methods: Using INT fusion proteins, CCL21 cDNA was integrated
into PVI Z vaults. C57BL/6 mice 6 10 weeks old were injected
with 1x10 6 GL261 cells into the left flank and given a single
intratumoral injection/week for 3 weeks of either 5ug of
recombinant PVI Z CCL21 vaults or 50uL PBS (control). Mice
were euthanized if tumors were ulcerating or larger than 15mm
in diameter. Survival and tumor growth rate were analyzed and
compared.
Results: GBM was successfully injected into our animal model.
Tumor size was measured weekly, and continual tumor growth
was present in 100% of untreated mice at each weekly interval.
In the treatment group with CC21 vault nanoparticles, 33% of
mice demonstrated tumor regression and decrease in size. For
the other cohort, tumor size decreased on average by day 25, and
stabilized until the conclusion of the study on day 38.
Conclusions: PVI Z CCL21 vault nanoparticles can be
bioengineered efficiently, and treatment with recombinant
vaults demonstrated the potential for tumor control. This study
demonstrates the in vivo efficacy of CCL21 vault nanoparticles,
and its potential to be used as a potential novel therapy for high
grade gliomas.
30
35. mTOR Inhibition As A Reasonable Strategy For
Meningioma Treatment
36. miR 124 Systemically Enhances Antitumor Clearance By
Inhibiting STAT3 Signaling And Reversing Glioma Associated
Immune Suppression
Christian Mawrin; Doreen Pachow; Elmar Kirches (Magdeburg,
Germany)
Amy B. Heimberger, MD, FAANS; Jun Wei, PhD; Fei Wang, PhD;
Ling Yuan Kong, PhD; Shuo Xu, PhD; Tiffany Doucette, PhD;
Sherise Ferguson, MD; Frederick Lang, MD; Ganesh Rao, MD;
Gregory Fuller, MD; George Calin, PhD (Houston, TX)
Introduction: Meningiomas are frequent intracranial tumors.
Increased morbidity due to aggressive tumor growth and/
or recurrence is a significant problem. Because the mTORC1
(mammalian target of rapamycin complex 1) pathway is activated
in many tumors, we explored the usefulness of mTORC1 inhibition
as therapeutic strategy in meningioma cell lines and mouse
models.
Introduction: MicroRNAs (miRs) have been shown to modulate
critical gene transcripts involved in tumorigenesis, but their role
in tumor mediated immune suppression is largely unknown.
Methods: On the basis of miRNA gene expression in gliomas using
tissue microarrays, in situ hybridization, and molecular modeling,
miR 124 was identified as the lead candidate for modulating signal
transducer and activator of transcription 3 (STAT3) signaling,
a key pathway mediating immune suppression of the tumor
microenvironment.
Methods: Tissue microarrays (53 meningiomas of all WHO grades)
were used for immunohistochemical evaluation of mTOR related
proteins. Expression of proteins and mRNAs was assessed by
western blotting and real time PCR in 25 tumors. Meningioma cell
lines including pairs of merlin positive or negative cells were used
to assess sensitivity towards mTORC1 inhibitors by MTT and BrdU
assays. Nude mice were either inoculated subcutaneously and the
effect of systemic temsirolimus treatment (20 mg/kg daily) was
monitored by measuring tumor weight and MRI estimated tumor
volume, respectively.
Results: MiR 124 is down regulated in all grades and pathological
types of gliomas. Upon up regulating miR 124 in glioma cancer
stem cells (gCSCs), the STAT3 pathway was inhibited, and miR
124 reversed gCSC mediated immune suppression of T cell
proliferation and induction of Foxp3+ regulatory T cells (Tregs).
Treatment of T cells from immunosuppressed glioblastoma
patients with miR 124 induced marked effector response including
up regulation of IL 2, IFN-Y, and tumor necrosis factor (TNF)-a.
Both systemic administration of miR 124 or adoptive miR 124
transfected T cell transfers exerted potent anti glioma therapeutic
effects in clonotypic and genetically engineered murine models
of glioblastoma and enhanced effector responses in the local
tumor microenvironment. These therapeutic effects were ablated
in both CD4+ and CD8+ depleted mice and nude mouse systems,
indicating that the therapeutic effect of miR 124 depends on the
presence of a T cell mediated antitumor immune response.
Results: The mTORC1 pathway was activated in most
meningiomas independent of their WHO grade. A significant
dosage dependent growth inhibition by temsirolimus was
observed in all cell lines which was also affected by NF2 status.
In xenograft models, temsirolimus treatment resulted in about
70% growth reduction of tumors (p‹0.01), which was paralleled by
reduction of Ki67 mitotic index (p‹0.05) and reduction of mTORC1
activity (p70S6K phosphorylation) within the tumors.
Conclusions: Preclinical data suggest usefulness of mTORC1
inhibitors to treat human meningiomas.
Conclusions: Our findings highlight the potential application of
miR 124 as a novel immunotherapeutic agent for neoplasms and
serve as a model for identifying miRNAs that can be exploited as
immune therapeutics.
31
2013 AANS/CNS SECTION ON TUMORS
SCIENTIFIC PROGRAM ELECTRONIC POSTER ABSTRACTS
100. Pineal Region Tumours: Management Challenges Revisited
Joseph Orinya Obande, MD; Abdullahi Jimoh, MD; Sunday
Adewuyi, MD (Zaria/Kaduna State, Nigeria)
Introduction: Pineal region tumours may affect only a relatively
small subset of neurosurgical patients, they present enormous
surgical challenge to the neurosurgeon; worse still in a resource
poor setting, due to thier deep location, almost equidistant from
all access points and surrounding neurovascular structures.
We present a case report of a patient who had combination
chemotherapy without histological diagnosis and had complete
tumour regression.
Methods: The patient's case folder was retrieved and information
relating to presentation, the working diagnosis and supporting
investigations were sought. She had pre chemotherapy ventriculo
peritoneal shunt insertion for obstructive hydrocephalus. After
due consultation with the Radio oncolgist, she had cyclical
combination chemotherapy with cisplatin, etoposide and
bleomycin.
Results: The patient's clinical condition improved following the
ventriculo peritoneal shunt insertion. Post chemotherapy Brain CT
scan showed complete tumor regression.
Conclusions: Tissue diagnosis may allow for precise, targeted
management of pineal region tumours, however, in the absence
of facilities which enable safe neurosurgery, resorting to the
traditional chemo radiation is still a viable alternative.
101. A Nomogram For Individualized Estimates Of Survival
Outcomes For Patients With Brain Metastasis
Andrew E. Sloan, MD, FAANS; Jaime Venoechea, MD; Changhong
Yu, PhD; Meihua Wang, PhD; James Dignam, PhD; Michael
Vogelbaum, MD; Paul Sperduto, MD; Minesh Mehta, MD; Mitchell
Machtay, MD; Michael Kattan, PhD; Jill Barnholtz Sloan, PhD
(Cleveland, OH)
Introduction: Brain metastases, which develop in 24 45% of
cancer patients, account for 20% of cancer deaths annually, and
are the most common intracranial mass lesions, with an incidence
of 98,000 170,000 cases each year in the US. There are several
therapeutic options, but selection of the optimal treatment for
individual patients remains controversial. Classification schemes
such as recursive partitioning analysis (RPA), and diagnosis
specific graded prognostic assessment (DS GPA) have been
validated, but these provide group, rather than individualized
estimates of outcome. The purpose of this study was to develop
and validate a nomogram for individualized patient prognosis
which could be used for counseling patients.
Methods: De identified data from 7 randomized controlled trials
of brain metastasis in 2367 patients was obtained from the
RTOG database. Overall survival was estimated using the Cox
proportional hazards regression, RPA, and random survival forests
(RSF) methods, and a nomogram was built using a concordance
index to identify the best approach for each variable.
Results: The Cox analysis outperformed other methods thus
the nomogram was built to estimate survival probabilities and
median survival based on the Cox model. The predicted values
approximated the observed value within a 95% confidence interval.
Conclusions: The nomogram based on the Cox model enabled
better and more refined survival predictions than those based
on RPA, DS GPA or RSF models. This predictor of outcome could
be readily applicable to clinical practice in enabling patients and
their physicians to make informed decisions regarding treatment
options and will be provided as free software application. Future
directions include external validation in a prospective dataset.
102. A Personalized Genetic Approach Using Circulating Mutant
DNA To Monitor GBM Tumor Dynamics
El Mustapha Bahassi; John Furgason, BS; Emily Cross; Ya Qin
Li; Wenge Li, PhD; Jan Vrijg, PhD; Christopher McPherson, MD;
Ronald Warnick, MD; Peter Stambrook, PhD; Olivier Rixe, MD,
PhD; El Mustapha Bahassi, PhD (West Chester, OH)
Introduction: Malignant gliomas are the most frequent and lethal
cancers originating in the central nervous system. The most
biologically aggressive subtype is the glioblastoma multiforme
(GBM), a tumor associated with dismal prognosis. The current
standard of care for GBM patients; surgical resection followed
by adjuvant radiation therapy and chemotherapy with the oral
alkylating agent temozolomide; produces a median survival of
only 15 months. Even with the addition of the last generation of
imaging studies, clinical assessment of tumor progression versus
pseudo progression remains difficult. This, combined with the
high cost of these imaging modalities, can pose serious delays
in treatment decisions and result in harm to the patient. Hence,
there is urgent need for a sensitive, specific, noninvasive and low
cost biomarker which could be used routinely to monitor disease
status in patients on treatment.
Methods: It is now well established that circulating mutant DNA
(cmDNA) that originates in the tumor can be detected in the
peripheral blood. We used next generation, paired end sequencing
to analyze several GBM genomes and their isogenic controls
and identified tumor specific mutations. These mutations were
detected by polymerase chain reaction (PCR) in the patients;
plasma and were used to follow disease progression over time.
32
Results: Here, we show that the amount of cmDNA detected in
the plasma of 10 GBM patients on treatment correlates with the
tumor status.
Conclusions: Mutation associated biomarkers offer a reliable
measure that would be useful for monitoring tumor response to
specific therapies, detecting residual disease after surgery, and
for long term clinical management.
103. Altered Expression Of The Endoribonuclease Dicer Has
Prognostic Significance In Meningiomas
Felipe Goncalves de Carvalho, MD; Sanjay Singh, PhD; Shahrzad
Jalali, PhD; Gelareh Zadeh, MD, PhD (Toronto, Canada)
Introduction: Meningiomas are the most common primary brain
tumors and, although usually benign, they may also present
malignant behavior. The endoribonuclease Dicer is crucial
for microRNA biogenesis. Low expression of Dicer has been
associated with cancer, even though there are no studies in
meningiomas.
Methods: We used tissue microarray (TMA) slides containing 59
samples of meningiomas from patients that underwent surgical
resection. We performed immunohistochemistry for Dicer and
scored its expression according to the following criteria: (0)
no staining; (1+) less than 25% of positive cells; (2+) less than
50%; (3+) between 50% and 75%; and (4+) more than 75%.
We considered the range from 0 to 2+ as low and 3+ to 4+ as
high Dicer expression. Clinical correlation was made between
WHO grade classification, tumor recurrence, post operative
radiation therapy, cavernous sinus invasion, Mib1 index and
Dicerexpression.
Results: From the total of 59 patients studied, 42 (71.2%) had high
Dicer expression and 17 (28.8%) low Dicer. In the high Dicer group,
the WHO grade distribution was: 34 (81.0%) grade I and 8 (19.0%)
grade II, with no grade III. The low Dicer group revealed: 7 (41.2%)
grade I, 8 (47.1%) grade II and 2 (11.8%) grade III. In addition,
the low Dicer group had higher percentage of tumor recurrence
(47.1% vs 26.2%), post operative radiation (54.5% vs 19.0%),
cavernous sinus invasion (45.5% vs 24.3%), and Mib1 index (4.05%
vs 1.50%) when compared to the high Dicer group.
104. Withdrawn
105. Case Presentation: Atypical Presentation Of Cervical
Meningioma Presenting With Acute Epidural Hematoma
John Franklin Hamilton, MD, PhD, FAANS; James Boddu, BS;
Joseph Watson, MD; Ernest Roos, MD (Great Falls, VA)
Introduction: Meningiomas can present anywhere along the
cranio spinal axis. The clinical signs and symptoms of spinal
meningiomas are typical of slow growing space occupying lesions
of the spinal canal. Clinical symptoms are normally indolent,
gradual in presentation, and dependent on the tumor level and
breadth. Spinal epidural hematomas are normally associated
with coagulopathy and/or trauma. These lesions have the
potential to rapidly expand and cause acute neurological decline,
often requiring emergent surgical intervention. There is ample
literature on the more common causes of epidural bleeds, but
sparse data describing spinal epidural hematomas presenting
secondary to cervical meningiomas. This study describes a
patient lacking the common risk factors for a spinal epidural
hemorrhage, who presented clinically with acute paraparesis from
a spontaneous cervical spinal hemorrhage.
Methods: The patient physical examination was most notable
for dense paraparesis. Clinical workup was unremarkable for
any typical causes of an acute epidural hematoma. A cervical
spine MRI revealed a meningioma at the C1 2 level, at the
proximal portion of the epidural hematoma. We hypothesized the
pathogenesis of the meningioma as the causative agent of the
acute epidural hematoma.
Results: The patient’s C2 T1 laminectomy revealed an epidural
hematoma compressing the cal sac from C3 T1 with an extra/
intradural mass lesion from C1 3 compressing the friable
posterior epidural venous plexus, and therefore causing the
hemorrhage.
Conclusions: This case provides evidence that, though not
previously considered, spinal meningiomas should be included in
the differential diagnosis of spinal hematomas. This is especially
the case when long term indolent pain is followed by acute
symptoms without the commonly reported risk factors.
Conclusions: Therefore, low Dicer expression in meningiomas can
be related to tumor aggressiveness and a worse clinical course.
33
106. Case Presentation: Management Of Subacute Complete
Paralysis Secondary To Intraspinal Neuroblastoma In The
Pediatric Patient
John Franklin Hamilton, MD, PhD, FAANS; James Boddu, BS
(Great Falls, VA)
Introduction: Neuroblastomas are the most commonly
encountered extracranial pediatric neoplasms. Prognosis of
affected patients is dependent on age, staging, and the pathology
of the neoplasms, and this in turn affects treatment. A review of
the literature reveals a constant debate between surgical or non
surgical management of these types of neoplasms. However,
the literature unanimously reveals a poor prognosis in patients
with severe acute progressive neurological deficits, regardless
of treatment type. The novel case herein reports a 3 month old
patient with full resolution of a 4 day history of complete lower
extremity paralysis status post neurosurgical intervention.
Methods: Magnetic resonance imaging showed complete spinal
cord compression by a thoracolumbar intracanal extradural mass
that was contiguous with a paraspinal mass. Further pathological
and radiological analysis, including MIBG and bone scintigraphy,
showed that the mass was consistent with a non metastatic
neuroblastoma. The patient subsequently underwent a multilevel
laminectomy that allowed for resection of the intraspinal mass
and decompression of the spinal cord.This was followed by
adjuvant therapy on a delayed basis.
Results: Fortunately, despite their prolonged lower extremity
paralysis the patient regained full neurological function with
resolution of spinal cord compression on radiographic imaging at
6 months follow up.
Conclusions: Currently, research states that patients with
prolonged severe neurological deficits secondary to an intraspinal
neuroblastoma have a very slim chance in regaining neurological
function, irrespective of surgical or non surgical management.
This novel case seems to suggest that prompt surgical
intervention followed by adjuvant therapy is the best treatment
for these patients, given the potential benefit of rapid recovery of
neurological function.
107. Withdrawn
108. Comparison Of Coagulation Activation In Malignant Primary
Brain Neoplasms And Meningioma
Lara K. Ronan; Brett Gourley, MD; Deborah Ornstein, MD; Camilo
Fadul, MD (Lebanon, NH)
Introduction: Patients with malignant gliomas have a venous
thromboembolism (VTE) risk of up to 30% over the course of the
disease and are associated with systemic coagulation activation as
assessed by increased blood levels of certain surrogate markers
of coagulation activation. Meningiomas are benign brain tumors
that are also associated with an increased VTE risk. Whether
the presence or resection of meningiomas leads to systemic
coagulation activation has not been clarified.
Methods: We hypothesize that patients with glioblastoma
multiforme (GBM) demonstrate increased systemic coagulation
activation compared to healthy individuals. We further hypothesize
that meningiomas are not associated with a significant increase in
systemic coagulation activation and that this may account for the
difference in VTE risk. We will test this hypothesis by measuring
surrogate markers of systemic coagulation activation in patients
with GBM and meningiomas before and after treatment and in
age and sex matched healthy control blood donors. Markers of
coagulation activation assayed for this study will include plasma D
dimers, P selectin, tissue factor pathway inhibitor (TFPI), thrombin
generation via calibrated automated thrombography and tumor
tissue factor and TFPI expression by immunohistochemistry.
Results: We are currently actively recruiting to this study and
expect to complete arcual by the end of 2014.
Conclusions: We expect this work to lead to clarification of
coagulation abnormalities in patients with primary brain tumors
and may result in identification of novel markers of VTE risk in
these patients.
109. Concurrent Glioblastoma With Primary CNS Lymphoma
Zaitun Zakaria; Eoin Fenton, MD; Ayman Khalil, MD; Muhammad
Taufiq Sattar, MD (Dublin 9, Ireland)
Introduction: The standard treatment of Glioblastoma(GBM)
includes maximal surgical resection,followed by radiotherapy and
concomitant and adjuvant chemotherapy. This however does not
exclude the immunocompromising effect,which includes risks of
lymphomatous disease.
Methods: A 69 year old male underwent right temporal
craniotomy and debulking of the lesion, confirmed to be GBM
with positive MGMT promoter. He was commenced on Stupp
prorocal with concurrent Temozolomide. His treatment completed
2 months after his initial presentation and a month later, he
proceeded with first cycle of adjuvant chemotherapy. This was
complicated with large pulmonary embolism and left lower limb
deep vein thrombosis. Follow up MRI Brain revealed a recurrence
of his tumour. There was also a new enhancing lesion in the left
frontal lobe, measuring 1.5cm in dimension, thought likely to be a
multifocal disease. He subsequenly underwent further debulking
of his original tumour and stereotactic biopsy of the contralateral
lesion. His debulking specimen revealed Astroctoma Grade III.
Histopathologic evaluation from the left side showed primary CNS
B cell Lymphoma. He deteriorated during chemotherapy and died
10 months after his original presentation.
Results: We describe herein an interesting case of primary GBM
with concurrent primary CNS lymphoma diagnosed 2 months after
completion of Temozolomide treatment. To best of our knowledge,
this is the first case reported in literature. This was observed
on his surveillance MRI Brain 2 months after completion of
treatment, therefore, the suspicion exists that the lesion may have
developed while he was on treatment. To best of our knowledge,
this is the first case reported in literature.
34
Conclusions: Regular follow up of glioma patients who
recieve Temozolomide is recommended, particularly with
risk for secondary malignancy from treatment associated
immunosuppression.
111. Cortical GABAergic Excitation Contributes To Epileptic
Activities Around Human Glioma. An Electrophysiological Study
Johan Pallud, MD; Laurent Capelle; François Xavier Roux; Gilles
Huberfeld (Paris, France)
Introduction: Brain gliomas induce seizures in a majority of
patients. Excitatory glutamatergic mechanism are shown to be
involved in the generation of epileptic activities in the cortex
surrounding gliomas. However, the contribution of defective
Chloride homeostasis and paradoxical excitatory GABAergic
mechanisms, crucial in other epilepsies, is unknown.
110. Correlation Of Histopathology To ALA Induced Fluorescence
in Meningiomas
Sam Eljamel, MD, FRCS; Tan Hon, MBBS; Carol Goodman, RN
(Dundee, United Kingdom)
Introduction: Meningiomas comprise 13 30% of primary
intracranial tumors and are only less frequent than intracranial
gliomas. They can occur anywhere in the cranium and the spine
and have varied pathology. Removal of meningiomas in certain
locations can be challenging, we explored the use of ALA induced
fluorescence to guide intracranial meningiomas; resection and its
corrolation to histopathology.
Methods: We studied in neocortical slices from the security
margin resected around human brain gliomas, the occurrence,
networks, cells, signaling and origin of epileptic activities.
Results: Postoperative glioma tissues of 69% patients
spontaneously generated interictal like discharges. These events
were synchronized in superficial layers of cortical columns in
the neocortex surrounding glioma areas that presented a tumor
infiltration and had a high frequency oscillation signature.
Interictal like events depended on glutamatergic transmission but
also on depolarizing GABAergic signaling. Up to 65% pyramidal
cells were depolarized by GABA released by interneurons. This
effect was related to perturbations in Chloride homeostasis, due to
an abnormal load by the co transporter NKCC1. Ictal like activities
could be exclusively generated in these epileptogenic areas.
Methods: Twenty nine consecutive lesions with MRI differential
of meningiomas were included in this analysis, including 17
supratentorial, 10 infratentorial and one thoracic. Twenty
three were females, the mean age was 55.4 years and the final
diagnosis was meningioma in 21 (72.4%). All these patients
received 1.5 g 5 aminlevulinic acid (ALA) orally about 3 hours
before surgery. Surgical resection was aided by using the
blue light of the microscope (Pentero, Zeiss, Germany). The
fluorescence was graded into strong (very red fluorescent), faint
(pink) and moderate (in between red and pink).
Conclusions: These activities sustained by excitatory effects of
GABA, as those reported in human temporal lobe epilepsies,
suggest that cellular Chloride regulation processes affecting
oncogenesis are involved in the excitatory/inhibitory imbalance
causing epileptic activity in peri tumoral tissue.
Results: Fluorescence was detected in 22 (78.6%), of which twenty
were intracranial meningiomas. Strong fluorescence signal was
observed in nine of all lesions (32%) all of which were intracranial
meningiomas (45%). Moderate fluorescence was noted in seven
lesions (25%) all of which were intracranial meningiomas (35%).
Faint signal was observed in six (14.3%) four of which were
meningiomas (20%). Seventeen of intracranial meningiomas were
WHO grade I (85%) and three (15%) were grade II. Total excision
(Simpson grade 1) was achieved in all meningiomas. There was
no correlation between histological type, ALA dose, or time to
fluorescence and the intensity of fluorescence. Only two patients
developed significant drop in their blood pressure (7.1%).
Conclusions: Intracranial meningiomas fluoresce after oral ALA
at a dose of 12 35 mg/kg body weight. ALA induced fluorescence
is safe and helpful in intracranial meningioma surgical resection,
but there was no correlation to histology.
35
112. Defining The Target For Radiation Therapy Of Meningiomas:
A Multidisciplinary Study Of Interobserver Variability
day to under 100 cc/day by the 11th day of radiation therapy. On
postoperative day #22 the EVD was clamped, and the patient
remained asymptomatic the following day. A new brain MRI
showed significantly decreased size of the germinoma along with
flow artifact across the floor of the third ventricle, and his EVD
was removed. The patient's hydrocephalus did not recur over the
following month.
Stephanie Elizabeth Weiss, MD; Paul Kelly, MD; Edward Mannarino,
BS; Fred Hacker, PhD; John Lewis, PhD (Philadelphia, PA)
Introduction: We hypothesize significant inter observer variability
exists in GTV and CTV for meningioma radiation planning. We
undertook a multidisciplinary study among brain tumor experts to
test this hypothesis.
Methods: The expert group included 2 CNS radiation oncologists,
3 tumor neurosurgeons, and 2 neuro radiologists. De identified
contrast enhanced MR/CT datasets of 2 cases of meningioma were
co registered in the treatment planning system. Each observer
received tutorials on GTV/CTV concept and contouring tools. Each
was asked to define GTV and CTV for two cases, blinded to the
delineations of other participants. CERR Matlab tool was used to
compare volumes. Kappa statistics measured of corrected overlap
agreement: 0= poor, 0.01; 0.20 slight, 0.21; 0.40 fair, 0.41; 0.60
moderate, 0.61; 0.80 substantial, and 0.80; 1.00 almost perfect
agreement. CCC measured inter observer reproducibility.
Results: Case 1, Grade 1 sphenoid meningioma: kappa=GTV 0.56,
CTV 0.53 (<0.001); Case 2, atypical parasagittal meningioma:
kappa = GTV 0.37, CTV 0.27 (GTV 0.41 (95% CI: 0.375 0.852,
p<0.001) indicating poor reproducibility. CCC for CTV was not
computed due to extreme variation.
Conclusions: In this pilot substantial inter observer variability
exists in meningioma target definition. Over contouring increases
normal tissue exposure. Under contouring increases recurrence
risk. Radiosurgery effectively reduces margins to zero (GTV=CTV),
an approach counter conceptual to the maxim of maximal safe
resection. Our findings suggest lack of physician consensus
regarding target volume. We suggest a large scale study to
confirm these findings and consideration of a multidisciplinary
consortium to standardize target volumes.
113. Delayed Patency Of Endoscopic Third Ventriculostomy With
Radiation Induced Reduction In Mass Effect: Case Illustration
William C. Gump, MD; Ian Mutchnick, MD (Louisville, KY)
Introduction: Endoscopic third ventriculostomy (E3V) is an
established option for treatment of obstructive hydrocephalus
and is often performed concurrently with biopsy of an obstructing
mass lesion. Delayed failure is a known complication. We report
the case of a patient whose E3V became functionally patent in a
delayed fashion, three weeks postoperatively, when mass effect
on the brainstem had been adequately relieved.
Methods: A 13 year old boy presented to the emergency
department with symptomatic obstructive hydrocephalus from a
pineal region tumor. He underwent endoscopic biopsy, E3V, and
external ventricular drain (EVD) placement.
Results: Pathology was consistent with pure germinoma. The
patient returned to surgery four days later for a secondary E3V.
He remained drain dependent, and initiated radiation therapy
on postoperative day #7. EVD output declined from over 300 cc/
Conclusions: Resolving mass effect from a rapidly shrinking
pineal region tumor can delay relief of hydrocephalus from E3V,
but has the potential to ultimately result in shunt independence.
114. Development Of A Three Dimensional Cell Culture Of
Glioblastoma And Characterization Of A Novel Anti Tumoral
Metabolic Treatment
Anna Magdalena Wilk; Jennifer Mullinax, MD; Luis Del Valle, MD;
Frank Culicchia, MD; Krzysztof Reiss, PhD (New Orleans, LA)
Introduction: Because of the rapid growth, rate of recurrence,
heterogeneity and resistance to therapies, Glioblastomas
constitute one of the most aggressive human cancers. Therefore,
advancements in research tools, including cell culture and
animal models represent a challenge for basic research and are
necessary for the development of more effective treatments.
Methods: We are developing the 3 Dimensional cell culture
model in which primary Glioblastoma cells are forced to form
multi cellular Glio Spheres. This approach allows cells to grow
for several months without losing their glial phenotype, the main
problem with Glioblastoma culture. We use Seahorse Analyzer to
characterize metabolic properties of Glio Spheres by measuring
Extracellular acidification and Oxygen consumption rates; We also
evaluate mitochondrial membrane potential, cell survival and
response to a common lipid lowering drug, fenofibrate.
Results:
1) Glio Spheres utilize both glycolysis and oxidative
phosphorylation to sustain their metabolism, but unexpectedly,
they do not show glycolytic reserve;
2) Fenofibrate induces acute inhibition of mitochondrial
respiration which was partially compensated by glycolysis and/or
glutaminolysis;
3) Fenofibrate compromises mitochondrial potential, accompanied
by a G0/G1 cell cycle arrest, which was followed by massive
apoptosis.
Conclusions: Here, we demonstrate a new approach to develop
3 dimentional cell culture system for primary Glioblastoma (Glio
Spheres) and present their metabolic profiles. We also include
studies on fenofibrate, which has strong anti tumoral effect with
low systemic toxicity, and could be introduced as a supportive
regimen to the conventional therapies. The Glio Spheres can be
also implanted into the brains of immunodeficient mice, providing
a clinically relevant model for testing anti tumoral regiments
against Glioblastoma.
36
115. Discovery Of Novel Oncogenic SMO And AKT1 Mutations
In Meningiomas
116. Dynamic Susceptibility Contrast And Dynamic Contrast
Enhanced MR Imaging Characteristics Distinguish Microcystic
Meningiomas From Traditional Grade I Meningiomas And High
Grade Gliomas
Peleg Moshe Horowitz, MD; Priscilla Brastianos; Sandro
Santagata; Robert Jones; Aaron McKenna; Gad Getz; Keith Ligon;
Paul van Hummelen; Emanuele Palescandolo; Matthew Ducar;
Laura MacConaill; Anat Stemmer Rachamimov; David Louis;
William Hahn; Rameen Beroukhim; Ian Dunn, MD (Boston, MA)
Namath Hussain, MD; Bart Keogh, MD, PhD; Steven Rostad, MD;
David Newell, MD; Ryder Gwinn, MD; Gregory Foltz, MD; Marc
Mayberg, MD; Brian Aguedan; Valerie Good; Sarah Fouke, MD
(Bloomfield Hills, MI)
Introduction: Meningiomas are the most common primary
tumor of the central nervous system. Although most are cured
by surgery, 20%recur and tend to be minimally responsive to
systemic therapy. The tumor suppressor NF2 is disrupted in
approximately half of meningiomas, but the complete spectrum of
genetic changes remains undefined.
Introduction: Microcystic meningioma is a variant of meningioma
with a multicystic appearance that can mimic intrinsic
primary brain tumors, hemangioblastomas, and other non
meningiomatous tumor types. Dynamic susceptibility contrast
(DSC) and Dynamic Contrast Enhanced (DCE) imaging have been
developed to differentiate such tumors types.
Methods: We performed whole genome or whole exome
sequencing of 17 Grade I meningiomas and focused sequencing
of an additional 48 tumors to comprehensively identify mutations,
insertion deletions, copy number alterations, and genetic
rearrangements contributing to oncogenesis. A mutational
significance algorithm was used to distinguish driver and
passenger events.
Methods: 18 subjects with histopathological diagnosis of
microcystic meningioma and a cohort of 12 subjects with grade
I meningioma and 54 subjects with grade IV primary glioma
were considered. Clinical variables including patient sex, age,
extent of resection, surgical blood loss and need for adjunctive
therapy were considered. DSC images were acquired at a
temporal resolution of either 1500ms (3T) or 2000 ms (1.5T).
Parameters including nCBV and kTrans were calculated with ROIs
corresponding to enhancing tumor volume.
Results: Overall, the tumors showed few somatic genetic events,
consistent with their benign clinical status, but underscoring the
potential importance of each individual event. Several tumors
harbored more complex patterns of copy number changes and
rearrangements including one tumor with chromothripsis. As
expected, the NF2 gene was identified as the most frequently
altered, with over half of tumors harboring NF2 disruptions. One
sample had a novel translocation affecting the NF2 gene and a
nearby region of chr22. In addition, several known cancer driver
mutations including in SMO and AKT1 were seen primarily in NF2
wildtype tumors.
Results: Preoperative DSC analysis demonstrated mean
enhancing tumor nCBV values of 1.66 (+/ 0.60) for grade I
meningiomas (meningoepithelial subtype), 5.74 (+/ 2.24) for Grade
IV Astrocytomas, and 12.32 (+/ 3.81) for grade I meningiomas
(microcystic subtype). nCBV measured within the enhancing
portion of the tumor is significantly elevated in the microcystic
meningioma subtype when compared with typical meningiomas
(p<0.001) and Grade IV astrocytomas (p<0.0001). Preoperative
DCE analysis demonstrated kTrans values of 0.49 min(e 1) (+/
0.20) in grade I meningiomas (meningoepithelial subtype), 0.27
min(e 1) (+/ 0.12) for Grade IV Astrocytomas, and 1.35 min(e 1)
(+/ 0.73 ) for grade I meningiomas (microcystic subtype). kTrans
measured within the enhancing portion is significantly elevated
in microcystic meningioma when compared with corresponding
typical meningiomas (p<0.05) and Grade IV astrocytomas
(p<0.0001). Intraoperative blood loss tended to increase with
nCBV (R= 0.45) but was not statistically significant (p=0.085).
Conclusions: This study begins to define the spectrum of genetic
alterations in meningiomas. The discovery of novel drivers of
meningiomagenesis with existing targeted therapeutics has the
potential to rapidly transform the clinical management of
meningiomas.
Conclusions: An enhancing cystic lesion with elevated nCBV
(‹10.3) or kTrans (0.49 min(e 1)) should lead surgeons to consider
the diagnosis of microcystic meningioma, versus high grade
glioma. Higher nCBV values are associated with a trend to
increased intraoperative blood loss.
37
117. Endocrinological Outcomes Of Pure Endoscopic
Transsphenoidal Surgery: An Uzbek Endocrine
Center Experience
118. Endonasal Endoscopic Anatomy Of The Clinodial (C5) And
Proximal Ophthalmic (C6) Internal Carotid Arteries
Amjad Anaizi, MD; Almaz Kurbanov, MD; Vincent DiNapoli,
MD, PhD; Jeffrey Keller, PhD; Lee Zimmer, MD, PhD; Philip
Theodosopoulos, MD (Cincinnati, OH)
Farrukh Karimov, MD; AM Akbutaev; RB Fayzullaev; SI Ismailov
(Taskent, Uzbekistan)
Introduction: Aim To analyze early remission, complications,
and pituitary function recovery after pure endoscopic endonasal
transsphenoidal surgery (PEETS), a novel method in pituitary
adenoma treatment.
Introduction: Increasing use of endoscopic approaches for the
treatment of various intracranial pathology has necessitated
neurosurgeons have a thorough understanding of the anatomy
from an endoscopic endonasal perspective. We present a
cadaveric anatomic study of the clinoidal and ophthalmic ICA from
an endonasal endoscopic perspective.
Methods: Testing of all basal hormone values and magnetic
resonance imaging (MRI) were performed preoperatively and
postoperatively in 121 consecutive patients who underwent PEETS
in the period between 2011 and 2012. The series consisted of 37
somatotroph adenomas, 4 prolactinomas, and 8 corticotroph and
72 nonfunctioning adenomas. 110 were macroadenomas and
11 were microadenomas. Remission was defined as hormonal
excess normalization on the third postoperative day in functioning
adenomas and as normal MRI findings approximately four months
postoperatively in nonfunctioning adenomas. Hypocortisolism
was assessed through necessity for replacement therapy within 3
months postoperatively.
Methods: Embalmed heads underwent thin cut CT scans for
the purpose of neuronavigation. The heads were registered
with our neuronavigation system. An endonasal endoscopic
transsphenoidal exposure was performed. Various measurements
were taken some of which include: the inter carotid distance at
the level of the distal dural rings (DDR), the distance between the
ICA at the distal dural ring and the optic chiasm and the distance
between the ICA and the pituitary stalk. The ratio of inter carotid
distance to distance between the OCRs was also calculated.
Results: A total of 10 cadaver heads were studied.
Neuronavigation was used achieving excellent accuracy in all
cases. The average distance between the carotids at the distal
dural rings was 10.4mm. The average distance between the ICA at
the distal dural ring and the optic chiasm is 9.5mm. The average
ratio of inter carotid distance at the DDR to inter OCR distance is
0.354. We also observed significant variability in the course of the
distal C4, C5 and proximal C6 ICA.
Results: Remission was achieved in 84% of patients: in 100% of
microadenoma and 70% of macroadenoma patients (P ‹0.001,
odds ratio [OR], 28.16, 95% confidence interval [CI], 1.61 491.36),
respectively. Endocrinological complications occurred in 17.1%
of patients: in 9% of microadenoma and 24% of macroadenoma
patients (P = 0.049, OR, 3.06; 95% CI, 1.03 9.08). Duration of
hydrocortisone replacement therapy was significantly shorter
in microadenoma patients (P ‹0.001). Seventy five percent of
preoperatively present hormonal deficiencies improved after
the surgery. Between tumor types there were no significant
differences in remission, complications, and normal pituitary
function recovery.
Conclusions: Expansion of endonasal endoscopic techniques
for treatment of various intracranial pathology necessitates
improved understanding of the clinoidal and proximal intradural
ICA anatomy and its relationship to surrounding structures. This
will enable surgeons to more reliably predict the location of the
ICA and its relationship to surrounding structures, decreasing the
potential for vascular injury.
Conclusions: Patients with microadenomas had higher
remission and lower complication rates following PEETS,
emphasizing the necessity for early detection and treatment of
pituitary adenomas. PEETS is a discussion worthy method for
microprolactinoma treatment.
119. Endoscopic Surgical Management Of Grade IV Juvenile
Nasopharyngeal Angiofibromas
Amjad Anaizi, MD; John York, MD; Lee Zimmer, MD, PhD; Philip
Theodosopoulos, MD (Cincinnati, OH)
Introduction: Juvenile nasopharyngeal angiofibromas (JNA)
are histologically benign vascular tumors found in prepubertal
and adolescent males. These can be locally aggressive with
potential intracranial extension. Traditionally these lesions have
been treated using open surgical techniques, however recently
endoscopic approaches have been implemented in hopes of
minimizing morbidity. We present a series of stage IV JNAs treated
endoscopically at our institution.
Methods: We retrospectively reviewed the charts of patients
with Stage IV JNAs treated endoscopically at our institution. We
recorded the number of operations, estimated blood loss, extent
of resection, any complications and length of hospital stay.
38
Results: 4 patients were surgically treated for stage IV JNAs.
All are male with an average age of 16 years. Average follow
up is 29.7 months. All patients underwent pre operative tumor
embolization. All underwent an endonasal endoscopic approach
with/without a Caldwell Luc approach. One patient underwent
an initial open transfacial approach and required a subsequent
endoscopic approach. Patients underwent an average of
2.25 resection operations. Mean EBL was 1829cc. A subtotal
resection was achieved in all cases. Two patients underwent
radiation therapy during the course of their treatment. There
were no mortalities.
Conclusions: Stage IV JNAs are difficult lesions to treat. Open
surgical resection can achieve good tumor control, but can
be exceedingly morbid. Given the tendency for these lesions
to regrow, multiple surgeries are often required. We believe
an endoscopic approach for subtotal resection in combination
with pre operative embolization and post operative adjuvant
treatment in select patients can achieve good tumor control while
minimizing morbidity.
120. Epidemiological Datas Support Early Surgery Of Incidentally
Discovered Diffuse Low Grade Glioma
Emmanuel Mandonnet; Philip de Witt Hamer, MD, PhD; Johan
Pallud, MD; Hugues Duffau (Paris, France)
Introduction: Early surgery for incidentally discovered diffuse
low grade glioma (DLGG) has been subject of debate, because
of potential overtreatment in these clinically silent patients.
We thus propose to compare the number of patients with silent
DLGG Dying from Another Cause over a period of N years DAC(N)
with the number of patients Dying from their Silent Glioma that
became symptomatic during the same period DSG(N).
Methods: We used DAC(N)=pxmxN, where p and m respectively
denote the prevalence of silent DLGG and the overall mortality
rate in the population. DSG(N) is given by DSG2+DSG3+DSG4,
where DSGn(N)=inxdn(1)+inxdn(2)+…+inxdn(N), in being the
incidence of symptomatic glioma of grade n arising from a silent
DLGG and dn(x) the proportion of symptomatic glioma patients
dying from their glioma of grade n after x years. To compute i3
and i4, we assumed that among high grade glioma, only those
IDH1/2 mutated arised from a silent DLGG. Numerical values were
estimates from the french register of CNS tumors, the national
institute of statistics, and published series of glioma survivals.
121. Epilepsy Associated With Protoplasmic Astrocytoma: Case
Report And Review Of The Literature
William C. Gump, MD; Karen Skjei, MD; Shefali Karkare, MD
(Louisville, KY)
Introduction: Protoplasmic astrocytoma is a rarely described WHO
grade II infiltrative tumor. We report a new case in a pediatric
patient.
Methods: A 4 year old girl presented with generalized seizures.
MRI of the brain revealed an extensive diffuse nonenhancing area
of abnormal signal involving the right frontal and temporal lobes.
She was taken to surgery for biopsy, and returned to surgery
eight months later for electrocorticography guided seizure focus
resection. Seizure frequency decreased to zero over the following
three months.
Results: Protoplasmic astrocytomas account for roughly 5% of low
grade astrocytomas. Compared with gemistocytic, protoplasmic
astrocytomas have less potential to behave aggressively. In
two case series encompassing 18 patients, average age at
presentation was 25 years. Most lesions were in the frontal or
temporal lobes. For 7 patients with unresectable lesions, biopsy
was performed; all others underwent attempted gross total
resection. Five patients subsequently received radiation therapy and
one also had chemotherapy. The youngest patient (age 2 years at
diagnosis) died 36 months after subtotal resection without further
adjuvant therapy; all others were alive with or without residual
tumor 2 to 108 months postoperatively. One additional case report
describes a 3 year old with diffuse leptomeningeal disease who
died from tumor progression despite chemotherapy. Although all
patients presented with seizures, seizure outcomes have not been
well documented. Our patient achieved seizure freedom.
Conclusions: Protoplasmic astrocytoma is a rare low grade
glioma which can be associated with medically resistant epilepsy.
Tailored surgery for unresectable lesions can be beneficial for
seizure control.
Results: We found DAC(N)=Nx0,3/100 000. The curve DSG(N) was
shown to grow exponentially with N, being below DAC(N) up to 4
years, crossing the curve DAC(N) at 4 years, and DSG(N) being
twice DAC(N) at 8 years.
Conclusions: Patients with silent DLGG are more likely to
die from transformation of the silent DLGG to symptomatic
glioma than dying from another cause with the silent DLGG,
unless patient survival is expected to be less than 4 years.
This epidemiological argumentation supports early surgery for
incidentally discovered glioma.
39
122. Establishing Standard Performance Measures For Adult Brain
Tumor Patients: A Nationwide Inpatient Sample Database Study
Maryam Rahman, MD; Dan Neal, MS; Kyle Fargen, MD; Brian Hoh,
MD (Philadelphia, PA)
Introduction: The Agency for Healthcare Research and Quality
(AHRQ) patient safety indicators (PSIs) and the Centers for
Medicare and Medicaid Services (CMS) hospital acquired
conditions (HACs) are used to evaluate the safety and quality of
healthcare. We determined the incidence rates of PSIs and HACs
among brain tumor patients in the Nationwide Inpatient Sample
(NIS) database.
Methods: We queried the NIS, part of the AHRQ Healthcare Cost
and Utilization Project (Rockville, MD), for all hospitalizations
between 2002 and 2010 involving a brain tumor using ICD 9 codes.
To identify patients who had undergone surgery, we used brain
tumor surgery ICD 9 codes. We used the SAS statistical software
package (Version 9.3) to calculate means, standard deviations
and frequencies for all patient and hospital characteristics and to
estimate all PSI and HAC incidence rates.
Results: Among the 501,908 hospitalizations involving a brain
tumor in the NIS database, there were 102,046 occurrences of an
AHRQ PSI, with 16% of patients experiencing one or more AHRQ
PSI. For brain tumor patients treated without surgery 17.2% of
patients experienced one or more PSI. For brain tumor patients
treated with surgery 9.8% patients experienced one or more
PSI. The most common PSIs included postoperative respiratory
failure, deep vein thrombosis, and sepsis. The total number of
HACs associated with brain tumor patients was 13,778, with 2.63%
patients experiencing one or more HAC. For brain tumor patients
treated without surgery 3.0% experienced one or more HAC. For
brain tumor patients treated with surgery 7.4% experienced one
or more HAC. The most common HACs included falls and trauma
and pressure ulcers. Increasing comorbidity score was associated
with increased likelihood of almost all PSIs and HACs.
Conclusions: Patient safety and delivery of quality care is an
important part of our national healthcare agenda. Our results
demonstrate baseline national rates of PSIs and HACs in brain
tumor patients. These data may be used to determine individual
institutional improvements or success by comparison.
123. Expression Of JCV T Antigen In Glioblastomas Causes
Nuclear Translocation of IRS 1 And Alterations In Faithful DNA
Repair Mechanisms
Anna Magdalena Wilk; Amanda Parker Struckhoff, PhD;
Krzysztof Reiss, PhD; Frank Culicchia, MD; Luis Del Valle, MD
(New Orleans, LA)
Introduction: Despite significant advances in surgical techniques
and new chemotherapeutic agents, Glioblastomas are
always associated with poor prognosis. One of the molecular
hallmarks of Glioblastomas is genomic instability, which
leads to the development catastrophic mutations. Thus, basic
DNA repair mechanisms responsible for the preservation of
genomic integrity could be impaired in Glioblastomas. We have
previously reported the detection of DNA sequences of the
human neurotropic JC Virus and expression of its oncoprotein, T
Antigen, in brain tumors of glial and neuroectoermal origin. Here
we study the association of T Antigen with proteins that impair
faithful DNA repair in Glioblastomas.
Methods: We performed immunohistochemistry for gH2AX
(a marker of DNA damage), IRS 1 and T Antigen and Rad 51
(the main component of homologous recombination DNA
repair) in archival samples and primary cell lines derived from
Glioblastomas.
Results: We demonstrate the accumulation of IRS 1 in the
cytoplasm of T Antigen negative tumors, while in T Antigen
positive samples IRS 1 in translocated to the nucleus. Double
labeling studies corroborate the co localization between IRS 1
and T Antigen. Immunohistochemistry for histone gH2AX, showed
a much stronger immunolabeling in the nuclei of JCV T Antigen
positive Glioblastoma cells, as well as co localization between
gH2AX and nuclear IRS 1, and between nuclear IRS 1 and the
major enzymatic component of HRR, Rad51.
Conclusions: Our findings suggest the involvement of JCV T
Antigen / IRS 1 signaling in the impairment of homologous
recombination in Glioblastomas, a critical mechanism for the
fidelity of DNA repair, which could provide a novel target for the
treatment of these highly aggressive tumors.
124. Extracranial Metastatic Meningioma: Imaging Appearance
With Bevacizumab
Christine Lauro; Douglas Ney, MD; Robert Bert, MD, PhD; Allen
Waziri, MD; Bette DeMasters, MD; Denise Damek, MD; Laurie
Gaspar, MD (Aurora, CO)
Introduction: Metastatic meningioma is a rare entity, occurring
in less than 1% of all meningiomas. Bevacizumab has recently
demonstrated encouraging anti tumor effect in the treatment
of recurrent and progressive meningiomas. The imaging
characteristics of meningiomas undergoing bevacizumab
treatment have not been extensively described.
Methods: While undergoing systemic therapy on bevacizumab with
a sustained intracranial response, a 55 year old man with a locally
recurrent WHO grade III meningioma developed a biopsy proven
left sided neck metastasis and radiographic findings consistent
40
Conclusions: Fluorescence guided resection for complex
meningiomas have shown to be an effective intraoperative tool to
achieve maximal citoreduction. In meningioma lesions we assume
that the breakage of the blood brain barrier increasing vascular
permeability and by this mechanism the 5 ALA reaches the
peritumoral area.
with pulmonary metastases. The magnetic resonance imaging
(MRI) appearance of this patient’s extracranial neck disease and
pulmonary metastases differed from his intracranial disease.
Results: The primary intracranial meningioma was a
homogeneously, avidly enhancing extra axial mass on magnetic
resonance imaging (MRI). The recurrent intracranial lesion was
isointense to surrounding brain on T1 imaging and hyperintense
on T2 weighted images. The radiographic characteristics of the
patient’s neck metastasis differed from the primary lesion. The
neck metastasis was weakly, inhomogeneously enhancing on
both computed tomography (CT) and MRI. The mass was centered
in the obliquus capitis inferior muscle and was associated
with erosive bony changes. The neck lesion was isointense to
muscle on noncontrast T1 imaging, and nearly isointense to gray
matter on T2 weighted images. There were four subcentimeter,
nonenhancing parenchymal lung nodules appreciated on chest CT,
consistent with pulmonary metastatic disease.
126. Hyperostosis In Intracranial Pediatric Meningioma
Jeffrey Murray; John Honeycutt, MD; Hayden Head, MD; Linda
Margraf, MD (Fort Worth, TX)
Introduction: Meningioma is the most common intracranial
neoplasm in adults, though rare in children and adolescents.
Cranial hyperostosis in association with adult meningioma occurs
frequently. The osteopathophysiology of this phenomenon is poorly
understood and controversial, with actual bone invasion by tumor
or reactive changes due to adjacent tumor having been posited
as explanations. Metalloproteins have also been suggested as
playing a role. Hyperostosing meningioma is rarely reported in
children.
Conclusions: This case illustrates the imaging appearance of
intracranial anaplastic meningioma and extracranial metastases
while on bevacizumab. Further study of imaging characteristics
of recurrent and progressive meningiomas while undergoing
treatment with anti angiogenic therapies is warranted.
Methods: Following IRB approval, the medical record of a child
with intracranial hyperostosing meningioma was abstracted for
diagnostic, treatment and outcome details. The medical literature
on meningioma and hyperostosis conditions was surveyed.
125. Fluorescence Guided Resection Of Complex Meningiomas
Results: A 15 year old boy presented with progressive nausea,
vomiting and headaches. Gastroenterologic evaluations were
negative and therapy for reflux disease was ineffective. Imaging
revealed a lobulated solid cystic mass in the right frontal
region, with overlying irregular cranial bone thickening. Skull
palpation revealed painless fullness without scalp changes.
Via a large craniotomy flap, the tumor was found to be arising
from the dura and adherent to the skull, without gross invasion.
The flap was hyperostotic and the inner table and cancellous
bone were drilled out using a high speed air drill. The tumor
was microsurgically completely resected and the bone flap was
replaced. The lesion showed classic syncytial features, yet with
hypercellularity and an elevated MIB 1 index, consistent with
atypical meningioma, W.H.O. grade 2. Tumor was identified in
the bone curettings. Due to the higher grade histology and tumor
in the bone, adjuvant radiation therapy was administered. He
remains in remission three years later.
Salvador Manrique, MD; Lucino Castillo, MD; Jaime Torres Corzo,
MD; Ricardo Berrone, MD (Mexico City, Mexico)
Introduction: Recently, 5 aminolevulinic acid (5 ALA) has
demonstrated optimizing surgical resection for high grade
tumors incorporating selective accumulations of photosensitive
protoporphyrin IX (PpIX). The extent of resection in intracranial
brain tumors determine survival rate. For extra axial tumors, such
as, meningiomas the usefulness of fluorescence guided surgery
will help to achieve maximal resection in complex cases where
occult tumor cells spreads beyond the arachnoid layer or in to
bone structures.
Methods: We present an illustrative case of a 37 year old female
with past medical history relevant for overweight and penicillin
allergy. Her symptoms were characterized by headache, nausea,
amaurosis fugax, left eye ptosis with facial asymmetry. An MRI
was done and a left frontal extra axial lesion was found. After
written informed consent, she was brought in to operative room
and standard microsurgical (Carls Zeiss Opmi Pentero 900®)
and neuro navigations (AxiEM Medtronic, Inc.®) techniques were
performed. 5 ALA was orally administered (20 mg/kg [Medac
GmbH®)4 to 6 h prior to skin incision. There were no surgical
complications. She was discharged 4 days after the tumor
resection.
Conclusions: Only a paucity of pediatric cases of hyperostosing
meningioma have ever been reported. There is no reported
correlation between hyperostosis and histologic tumor
grade and bone invasion by tumor. Our report confirms that
this phenomenon occurs in children. The pathophysiologic
mechanisms may be the same as in adults. We recommend
ongoing reporting of this rare condition in youth, so as to inform
of preferred management strategies.
Results: The patient did not experience any additional
neurological deficits after surgery. There was no evidence of
increased liver function test. The pathology report was consistent
with a WHO Grade I meningioma. Currently the patient is
seen in the outpatient clinic. Most of the general symptoms
have remarkable improved. Facial asymmetry has also been
substantially reduced.
41
127. Histopathologic Transformation Of Anaplastic Glioma
And Not Radiographic Progression Is Associated With
Reduced Survival
Allen L Ho; Andrew Chi, MD, PhD; Fred Barker II, MD; Tracy
Batchelor, MD, MPH; Shota Tanaka, MD; April Eichler, MD;
Daphne Wang; Daniel Yang; Daniel Cahill, MD, PhD;
William Curry, MD (Irvine, CA)
Introduction: Histologic transformation to glioblastoma (grade IV)
is often presumed when anaplastic (grade III) gliomas progress
radiographically. We aimed to determine the clinical impact of
histologically proven transformation.
Methods: We retrospectively identified patients with anaplastic
gliomas who had surgery at our center upon first radiographic
progression. We examined the impact of clinical and molecular
factors on transformation and outcome.
Results: Between 1993 and 2012, 85 patients met study criteria;
24 with oligodendrogliomas, 22 with oligoastrocytomas, and
39 with astrocytomas. 33 (38.8%) patients transformed to
glioblastoma. Transformation was associated with shorter overall
survival (OS) from initial diagnosis (median OS 6.3 vs 17.4 years,
p=0.001) and from second surgery (1.5 vs 10.8 years,).
Conclusions: Fewer than half of radiographically progressive
anaplastic gliomas transformed to glioblastoma histologically.
Transformation is associated with reduced OS from the time of
diagnosis and from the second surgery. Tissue diagnosis may be
warranted for prognostic counseling at the time of radiographic
progression.
128. Imaging Genomic Necrosis Mapping Reveals Gender
Specific Survival And Molecular Determinants in GBM
Pascal Zinn, MD, PhD; Pascal Zinn, MD, PhD; Rivka Colen, MD
(Houston, TX)
Introduction: Despite recent discoveries of new molecular targets
and pathways, the search for an effective therapy for Glioblastoma
(GBM) continues. A newly emerged field, imaging genomics,
links gene expression profiles with MRI phenotypes. Cell death
in GBM may arise from tumor suppressor and/or oncogene
activation, amongst other mechanisms. Thus, an imaging genomic
necrosis screen has the potential to uncover novel molecular
determinants of cell death in GBM. Here, we present the first
comprehensive radiogenomic analysis using quantitative necrosis
MRI volumetrics and large scale gene and microRNA expression
profiling in GBM.
Methods: Based on The Cancer Genome Atlas (TCGA) and The
Cancer Imaging Archive (TCIA) gene, microRNA, and quantitative
MR imaging as well as histopathology data sets were created in
78 patients. Gender specific analysis was performed and the top
concordant genes and microRNAs correlated with high volumes
of necrosis were further characterized using Ingenuity Pathway
Analysis, whole genome transcriptional factor analysis, and
cognate microRNA gene networks were created.
Results: Female patients demonstrated significantly lower
volumes of necrosis than male patients. Thus, a gender specific
analysis was chosen and revealed in both MRI and histopathology
data that female patients with high necrosis had a significantly
shorter survival compared to both females with lower necrosis or
males with high necrosis. Survival in males was not statistically
different in patients with high versus low tumor necrosis.
The survival data was concordant with the genomic analysis
suggesting that predominantly MYC driven oncogenic pathways
were associated with necrosis in female patients, while male
patients showed a strong positive association of the MRI necrosis
phenotype with the P53 tumor suppressor pathway. Gender
independent necrosis pathway analysis showed equal distribution
of both tumor suppressors and oncogenes.
Conclusions: Here, we propose a novel diagnostic method
to screen for molecular correlates of necrosis in GBM. Our
findings suggest distinct oncogenic pathways promoting MRI
and histopathology necrosis phenotypes in male versus female
GBM patients.
129. Impact Of Antidepressant Therapy On Overall Survival In
High Grade Glioma
Heather M. Kistka; Elliot Min, BA; Rebecca Kasl, BS; Soo Yang,
BA; Lola Chambless, MD (Nashville, TN)
Introduction: The prevalence of depression in patients with
high grade glioma(HGG) is significantly higher than that of
the general population. In prior studies, depression has been
associated with decreased quality of life and shorter overall
survival. Antidepressant therapy is a widespread and generally
well tolerated treatment of depression which can increase quality
of life. We investigated whether pharmacologic treatment of
depression has an impact on overall survival.
Methods: We conducted a retrospective cohort study of 206
patients with a diagnosis of HGG(WHO III/IV) between 2000 and
2011 treated at our institution. Univariate analysis isolated
possible predictors of survival. Variables with p<0.1 were then
included in a multivariate Cox model.
Results: Median survival was 15.8 months. 37% of patients had
a diagnosis of depression and 33% of patients were treated
with an antidepressant. Univariate analysis of antidepressant
treatment revealed significantly prolonged survival in the
treatment group(p=0.02, median survival 18.0 vs. 14.3 mos).
Analysis based on class of antidepressant was not significant.
Multivariate analysis controlled for age, tumor grade, extent
of resection, Karnofsky Performance Score, reoperation,
antidepressant therapy, diabetes, radiation and temazolamide
therapy. Antidepressant therapy was not an independent predictor
of prolonged survival in this analysis(p=0.90).
42
Conclusions: Patients with HGG on antidepressant therapy have
significantly prolonged overall survival in univariate analysis.
Although this effect did not reach significance in multivariate
analysis, the trend warrants further investigation. Prospective
studies closely monitoring antidepressant treatment and its
effects are necessary to evaluate the potential benefit of both
improving quality of life and prolonging survival with a single therapy.
130. Withdrawn
131. Induction Of Antitumor Effect Of 5 Aminolevulinic Acid In
Malignant Glioma By Low Frequency Ultrasound
Fumio Yamaguchi, MD, PhD; Takayuki Asakura; Tadashi Higuchi,
MD; Hiroshi Takahashi, MD, MSC; Takayuki Kitamura, MD, MSC;
Akira Teramoto, MD, MSC (Tokyo, Japan)
Introduction: High frequency sonodynamic therapy has
been reported to be effective; however the effectiveness of
low frequency sonication with sonodynamic agents was not
studied. We investigated the feasibility of sonodynamic therapy
for malignant glioma by low frequency ultrasound with 5
aminolevulinic acid (5 ALA), a precursor of protoporphyrin IX
(PpIX) in heme synthetic process.
Methods: In vivo tumor model was made by inoculating human
glioma cell line U87 MG subcutaneously in nude mice. The
tumor was sonicated by 25 kHz ultrasound 4 hours following
administration of 5 ALA.
Results: The tumor size decreased in 5 ALA administered
(ALA(+)US(+)) mice, while increased in non 5 ALA administrated
(ALA( )US(+)) mice and non sonicated mice (ALA(+)US( ). The
immunohistochemical analysis revealed an apoptotic change
in tumor tissue of 5 ALA (+) mice. The results showed the
therapeutic effect of 25 kHz ultrasound for the glioma in 5 ALA
administered tumor bearing mice by inducing apoptotic change of
tumor cells.
Conclusions: This is a first report to elucidate the feasibility of
therapeutic use of 25 kHz ultrasound in sonodynamic therapy
using 5 ALA as a sonosensitizer precursor. This may be a
realistic intraoperative malignant gioma therapy in addition of
tumorectomy, since 25kHz is a frequency of ultrasonic aspirator.
132. Integration Of Genome Wide Approaches Identifies lncRNAs
Of Adult Neural Stem Cells And Their Progeny In Vivo
Alexander Ramos; Aaron Diaz, PhD; Abhinav Nellore, PhD; Ryan
Delgado, BS; Ki Youb Park, PhD; Gabriel Gonzales Roybal, PhD;
Joanna Phillips, MD, PhD; Michael Oldham, PhD; Jun Song, PhD;
Daniel Lim, MD, PhD (San Francisco, CA)
Introduction: An emerging class of functional long noncoding
RNAs (lncRNAs) have recently been characterized in
developmental processes and disease states, including cancer.
The subventricular zone (SVZ) of the adult mouse brain
represents an ideal system for the study of lncRNAs in vivo.
Throughout life, SVZ neural stem cells (SVZ NSCs) generate
large numbers of neuroblasts that migrate to the olfactory bulb
(OB) where they differentiate into interneurons. We leveraged
this unique developmental system to interrogate lncRNA
expression and function.
Methods: We utilized complementary genome wide techniques
including RNA seq, RNA CaptureSeq, and ChIP seq to associate
specific lncRNAs with neural cell types, developmental processes,
and human disease state, and performed shRNA mediated
knockdown experiments in cultured SVZ NSCs to assess the
function of these lncRNAs.
Results: We were able to identify thousands of lncRNAs loci,
including loci uniquely expressed in the SVZ. By integrating data
from chromatin state maps, custom microarrays, and FACS
purified cells, we stringently identify lncRNAs with potential roles
in adult neurogenesis, and accurately predict their expression
patterns in the SVZ and OB. shRNA mediated lncRNA knockdown
demonstrated a role of lncRNAs in SVZ neurogenesis. Finally, we
used our custom lncRNA microarrays to discover lncRNAs that
are dysregulated in mouse models of glioma.
Conclusions: Our data indicate that lncRNAs can play a role in
neurogenic lineage specification of SVZ NSCs. More broadly, our
data and workflow provide a uniquely coherent in vivo lncRNA
analysis that will be relevant for future studies of lncRNAs in
development and tumorigenesis.
43
133. Intermittent Obstructive Hydrocephalus Secondary To
Third Ventricular Cysts
J. Bryan Iorgulescu; Konstantinos Margetis, MD; A. Tsiouris, MD;
Joshua Marcus, MD; Mark Souweidane, MD (New York, NY)
Introduction: Mass lesions within the third ventricle have long
been postulated to present a risk for intermittent cerebrospinal
fluid obstruction. This phenomenon, however, has seldom
been documented with an imaging correlate and quantitative
evaluation.
Methods: The clinical and radiographic features, quantitative
assessments, treatments, and outcomes were reviewed
for two patients with lesions in the third ventricle, in which
remitting clinical symptoms of raised intracranial pressure
were either characteristic of or associated with intermittent
ventriculomegaly on imaging. Additionally, the few documented
cases of intermittent obstructive hydrocephalus with concomitant
intraventricular cysts are examined.
Results: Two patients, a 3 month and a 9 year old male, presented
with paroxysmal symptoms of raised intracranial pressure and
imaging confirmation of varying ventriculomegaly with a third
ventricular pineal and choroid plexus cyst, respectively. Both were
treated by a primary endoscopic cyst fenestration and remain
without symptoms, complications, or placement of an indwelling
shunt at 20 and 3 months of follow up, respectively.
Conclusions: Our cases add to a growing body of evidence that
a normal sized ventricular system cannot rule out the diagnosis
of intermittent hydrocephalus in a patient who presents both
with symptoms suggestive of increased intracranial pressure
and a lesion that can potentially obstruct CSF flow. Additionally,
an absence of intraventricular cysts on traditional CT or MR
imaging should not automatically rule out the possibility of
an intermittently obstructive cyst. Our findings suggest that
patients experiencing symptoms of raised intracranial pressure
concomitantly with third ventricular cystic masses and normal
sized ventricles should be offered cyst decompression.
134. Intradiploic Meningioma Of The Orbit Mimicking Osteoma:
A Rare Case Report And Literature Review
Maria Blagia; Giuseppe Orunesu, MD; Salvatore Serra, MD;
Salvatore Cossu, MD (Nuoro, Italy)
Introduction: Intradiploic meningiomas, are a subset of extradural
meningiomas that arise in bone. These types of meningiomas
are relatively rare cranial lesions and constitute fever than 2%
of meningiomas overall, but they represent two thirds of all
extradural meningiomas. On radiographic findings, these lesions
may present as an osteolytic or osteoblastic skull lesions.
Methods: We report a case of a 53 year old female who presented
with a gradual onset exopthalmos of the right eye. The plain
radiographs of the skull showed hyperostosis af the right orbital
roof and the lateral orbital wall. The computerized tomography
(CT) scan revealed an extra axial, intradiploic orbital roof tumor
involving the frontal and temporal bone.
Results: The tumor, including the surrounding normal bone,
was totally excised by an extradural route using a basal fronto
temporal craniotomy. The histopathological study confirmed
a meningotheliomatous meningioma. A split calvarial frontal
bone graft was used to reconstruct the orbit. The patient was
discharged after 6 days. There is no evidence of recurrence after a
follow up of 3 months.
Conclusions: Intradiploic meningiomas are often asymptomatic,
but can cause proptosis and neurological symptoms
depending on their size and location. Radiographic and clinical
presentations generate diagnostic suspicion that may assist
with preoperative planning. The majority of these tumors
cause hyperostosis that may mimic meningioma en plaque,
osteoma, osteosarcoma, Paget disease, and fibrous displasia.
The treatment of choise is resection, which is potentially
curative. Tumors that cannot be compleely resected may be
require adjuvant therapy, which may include radiation therapy,
chemotherapy, or bisphosphonate therapy.
135. Intraoperative MRI Obtained T2 And FLAIR Signal Volumes
Compared To Pre And Post Operatively Measured Comparison
Volumes.
Randy Lynn Jensen, MD, PhD, FAANS; Karen Salzman, MD (Salt
Lake City, UT)
Introduction: Intraoperative MRI is a useful tool in the operative
management of human gliomas. In non contrast enhancing
gliomas, and to a lesser extent enhancing tumors, the T2 and
FLAIR signals are important targets to determine target volumes
for resection margins. We hypothesized that intraoperatively
obtained MRI T2 and FLAIR signal volumes might not reflect
corresponding post operative volumes due to tumor edema after
resection and brain manipulation.
Methods: We examined 12 low grade gliomas (LGG, 9 low grade
astrocytomas and 3 oligodendrogliomas) and compared them
to 13 high grade tumors (HGG, 4 anaplastic astrocytomas, 3
anaplastic oligodendrogliomas, and 5 glioblastomas). Volumetric
assessment of T2 and FLAIR signals were performed using
the OSRIX image analysis program and ratios calculated for
preoperative, intraoperative, and post operative MRI images for
each patient.
Results: Not surprisingly, for both LGG and HGG intraoperative
and postoperative FLAIR and T2 signal volumes were significantly
lower than post operative volumes. Interestingly, for LLG the ratio
of intraoperative FLAIR volume was on average 249% higher than
postoperative FLAIR volume (range of 11 982%) and intraoperative
T2 volume was 56% (range 0 149%). of postoperative T2 signal
volume. For HGG, the ratio of intraoperative FLAIR volume was
on average 255% higher than postoperative FLAIR volume (range
of 19 1432%). Intraoperative T2 volume was 79% (range 27 168%)
of postoperative T2signal volume. When all tumor grades are
analyzed together similar trends are found.
Conclusions: Postoperative FLAIR signal volumes are
significantly lower and T2 signal volumes significantly higher than
44
Methods: We analyzed the relation between the sphenozygomatic
suture and the marginal tubercle of the frontal process of the
zygoma 60 dried skulls. Minipterional craniotomy was performed
in 10 cadaveric specimens. The approach was utilized to 18
sphenoid wing meningiomas.
intraoperatively obtained corresponding volumes for LGG. HGGs
demonstrated a similar trend for FLAIR signal volumes while T2
signal volume was similar for both intraop and post op images.
136. Withdrawn
Results: The marginal tubercle was hiding the sphenozygomatic
suture when it is ‹8mm, it required drilling to enhance the
exposure. Anterior to posterior sub periosteal dissection and
retraction of the temporalis muscle, and avoiding cuts along
the origin of the muscle allows excellent cosmetic outcome. All
18 meningiomas (3 to 5 cm in size) were successfully resected
without morbidity or mortality through a 3.5 to 4 cm bone flap
137. Withdrawn
138. Withdrawn
139. Meningiomas A Population Based Perspective
Conclusions: Minipterional approach is an excellent option to
approach sphenoid wing meningiomas. The minimally invasive
access allows minimal soft tissue trauma, smaller bony opening,
less pain, and excellent cosmetic outcome
Quinn T. Ostrom; Carol Krutcho, BS; Jill Barnholtz Sloan, PhD
(Cleveland, OH)
Introduction: The Central Brain Tumor Registry of the United
States (CBTRUS) database contains the largest aggregation of
population; based data on the incidence of all primary brain and
CNS tumors in the United States. We used this data to describe
the current epidemiology of meningiomas in the United States
between the years of 2005 and 2009.
142. Minimally Invasive Eyelid Approach For Anterior Skull Base
Meningiomas
Khaled M. A. Aziz, MD, PhD, FAANS; Mohab Darwish, MD;
Mohamed Ragaee, MD; Alexander Yu, MD; Erik Happ, MD;
Sebastian Froelich, MD (Pittsburgh, PA)
Methods: Using incidence data from 49 population based cancer
registries (44 NPCR and 5 SEER), we calculated age adjusted
incidence rates per 100,000 person years and 95% confidence
intervals for meningiomas by gender, race, and Hispanic ethnicity
using SPSS and SEER*Stat. We also calculated survival rates for
all malignant menginiomas.
Introduction: Fronto orbital minicraniotomy is the most
commonly used minimally invasive approaches for anterior cranial
fossa lesions.
Methods: We describe our novel technique with the transpalpebral
eyelid incision to obtain access to the anterior cranial fossa.
We describe the approach and technique of the transpalpebral
eyelid incision in a step by step fashion and discuss the results of
retrospectively analyzed eighteen cases.
Results: Meningiomas are the most common type of brain
tumor in the United States, compromising 35.5% of all brain
tumors. There was an overall incidence rate of 7.22. They are
more common in women than men (incidence rates of 9.75
and 4.28, respectively). They are more common in blacks than
whites (incidence rates of 8.55 and 7.00, respectively) 1.7% of all
meningiomas diagnosed in this time period were malignant. For
malignant menginiomas, there were 1, 5 and 10 year survival
rates of 82.0%, 64.2% and 55.3%, respectively.
Results: Incisions in the eyelid region should therefore be as
horizontal as possible. A relative safety zone; free of facial nerve
branches was identified that exists up to 2.5 cm lateral to the
lateral canthus. We apply knowledge of upper eyelid anatomy,
which allow us to utilize an avascaular plane of dissection that
maintains functionality of the eyelid and avoids disfiguring
cosmetic results. We describe the bony cuts necessary to
complete our one piece fronto orbital approach. We perform
an eyelid craniotomy Eighteen Tumors: 9 Supra/para sellar
meningioma, 6 Olfactory groove meningioma, 1 Large frontal
cavernoma, 2 Medial sphenoid wing osteoma We describe
the closure process necessary for a good cosmetic result,
including dural closure, bone flap re approximation, temporalis
reattachment and skin closure. Complications in one patient who
developed deep wound infection required re operation.
Conclusions: Though most menginiomas are not malignant,
their frequency and potential resulting morbidity makes them
of significant clinical and scientific relevance. Awareness of the
populations most at risk for these tumors assists physicians and
scientists in focusing on developing new ways to serve these
patient populations.
140. Withdrawn
141. Mini Pterional Craniotomy: An Alternative Approach For
Sphenoid Wing Meningiomas
Conclusions: The transpalpebral approach provides dissection in
natural anatomical planes, affords preservation of the frontalis
muscle, avoids injury to nerve VII branches, and results in an
excellent cosmetic outcome.
Khaled M. A. Aziz, MD, PhD, FAANS; Mohab Darwish, MD;
Mohamed Ragaee, MD; Alexander Yu, MD; Mohamed Hammad,
MD, PhD; Sebastian Froelich, MD (Pittsburgh, PA)
Introduction: Mini pterional craniotomy is a modification of the
standard pterional (fronto temporal) Craniotomy. It provides the same
microsurgical exposure as the standard frontotemporal approach.
45
143. Modern Treatment Of Planum/Olfactory Meningiomas
Results: Incidence of cortical injury while making dural incision,
adequacy of operative exposure and ease of the actual excision
of the tumor, difficulties encountered during dural closure and
post operative CSF leaks were minimized while using the modified
dural incisions.
Corinna C. Zygourakis, MD; Michael Sughrue, MD; Andrew Parsa,
MD, PhD; Mitchel Berger, MD; Michael McDermott, MD (San
Francisco, CA)
Introduction: Given their location and slow growth, olfactory
groove and planum sphenoidale meningiomas often grow to
large sizes before they present with clinical symptoms and pose
significant surgical challenges. The goal of our study is to identify
which preoperative symptoms and MRI findings are correlated
with specific postoperative outcomes in order to better counsel
patients pre operatively.
Conclusions: The modified dural incisions are safe, easier to
perform and close with lesser complications.
145. Molecular Genomic Alterations In Meningiomas
Methods: We retrospectively identified 44 patients with planum/
olfactory meningiomas treated at our institution between 1996 and
2006. We then used univariate and multivariate regression models
to analyze the effect of several MRI characteristics (including
tumor volume, distance to optic chiasm, anterior cerebral artery
encasement, paranasal sinus invasion, and sellar invasion) on
preoperative symptoms and postoperative outcomes, including
complication rate and tumor recurrence.
Results: Only brain tumor volume (‹42 cm3), but not distance to
the optic chiasm, is independently associated with an increased
likelihood of preoperative visual symptoms. Tumors with nasal
sinus invasion are significantly more likely to cause postoperative
surgical complications, and tumors with ACA encasement
are associated with a higher likelihood of both postoperative
complications and tumor recurrence.
Conclusions: We conclude that large tumor bulk is the most
likely factor to cause a planum/olfactory meningioma to become
symptomatic. In terms of predicting surgical complications, nasal
sinus invasion and ACA encasement are associated with higher
risk profiles when surgery becomes necessary. Thus, it is prudent
to take these specific variables into consideration when advising
patients about the risks of observation and surgery for olfactory/
planum meningiomas.
144. Modified Dural Incisions
Mohammad Arif Malik, MBBS, FCPS; Muhammad Usman Malik,
MBBS (Rawalpindi, Pakistan)
Introduction: Dural incisions in cranial and spinal surgeries are
standardized and being practised without much modifications.
While making these dural incisions we encountered certain
difficulties whole opening the dura, while performing the
procedure and during closure of dural incisions. To overcome
these difficulties we modified some of these incisions. The
potential benefits and possible complications along with outline
of various dural incisions for cranial and spinal tumors will be
presented supplemented by personal experience.
Methods: Prospective descriptive study documenting the benefits
and pitfalls of various dural incisions for sellar/supra sellar
lesions, pterional trans sylvian approach, midline cerebral lesions
and intra dural extra medullary spinal tumors.
Jing Wu; Riane Hoffman, BA; Carolyn Quinsey, MD; D. Hayes, MD,
MPH; Matthew Ewend, MD (Chapel Hill, NC)
Introduction: Meningioma, when inoperable or recurrent, can
have significant neurological consequences and few options for
effective treatment. Potentially actionable molecular alterations
that might be driving the growth of these neoplasms have been
reported. To better understand these molecular alterations and
their correlation with clinical outcomes in cancer patients, we
developed a clinical sequencing program, UNCSeqTM, capable of
reporting a broad spectrum of clinically actionable mutations.
Methods: All adult patients with brain tumors including
meningioma undergoing surgery are offered enrollment; the
collected tumors undergo next generation sequencing of tumor
DNAs. Confirmed, actionable molecular targets are identified
and are made available for clinical use. Other potential targets
and genetic alterations are also evaluated but not reported to the
treating physicians.
Results: 17 patients have been enrolled and will be discussed.
As of the submission date, 7 patients have been sequenced
and 5 confirmed. 60% have actionable somatic mutations
including c.134delA mutation in NF2 gene, and two AKT1
gene abnormalities: SMO c.1234C<T mutation and c.49G<A
mutation. Mutations in the AKT1 and SMO genes were found in
grade I meningiomas; the NF2 mutation was found in an atypical
meningioma.
Conclusions: Newly characterized genetic alterations in
meningioma have been found through UNCSeqTM. 60% of
the first cohort in this ongoing analysis had genetic targets
identified amenable to treatment with available targeted agents.
Next generation sequencing can identify targets, providing a
personalized approach to meningioma therapy.
146. Neuro Oncologic Disease Patterns In A Prospective Study Of
2502 Consecutive Patients Of Haiti
Ernest Barthelemy; Ernest Benjamin, MD; Geneviève Poitevien,
MD; Irene Osborn, MD; Marlon Bitar, MD; Jerry Bitar, MD; Isabelle
Germano, MD (New York, NY)
Introduction: No study has yet explored CNS tumor prevalence in
Haiti. Characterization of Haitian neuro oncologic disease patterns
will enable productive allocation of neurosurgical resources
and training efforts. This study sought to describe disease
presentation of patients with CNS masses admitted to a Haitian
emergency room (ER).
46
Methods: A prospective study of consecutive ER admissions was
conducted at a metropolitan Haitian hospital with a CT scanner
from August 1st to October 31st 2012. Ethical approval was
obtained at both US and Haitian institutions. De identified data
on patients with CNS masses was collected using Microsoft
Excel and analyzed using standard statistical analysis for disease
presentation and prevalence.
Conclusions: Though this is an ongoing study and more sample
size is needed for conclusion, our preliminary data indicates
that in most of our GBM cases, notch signalling contributes
significantly to the process of tumorigenesis, strongly supporting
this pathway as a promising therapeutic target for this
malignancy.
Results: During the study period, there were 2502 ER admissions.
Of these, 86 required neurosurgical consultation including five
(6%) diagnosed with cerebral masses. Presenting symptoms
were seizures (80%), neurological deficits (60%) and fever (40%).
A single patient had head CT without and with contrast; two had
non contrast CT. In all 3 cases, images were consistent with brain
tumor. No images were obtained in 2 patients; one of which had an
exploratory craniotomy revealing a subdural empyema.
148. O6 Benzylguanine (BG) And Temozolomide (TMZ) Therapy
Of Glioblastoma Multiforme (GBM) With Infusion Of Autologous
Lentiviral Transduced P140KMGMT+ Hematopoietic Progenitors
To Protect Hematopoiesis: Preliminary Results Of A Phase I Study
Andrew E. Sloan, MD, FAANS; Jane Reese, PhD; Lisa Rogers, DO;
Hillard Lazarus, MD; Dona Kane, RN; Boro Dropulic, PhD; Stanton
Gerson, MD (Cleveland, OH)
Introduction: Radiation therapy (RT) and concomitant
temozolomide (TMZ) for the treatment of newly diagnosed
glioblastoma (GBM) is associated with modestly prolonged
survival and this benefit is restricted to patients whose tumor
exhibits MGMT Promotor methylation.
Conclusions: In our sample, the diagnosis of cerebral mass
accounted for 6% of admissions requiring neurosurgical
consultation. Seizures were the most common presenting
symptom. While Haitian CNS tumor prevalence cannot be
determined by this survey, the data indicates the need to
further study this disease pattern. Limitations on availability
of diagnostic tools and neurosurgical resources are significant
barriers to the identification and management of patients in Haiti
with CNS tumors.
Methods: We used ex vivo gene transfer of autologous
hematopoetic progenitor cells (HPCs) transduced with lentiviral
P140K MGMT, an MGMT mutant highly resistant to inactivation by
the irreversible MGMT inhibitor O6 benzylguanine (BG), to combine
to reduce or prevent the myelosuppressive effects of combined
TMZ+ BG. The primary objective is to assess the safety and
feasibility in newly diagnosed GBM. This Phase I study includes
three cohorts of at least three evaluable patients per cohort.
Cohort 1 receives standard RT and concomitant TMZ prior to
infusion of autologous lentiviral P140K MGMT transduced HPCs,
followed by adjuvant TMZ+ BG. Cohort 2 will receive induction
TMZ+BG followed by infusion of autologous LV P140K MGMT HSCs
prior to concomitant RT +TMZ and adjuvant TMZ+ BG. Cohort 3 will
include GB and intra patient dose escalation of TMZ in patients
who exhibit detectable levels of P140K MGMT marked cells in vivo,
using the design (i.e. cohort 1 or 2) proven to be safest and most
effective.
147. Notch Pathway In Glioblastoma Multiforme: Therapeutic
Stratification On The Basis Of HES 1 Gene Expression
Puneet Gulati, MD; Tapojyoti Das, MD; Sumit Deb, MD; S.N Ghosh,
MD; Uttara Chatterjee, MD; Sarang Rote, MD; Surajit Dhara, PhD
(Calcutta, India)
Introduction: Glioblastoma Multiforme (GBM) is the most common
Central Nervous System (CNS) malignancy characterised by
high proliferation and local invasiveness. In spite of optimal
treatment, median survival is less than 15 months. Aberrant
activation of notch signalling is reported in many human
malignancies including GBM and targeted therapy in this disease
with pharmacological inhibitors of this pathway is under clinical
trial. Stratification of GBM patients on the basis of notch pathway
activity is crucial for targeted therapy with the appropriate
inhibitors. For this reason, we sought to classify a series of GBM
cases in eastern India based on their expression patterns of HES
1, a key notch target gene.
Results: The first two patients have undergone debulking surgery,
RT, HPC mobilization and infusion of transgene therapy followed
by three cycles of adjuvant BG + TMZ. Post infusion enrichment
has resulted in P140k MGMT gene marking in 0.3 5.5 % of both
blood and bone marrow. Toxicity has been minimal and well
tolerated.
Methods: We estimated the mRNA expression levels of HES 1,
the key notch target gene and the bona fide molecular marker for
notch pathway activity, and also of GFAP (Glial Fibrillary acidic
protein), an astrocytic marker, relative to the levels of β
actin (ACTB) expression by quantitative reverse transcriptase
polymerase chain reaction (qRT PCR) method in a cohort of 24
CNS tumors.
Conclusions: Transgene therapy for GBM patients is feasible and
may enable tolerance of higher dose adjuvant TMZ.
Results: We found Hes 1 expression in almost all tumors of
astrocytic/non astrocytic origin. We sub classified only the GBM
cases into three subgroups based on their HES 1 gene expression
levels (High, moderate and low Notch pathway activity)
47
149. Phase I Trial Of Superselective Intraarterial Cerebral
Infusion Of Temozolomide
Kartik Kesavabhotla; Sirish Kishore, MD; Ashley Ray; Athos
Patsalides, MD; Howard Riina, MD; John Boockvar, MD
(Plainsboro, NJ)
Introduction: High grade malignant brain tumors are the most
common and most aggressive adult brain tumors with median
overall survival durations of only 9 12 months for glioblastoma
multiforme (GBM), and 3 4 years for anaplastic astrocytoma (AA).
All patients experience a recurrence after first line therapy, so
improvements in both first line and salvage therapy are critical to
enhancing quality of life and prolonging survival. Temozolomide
is an oral alkylating agent often used along with radiation therapy
after initial GBM resection. A phase I clinical research trial was
designed to test the hypothesis that temozolomide can be safely
used by direct intracranial superselective intraarterial cerebral
infusion (SIACI) to increase delivery to the brain and ultimately
enhance survival of patients with primary GBM. By achieving
the aims of this study we will determine the toxicity profile and
maximum tolerated dose (MTD) of SIACI temozolomide.
Methods: Subjects with primary high grade glioma were treated
with mannitol followed by a single SIACI of temozolomide. Dose
was started at 75/m2 with intent to undergo dose escalation to 250
mg/m2 to determine maximal tolerated dose.
Results: Fourteen patients were treated at dose of 75 mg/m2, 100
mg/m2, or 150 mg/m2. The maximal tolerated dose has not been
reached. Two patients reported mild headaches and nausea within
the first month post infusion. One seizure was reported at 1 week
post infusion. One patient who received a 100 mg/m2 suffered a
brainstem toxic encephalopathy from streaming effect during the
catheterization.
Conclusions: Temozolomide can be safely tolerated through intra
arterial delivery at least up to a dose of 150 mg/m2. However,
particular caution must be used around small end artery infusion
to prevent streaming effect which can lead to high level of toxic
doses of temozolomide.
150. Withdrawn
151. Prenatal Diagnosis Of Craniopharyngiomas; A Novel
Treatment Paradigm Aimed At Reducing Operative Morbidity
Verrad Kwasi Nyame, MD; Chung Ho Chang, MD; Sandeep Sood,
MD (Detroit, MI)
Introduction: Craniopharyngiomas are histologically benign
lesions that result from disordered embryogenesis. They are
most commonly encountered in the pediatric population. Due
to their proximity to vital neural and vascular structures they
pose a significant operative challenge to the neurosurgeon and
a malignant clinical course to the patient. The neurosurgical
community has questioned the feasibility of total resection with
acceptable morbidity. The authors present a novel paradigm
and case illustration in the treatment of prenatally diagnosed
craniopharyngiomas aimed at reducing operative morbidity. We
also review the relevant literature supporting errors in neurulation
as the cause of these clinically malignant but histologically benign
tumors of childhood.
Methods: We report the case of a prenatally diagnosed
craniopharyngioma that has been completely resected without any
operative morbidity to illustrate a novel paradigm in management.
Results: An ultrasound at 30 weeks gestation demonstrated a
large suprasellar lesion. The patient was born at 35 weeks of
gestation via spontaneous vaginal delivery with poor feeding and
decreased activity. He underwent delayed total surgical resection
at four months of age without associated morbidity.
Conclusions: To our knowledge this is the seventh case of
a prenatally diagnosed craniopharyngioma reported in the
literature that underwent attempted resection. The literature
has questioned the feasibility of total resection with acceptable
morbidity. The trend however based on current literature has
advocated attempted total resection. We present this case to
support the feasibility of total resection with limited to no surgical
morbidity and postulate that the standard of care should be gross
total resection.
152. Proteostasis Modulators Prolong Missense VHL Protein
Activity And Halt Tumor Progression
Chunzhang Yang; Russell Lonser, MD; Zhengping Zhuang, MD,
PhD (Bethesda, MD)
Introduction: von Hippel Lindau disease (VHL) is a heritable
multisystem cancer syndrome attributable to a germline mutation
of VHL. The most frequent mutations are missense but the
mechanism of tumorigenesis is not known.
Methods: We investigated the protein stability and intrinsic E3
ligase function of mutant pVHL that carries pathogenic mutations.
Results: We found a quantitative reduction of missense mutant
VHL protein (pVHL) in VHL associated tumors associated with
physiologic mRNA expression. Mutant pVHL is unstable and
degraded contemporarily with translation. However, mutant
pVHL retains its E3 ligase function, including hypoxia inducible
factor degradation. We found that premature pVHL degradation
is due to misfolding and imbalance of chaperonin binding.
Histone deacetylase inhibitors (HDACis) modulate this pathway by
inhibiting the HDAC6 Hsp90 chaperone axis, stabilizing pVHL and
restoring activity comparable to wild type protein in vitro and in
vivo. HDACi mediated stabilization of missense pVHL significantly
attenuates the growth of 786 O xenografts.
Conclusions: These findings provide direct insight into the
pathobiology of VHL associated tumors, as well as elucidate a new
treatment paradigm for VHL.
48
153. Quantitative Resection Map Comparison Of Glioma Surgery
Using Brain Stimulation Mapping With 2 And 15 Years Of
Experience
155. Recurrence Rates Of Pituitary Adenomas After
Purely Endoscopic Resection With Modern Endocrine And
Imaging Criteria
Philip C. de Witt Hamer, MD; Eef Hendriks, MD; Emmanuel
Mandonnet, MD; Aeilko Zwinderman, PhD; Hugues Duffau, MD
(Bennebroek, Netherlands)
Christopher Ian Sanders Taylor, MD; Amjad Anaizi, MD; Jennifer
Kosty, MD; Lee Zimmer, MD; Phillip Theodosopoulos, MD
(Cincinnati, OH)
Introduction: Intraoperative brain stimulation mapping reduces
permanent deficits and extends tumor removal in resective
surgery for glioma. Successful application of this technique is
considered to depend on the level of experience of the surgical
team. In this study the extent of glioma resection (EOR) is
quantitated and compared between a surgical team with 15 and 2
years of experience with stimulation mapping.
Introduction: The purpose of this study was to define recurrence
rates and timing of recurrence following endoscopic pituitary
adenoma resection to aid in management of imaging surveillance.
Methods: Adult patients with glioma were consecutively included
who had resective surgery targeted at the MRI FLAIR hyperintense
volume and limited by functional boundaries. The senior surgical
team contributed 56, and the junior team 60 consecutive patients.
The surgical technique was very similar including the stimulation
mapping. Because the localization of tumor within the brain is
essential in comparing EOR, a novel approach was applied using
resection maps that quantitate and compare the likelihood of
resection throughout the brain at 1mm resolution. Considerations
for spatial dependence of voxels and multiple comparisons were
taken into account.
Results: The patient cohorts were comparable in age,
preoperative tumor volume, lateralization, and lobe localization.
The resection maps detected 0 of 705.164 voxels in left sided
tumors and 58 of 638.033 voxels in right sided tumors that were
differentially resected.
Conclusions: The EOR for patient cohorts can be quantitated
using resection maps. These resection maps are similar for
surgical teams with 2 and 15 years of experience in stimulation
mapping. This indicates that stimulation mapping is a robust
and reproducible technique and supports more universal
implementation.
Methods: A retrospective review was conducted from November
2005 to present for patients undergoing purely endoscopic
resection for pituitary adenoma by a single surgeon team. 200
patients were identified with postoperative imaging and operative
reports defining gross total versus subtotal resections. Patients
were followed with serial imaging occurring yearly with one
intermediate scan in the first year. Progression was defined as
enlargement on serial imaging or biochemical failure. Data was
analyzed using Fisher exact test to determine significance.
Results: Overall recurrence/progression rates were 16% with
non secreting tumors recurring/progressing at 10.4 % versus
secreting tumors at 30.4% (p = 0.001). Recurrence/progression
rates for non secreting tumors was 4.0% for gross total resection
versus 17.4% for subtotal resection (p = 0.012), whereas
recurrence/progression rates for secreting tumors was 29.0%
versus 33.3% for gross total and subtotal resection, respectively
(p = 0.763). Average time to recurrence/progression was 21.4
months (SEM = 1.3), ranging from 15.8 months to 25.3 months in
subgroups with a wide range of standard deviation (10.9 to 24.3
months). Six tumor recurrences occured on or after 5 years.
Conclusions: As expected secretory tumors recurred/progressed
at a significantly higher rate than non secreting tumors. Although
gross total resection proved to offer benefit in non secreting
tumors, there was no significant difference in recurrence
relating to resection in secreting tumors. Given the chronological
variability of recurrence/progression, continued long term
radiographic surveillance may be necessary.
154. Withdrawn
156. Withdrawn
49
157. Revisiting The Architecture Of The Cerebral Hemispheric
White Matter: A New Parcellation Strategy Reveals That Invasion
Of The Deep White Matter Is An Independent Predictor Of
Mortality For Glioma Patients
Jackson D. Hamilton, Jr.; Vinodh Kumar, MD; Dawid
Schellingerhout, MD; Komal Shah, MD; Linda Chi, MD; Jill Hunter,
MD; Tom Naidich, MD; Lakshmi Chavali, BS; Norman Leeds, MD;
Sujit Prabhu, MD; Ashok Kumar, MD; L Hayman, MD (Houston, TX)
Introduction: Underlying tumor stromal interactions may guide
diffuse glioma spread beyond gyral and sulcal anatomy. The shape
and position of cortex white matter architectural volume units
can be used to define if the tumor is growing in a single area or
spreading to other areas.
Methods: Seventy four patients with diffuse gliomas (Grade II
IV) with serial MR imaging and at least 2 years of follow up were
retrospectively reviewed by a consensus of 3 9 neuroradiologists,
blinded to survival data. Tumors were determined to be growth
pattern (GP; confined only to limbic system or within in a
neocortical volume defined by Brodmann numbered cortex and
underlying superficial/intermediate white matter) or were spread
pattern (SP; extension to the crossing, deep white matter fibers).
This was compared to other predictors of survival.
Results: Gliomas with GP (limited) spread had approximately 50%
longer survival than SP (diffuse) spread (47+/ 36 months versus
20 +/ 24; p =0.0002), independent of tumor grade or size. Patients
with GP glioblastomas had similar survivals to SP, grade II III
tumors. This single determination had similar performance to
previously verified multiparameter criterion (VAK) and improved
all modelling predictions by at least 5%.
Conclusions: Gliomas' shape and location is an independent
survival predictor much like the staging of other cancer sites.
This strategy is best demonstrated in common locations, such as
near the central sulcus and sylvian fissures, where well defined
white matter "stalks" course perpendicular to deep fibers. This
parcellation strategy could group outcomes for research, improve
communication and facilitate treatment planning.
158. Risk Factors For Postoperative CSF Leak And Meningitis
After Endoscopic Endonasal Surgery
Michael Edward Ivan, MD; Andrew Parsa, MD, PhD; Michael
McDermott, MD; Ivan El Sayed, MD; Steven Pletcher, MD; Manish
Aghi, MD, PhD (San Francisco, CA)
Introduction: Postoperative CSF leak is a serious complication of
transphenoidal surgery, which can lead to meningitis and often
require reparative surgery. We sought to identify preoperative risk
factors for CSF leaks and meningitis.
Methods: The results of 98 consecutive endoscopic endonasal
surgeries performed from 2008 20012 were retrospectively
analyzed for preoperative comorbidities, intraoperative
techniques, and postoperative care. Univariate and multivariate
analysises were performed.
Results: Pathologies addressed included pituitary adenoma,
meningioma, esthesioneuroblastoma, adenocarcinoma,
chondrosarcoma, chordoma, lymphoma, squamous cell carcinoma
and angiofibroma. There were 11 CSF leaks (11%) and11 CNS
infections (11%). Planum, tuberculum, sellar, and clival locations
were not found as a risk factor for CSF leak (p=0.84) however
planum lesions were found to have a higher risk for infections
(p=0.05). Multivariate analysis showed patients with non ideal BMI
were associated with higher rate of postoperative CSF leak and
meningtis (p<0.01 and p<0.01 respectively). Also, patients with
increasing age were associated with increased CSF leak (p<0.03)
in a univariate analysis. Endoscopic transphenoidal surgeries
combined with open cranial cases had a higher postoperative CSF
leak and CNS infection rate thantransphenoidal surgeries alone or
surgeries staged with open cases (p<0.01). 4 deaths were noted
in this study which were found to be associated with CNS infection
(p‹0.01).
Conclusions: In this series of endoscopic transphenoidal
surgeries preoperative BMI and age are two predictive values for
CSF leak and infection. Risks associated with complex surgical
resections when combining open and endoscopic approaches
could be minimized by staging these procedures.
159. Withdrawn
160. Role Of Microenvironment In Glioma
Anwar Hossain; Joy Gumin, BS; Feng Gao, MD; Tatsuya Takezaki,
MD, PhD; Javier Figueroa, MS; Frederick Lang, MD (Houston, TX)
Introduction: Mesenchymal stem cells (MSC) have been
implicated as components of the microenvironment of several
cancers, but their contribution to human brain tumors,
particularly gliomas, remains obscure.
Methods: We isolated MSC like cells, called Glioma Associated
human Mesenchymal Stem Cells (GA hMSC), from 20 of 31 human
glioma surgical specimens using established culture, surface
markers and mesenchymal differentiation criteria. We used
standard in vitro and in vivo techniques to delineate the role of GA
hMSCs in glioma.
50
Results: We have found that in contrast to Glioma Stem Cells
(GSCs), which are the tumor initiating cells in gliomas, GA hMSCs
were non tumorigenic and did not harbor common genetic
anomalies seen in GSCs. Importantly, in in vitro co culture
experiments, GA hMSCs significantly increased the proliferation
and self renewal of GSCs compared with controls. When grown
in vivo in the flanks of nude mice, GSCs mixed with GA hMSCs
formed larger tumors than GSC controls. After implantation
into the brain of nude mice, GSCs formed intracranial tumors
more frequently after co culture with GA hMSCs than after co
culture with controls. Likewise, the survival of mice implanted
intracranially with GSCs that were co culture with GA hMSCs, was
significantly shorter compared with mice implanted with GSCs co
cultured with controls. Increased proliferation and self renewal of
GSCs were dependent on GA hMSC secreted Interleukin 6, which
activated STAT3 in recipient GSCs. GA hMSC co cultured GSCs also
increased expression of mesenchymal genes in vitro.
patients and were worsened in 5.9%.
Conclusions: Our results have shown that surgery for cerebral
metastases in the central area can be done safely and improve or
stabilize the neurological function of most patients. Surgery also
promptly addresses symptoms related to cerebral edema, mass
effect, and midline shift. Microsurgical resection of central area
metastases should be a treatment option for patients with single
or multiple lesions who present a focal neurological deficit.
163. Study Of 5 ALA PD In Our 100 Cases Of Brain Tumor
Tadashi Higuchi; Fumio Yamaguchi, MD, PhD; Hirotomo Ten,
MD; Tomoko Oomura, MD, PhD; Koji Adachi; Akira Teramoto
(Kita ku, Japan)
Introduction: It has been established that 5 aminolevulinic acid
(5 ALA) induces the accumulation of fluorescent protoporphyrin,
a phenomenon potentially exploitable to guide tumor resection.
In this study, we examined the useful of photodiagnosis (PD) by 5
ALA for the 100 cases during brain tumor surgery.
Conclusions: Together these results represent the first evidence
that hMSCs are a stromal component of human gliomas and that
they enhance the proliferation and self renewal of GSCs by cross
talk via IL 6 activation of STAT3.
Methods: In our institute, 100 patients was performed tumor
resection using 5 ALA from 2005 to 2012. The patients received
oral doses of 5 ALA 2 hours before induction of anesthesia.
Retrospectively, we compared for positive/negative of
photodynamic diagnosis for each tumor.
161. Withdrawn
Results: 79 cases showed positive responses, and 21 cases
showed negative responses. Malignant brain tumors (i.e.
anaplastic astrocytoma, glioblastoma multiforme etc.) and
meningiomas tended to show strong positive fluorescence. On
the other hand, pilocytic astrocytomas, diffuse astrocytomas,
and recurrent high grade gliomas, etc. showed negative or weak
responses.
162. Selective Excision Of Cerebral Metastases From The
Central Area
Robert Givens Kellogg, MD; Lorenzo Munoz, MD (Chicago, IL)
Introduction: The surgical management of central area cerebral
metastases remains under discussion. Central area lesions
are often treated with whole brain radiation therapy (WBRT)
or stereotactic radiosurgery (SRS) because of the concern
for causing post operative neurological deficits. Surgery
has an important role in acutely alleviating symptoms from
cerebral edema and mass effect that radiation cannot address.
Additionally, there is evidence in the literature that radiation
therapy carries significant risk of complications. We present a
series of patients who were symptomatic from a central area
metastasis and underwent surgical excision.
Conclusions: 5 ALA PD contributes to increasing the tumor
resection volume. However, the sensitivity of PD varies among
tumors, therefore it is important to use this technique in
combination with the other intraoperative support tools.
Methods: During a 2 year period from 2010 to 2012, 17 consecutive
patients harboring a cerebral metastasis within the central area
underwent microsurgical resection. Cases were selected by
reviewing all cases of cerebral metastasis by the senior author
and identifying those patients with a central area lesion that was
surgically removed. The prerequisite for neurosurgical treatment
was stable systemic disease and life expectancy greater than 6
months as determined by the patient oncologist. Patients also
were required to harbor a symptomatic lesion within the central
area, defined as the pre or post central gyri.
Results: We present the 3 month neurological outcome for
this group of patients. Surgery was uneventful and without any
severe peri operative complications in all 17 patients. Gadolinium
enhanced T1 weighted MRI scans obtained on post operative day
#1 revealed a gross total resection in all patients. At 3 month
follow up, symptoms had improved or been stabilized in 94.1% of
51
164. Surface Down Modulation Of MICA On Malignant Glioma
Cells By Herpes Simplex Virus
167. Survival Advantage In Patients With De Novo Versus De
Differentiated Anaplastic Meningioma
Carl Irwin Odom; James Markert, MD, MPH; Kevin Cassady, MD
(Birmingham, AL)
Jennifer Moliterno Gunel, MD; William Cope, BS; Emma Vartanian,
BS; Anne Reiner, MS; Roselyn Kellen, BS; Shahiba Olgilvie,
MS; Jason Huse, MD, PhD; Murat Gunel, MD; Philip Gutin, MD
(Branford, CT)
Introduction: Oncolytic Herpes Simplex Virus (oHSV) vectors are
experimental adjuctive therapies for malignant gliomas. Deletions
of the diploid γ134.5 gene render oHSV aneurovirulent
and targets viral replication to malignant cells. Portions of tumor
clearance may occur by lysis. However, natural killer (NK) cells
may target infected glioma cells and restrict lytic replication. NK
cell cytotoxicity is regulated by activating and inhibitory ligands
on cell surfaces. An extensively studied ligand/receptor pair is
MHC class 1 polypeptide related chain A (MICA) and Natural Killer
Group 2 member D (NKG2D). Members of the herpes family,
including HSV 1, modify MICA presentation. We hypothesized that
HSV 1 is capable of MICA down modulation in glioma cells by a
post translational mechanism.
Introduction: While most meningiomas are benign, 1–3% display
anaplastic features with little being understood regarding the
molecular mechanisms underlying their formation. In a large,
single center cohort, we tested the hypothesis that 2 distinct
subtypes of anaplastic meningiomas, those that arise de novo and
those that progress from lower grade tumors, exist and exhibit
different clinical behavior.
Methods: Pathology reports and clinical data of 37 patients treated
between 1999 to 2012 for anaplastic meningioma at MSKCC, were
retrospectively reviewed. Patients were divided into those whose
tumors arose de novo and those whose tumors progressed from
previously documented benign or atypical meningiomas.
Methods: Flow cytometery was used to quantify surface
and total MICA and transferrin receptor during infection.
Immunofluorescence was used to visualize MICA and validate anti
MICA antibodies. RT qPCR was used to quantify MICA mRNA.
Results: Overall, the median age at diagnosis was 59 years
and 57% of patients were female. Most patients underwent two
craniotomies (38%, range: 1–5 surgeries), aimed at gross total
resection (59%), which afforded longer median survival when
compared with sub total resection (3.3 vs. 2.6 years, respectively
P=0.047).
Results: Flow cytometery demonstrated that HSV 1 down
modulates surface MICA; permeabilization showed no increase
in total MICA. Immunofluorescence did not show intracellular
sequestration. MICA mRNA decreased during infection, and were
lower with VHS containing virus. VHS decreases MICA mRNA but
is not required for surface protein down modulation. Transferrin
receptor increased for each condition, demonstrating that MICA
down modulation is protein specific.
23 patients (62%) presented with apparently de novo anaplastic
meningiomas. Compared with progressed tumors, de novo
patients were more likely to be female (70% vs. 36%, P=0.04),
experienced longer median survival (3.0 vs. 2.4 years, P=0.04), and
harbored cerebral hemispheric, as opposed to skull base tumors
(91% vs. 43%, P=0.02)
Conclusions: Further work is needed to determine the role NK
cells play in tumor lysis following oHSV therapy, as well as the
mechanism by which oHSV down modulates activating ligands.
If the recruitment of innate immune cells for tumor clearance
enhances oHSV efficacy, vectors may be modified to circumvent
immune ligand modulation.
Conclusions: Like malignant glial tumors, anaplastic
meningiomas can arise de novo or dedifferentiate from lower
grade tumors, and these groups appear to have distinct clinical
behavior. Similarly, de novo tumors may well be molecularly
distinct and this is being investigated. Aggressive GTR affords a
survival advantage in both groups.
165. Withdrawn
168. Susceptibility Changes In Meningiomas Increase The Mean
Apparent Diffusion Coefficient In Diffusion Weighted MRI
166. Withdrawn
Lucia Schwyzer, MD; Jatta Berberat, PhD; Larissa Boxheimer,
MD; Luca Remonda, MD; Ulrich Roelcke, MD (Zurich, Switzerland)
Introduction: Diffusion weighted magnetic resonance imaging
(DWI) provides information of water diffusivity which is expressed
by the apparent diffusion coefficient (ADC). In gliomas it has
been shown that ADC values correlate with tumor cell density
and allow early treatment response assessment. At the present
time it is not known which biological aspects of meningiomas are
reflected by their behavior in ADC images. Further it is not known
whether intra tumoral susceptibility changes alter ADC values.
In susceptibility weighted MRI (SWI) the hypointense changes
(SWIpos) in meningiomas can be associated with intra tumoral
calcification. Here we analyzed whether intra tumoral SWIpos
influences ADC values in untreated meningiomas.
52
Methods: We retrospectively analyzed pre operative SWI and
DWI of patients (n=35, ±17yrs; mean+SD) with newly diagnosed
meningiomas. We grouped our patients into meningiomas
with substantial intra tumoral SWIpos (n=11) and SWI negative
meningiomas (n=24). SWIpos was defined as dot like or fine
linear hypointense signal changes not to be attributed to flow
signal from vessels. ADC values were calculated based on region
of interest (ROI) analysis. ADC values of SWIpos and negative
meningiomaswere compared.
Conclusions: Targeted radiofrequency ablation represents a safe
and effective new technique in the treatment of malignant spinal
metastasis. This technique allows for treatment of lesions not
controlled by conventional therapy or in patients who may not
tolerate systemic therapy.
170. Targeting Glioma Stem Cells In GBM: A Randomized Phase
0/II Study Of Hedgehog Pathway Inhibitor GDC 0449
Andrew E. Sloan, MD, FAANS; Charles Nock, MD (Cleveland, OH)
Results: The mean age of patients with SWIpos meningiomas was
higher (63+12yrs) when compared to patients with SWI negative
meningiomas (56+15yrs). The mean ADC values in SWIpos
meningiomas were higher (1.14+0.28x10 3mm2/s) compared to
SWI negative meningiomas (0.82±0.08 x10 3 mm2/s; ppos
could be attributed to possible calcification based on the phase
shift ROI analysis.
Introduction: New therapeutic approaches are urgently needed
for recurrent GBM (rGBM). Recent studies suggest that GBM
recurrence is regulated by glioma stem cells (GSC). Our
hypothesis was that interrupting the sonic hedgehog signaling
pathway (SHh), an integral mediator of stem cell proliferation,
would slow tumor progression and improve progression free
survival (PFS) in correlation with decreased GSC proliferation;
self renewal.
Conclusions: SWIpos in meningiomas influences DWI results
by increasing ADC values on average by 38%. The frequency of
SWIpos in elderly patients is in line with the known age associated
calcification in meningiomas. The shift of ADC values due to
susceptibility changes needs to be considered when drawing
conclusions on tumor behavior from DWI.
Methods: Two armed, randomized phase 0/II study of GDC 0449,
an inhibitor of SHh, in 40 patients undergoing resection for rGBM.
Arm I was randomized to receive GDC 0449 pre operatively; all
patients were treated post operatively. Our primary objective was
to estimate PFS6, with secondary endpoints of mOS, response
and toxicity. Correlative studies included determination of PK, PD,
inhibition of SHh signaling and inhibition of GSC proliferation and
self renewal.
169. Targeted Radiofrequency Ablation Of Spinal Metastases:
Initial Multicenter Experience
Joseph Graham, DO; Jack Jennings, MD, PhD; Bassem Georgy,
MD; Frank D. Vrionis, MD, PhD; Shelby McCraw, BSN; Nam D.
Tran, MD, PhD (Tampa, Florida)
Results: Median PFS and OS was 1.8m and 8.3m respectively;
toxicity was minimal. PK/PD data and tumor specimens obtained
from 39/40 patients demonstrated plasma and tissue levels within
therapeutic range. SHh signaling intermediates (Gli 1, Gli 2,
PTCH 1b) determined by RT PCR were significantly lower in Arm I
(treated pre operatively) vs. Arm II (untreated pre op) (p<0.0002)
as were the proportion of tumor derived CD133+ neurospheres
undergoing proliferation (p ‹0.0053) and self renewal (p<0.003) in
Arms I vs. II.
Introduction: Approximately 85% of patients with metastatic
disease will develop bony metastasis. Nearly three fourth of these
will involve the axial skeleton, thus increasing the risk of bone
pain, pathologic fractures, and compression of neural elements.
Therapeutic goals are pain control, spinal stabilization, reducing
risk of spinal cord compression, and tumor control. Targeted
radiofrequency ablation (t RFA) of malignant spinal lesions
represents a novel minimally invasive approach to achieving these
goals in the oncology population.
Conclusions: GDC 0449 was well tolerated but poorly efficacious
as a single agent in rGBM. However, phase O/II studies suggest
the therapeutic PK, PD and biological activity of this agent
on proliferation and self renewal of GBM derived CD133+
neurospheres. Novel combinations pairing GDC 0449 with other
agents should be pursued despite lack of single agent efficacy.
Methods: Retrospective chart review was performed on patients
treated with t RFA at three centers, between 2011 and 2013
(n=85). Demographic data, type of tumor, tumor location, number
of levels treated, history of previous or concurrent therapy, pain
score (VAS), functional score (ODI, Karnofsky), opiod requirement,
total ablation time, use of cement augmentation, complications,
and tumor progression at treated level were collected.
Results: Spinal metastases involved a wide spectrum of tumor
etiology extending from T2 S2. Cement augmentation was
utilized in nearly all t RFA treated malignant spinal lesions. No
complications of thermal injury occurred. Cement augmentation
following t RFA resulted in predictable cement filling. All patients
reported improvements in pain, with significant improvements in
VAS. Functional performance increase was demonstrated in all
participants.
53
171. Temozolomide Conjugated To Perillyl Alcohol Demonstrates
Potent Anti tumor Effects In Vitro On Meningioma Cell Lines
to treat tumor volumes of 1 to 16 cc. Risk of PTE development was
8x higher in falx/parasagittal locations compared to other sites
(31% vs 4%). 75 % of patients with post GKRS PTE had evidence
of PTE pretreatment. All patients in parasagittal/falx locations
had pretreatment PTE. Time to first radiological signs of PTE
was 3 6 month. PTE peaked around 6 8 months and began to
resolve around 12 15 months. Clinical symptoms onset temporally
correlated with peak edema. Two patients whose symptoms were
resistant to aspirin and/or steroids were treated successfully
with bevacizumab with eventual resolution of symptoms. Prior
radiation therapy, tumor volume and treatment dose conformality
and gradient indexes did not significantly correlate with PTE.
Gabriel Zada, MD; Rocky Pramanik; Thomas Chen; Florence
Hofman (Los Angeles, CA)
Introduction: Limited chemotherapeutic options exist for invasive,
atypical, and anaplastic meningiomas. Perillyl alcohol (POH),
a naturally occurring limonene compound, has known anti
tumor properties. We tested the anti tumor potential of a newly
conjugated compound, temozolomide perillyl alcohol (TMZ POH)
using an in vitro meningioma cell model.
Methods: Human meningioma cells (IOMM Lee, CH157, and
primary tumor cells) were cultured in increasing concentrations
of temozolomide (TMZ) alone, equimolar TMZ and POH, or
conjugated TMZ POH for 48 hours. Cell survival was determined
via MTT assay as well as long term (<14 days) colony formation
assay (CFA). Flow cytomtery (FACS) was performed for DNA cell
cycle analysis.
Conclusions: PTE remains a significant complication following
GKRS for falcine and parasagittal meningiomas. Symptomatology
can appear as early as 3 months after GKRS and can be medically
controlled in the majority of the cases. Symptomatology from
PTE can last beyond 15 months and bevacizumab may be helpful
in resistant cases.
Results: More potent attenuation of cell survival occurred with
TMZ POH in all meningioma cell lines tested, compared to TMZ
alone or TMZ in combination with POH. The IC50 of IOMM Lee
cells assessed via MTT was 15.5 uM in the TMZ POH group versus
33 uM in the TMZ group (p50 of IOMM Lee cells was 8.4 uM for
TMZ POH vs. 20.1 uM for TMZ (p50 of CH157 cells was 44 uM in the
TMZ POH group and 132.5 uM in the TMZ group (MTT). The IC50 of
CH157 cells assessed via CFA was 20 uM in the TMZ POH group
vs. 50 uM with TMZ. In primary surgically resected meningioma
cells, the IC50 for TMZ POH was 140 uM, but cells treated with
TMZ alone did not reach IC50 at the highest concentration (250
uM) (MTT). TMZ POH and TMZ both induced apoptosis and cell
cycle arrest in the G2/M phase, but TMZ POH was at least.
173. The Influence Of Mesenchymal Stem Cell Exosomes In The
Tumor Microenvironment On Glioma Stem Cell Growth
Javier Figueroa; Tal Shahar, MD; Frederick Lang, MD (Houston, TX)
Introduction: Cells within the tumor niche use an intricate
network of communication not only to establish the tumor
microenvironment, but also promote the growth and evolution
of the malignancy. In this range of communication systems, the
contribution of exosome transfer between tumor forming glioma
stem cells (GSCs) and glioma associated mesenchymal stem cells
(GA MSCs) is not well established.
Methods: Therefore, we hypothesize that exosomes released
by GA MSCs represent a novel intra tumoral communication
mechanism that promotes aggressive behavior in GBM. Using
ultracentrifugation methods we harvested exosomes from four
GA MSC lines, extracted from patient tumors, and characterized
the content of these nano vesicles to include membrane bound
proteins and various RNA. Exosome transfer and uptake was
subsequently demonstrated when GA MSC exosomes labeled with
fluorescent membrane dye, were spontaneously absorbed and
sorted by four GSC lines (isolated from patient tumors), two of
which had matching GA MSC lines.
twice as potent.
Conclusions: Compared to temozolomide alone, TMZ POH
consistently demonstrated more potent anti tumor effects in the
in vitro meningioma cell model, although the mechanism of action
with regard to DNA damage was similar. TMZ POH may be an
effective therapeutic option for meningiomas, especially given its
potential for inhaled/intranasal delivery.
172. Temporal Evolution Of Peritumoral Edema After Gamma
Knife Radiosurgery Of Meningiomas
Results: In vitro experiments then revealed that the tumor
enhancing effects of GA MSCs on co cultured GSCs, could not be
solely attributed to excreted growth factors and other proteins, but
must also include exosome exchange. We found that the delivery
of a single concentrated dose of GA MSC exosomes increased the
proliferation of GSCs between 30% and 145%, when compared to
untreated controls. Furthermore, GSC clonogenicity increased
between 25% and 50% with the addition of GA MSC exosomes.
Sacit Bulent Omay, MD; Ben Taylor, MD, PhD; Frank Barbiero;
James Yu, MD; Veronica Chiang, MD (New Haven, CT)
Introduction: Analysis of the temporal evolution of peritumoral
edema (PTE) in meningiomas after GKRS (Gamma Knife Radio
Surgery).
Methods: Retrospective analysis of 83 patients who underwent
GKRS for treatment of intracranial meningiomas. Patients who
showed radiological signs of new and/or increased PTE were
analyzed for demographics, tumor locations, radiosurgery dosing
conformality and clinical outcomes.
Conclusions: Although exosome delivery and GSC altering
mechanisms have yet to be established, GA MSC exosomal miRNA
are likely candidates due to their ability to alter recipient GSC
gene expression, thus adding another significant pathway by
which the microenvironment can impact tumor progression.
Results: Of the 83 patients analyzed eight had MRI findings of new
and/or increased PTE (10%). 15 18Gy marginal doses were used
54
174. The Maxillary Strut: An Anatomic Evaluation And Its Clinical
Application
cells. The proportion wasassessed on the basis of the percentage
of immunopositivecells as follows: 0, 0 %; +1, less than 10 %; +2,
10 to 50 %; and +3, greater than 50 %.
Sanjeet Singh Grewal; Almaz Kurbanov, MD; Amjad Anaizi, MD;
Jeffrey Keller, PhD; Philip Theodosopoulos, MD; Lee Zimmer,
The staining intensity was evaluated as weak (+1), moderate
(+2) and strong (+3). The MIB 1 labeling index was calculated in
a representative maximal activity and evaluated by counting the
percentage of positive nuclei in a high powered field.
MD (Cincinnati, OH)
Introduction: The maxillary strut is bone that divides the foramen
rotundum and the superior orbital fissure. Tumors involving the
lateral wall of the sphenoid sinus, posterior ethmoid, or posterior
maxillary sinus may invade this region. We detail the anatomy of the
strut, and present a case series to emphasize the import and utility
of an endonasal endoscopic approach to lesions in this region.
Results: The expression level of COX 2 in meningioma cells was
significantly correlated with WHO grade (P = 0.0153). In addition,
COX 2 expression was significantly correlated with MIB 1 labeling
index for all 76 cases of meningioma (P = 0.0075), suggesting
tumor promotion by COX 2 in meningioma progression.
Methods: Endonasal endoscopic dissections were performed
on four formalin fixed cadaver heads. We also conducted
morphometric studies of one hundred skulls using CT scans and
Brain Lab software.
Conclusions: Our results may indicate the therapeutic value
of non steroidal anti inflammatory drugs against meningioma,
especially for patients with elevated proliferation, to regulate the
tumorigenic activity of COX 2 in meningioma cells.
We performed a retrospective review of two patients charts who
underwent procedures requiring exposure of the maxillary strut.
176. The Role Of 11C Methionine Positron Emission Tomography
In Prediction Of Meningioma Recurrence And Progression
Results: The strut is trapezoidal shaped with an average cross
sectional area of the strut 17.09mm2 + 0.76 and an average
thickness of 4.39mm + 0.15. The maxillary strut was present
bilaterally in all studied skulls. The average AP length of the
strut was 4.23mm + 0.15 on the right and 4.02 mm + 0.14 on the
left. Patient A is 53 year old male who underwent resection of
recurrent T3 squamous cell carcinoma involving the infratemporal
fossa and extending up to the foramen rotundum. The maxillary
strut was removed and superior extent of the tumor visualized
and resected. A gross total resection was achieved without
complications. Patient B is a 31 year old female with an expansile
lesion involving the left pterygopalatine fossa and petrous apex. V2
was visualized and followed back to the foramen rotundum. The
maxillary strut was drilled, revealing abnormal bone consistent
with a benign bone cyst.
Yuzo Terakawa; Hidetoshi Ikeda, MD; Naohiro Tsuyuguchi, MD;
Noritsugu Kunihiro, MD; Kenichi Ishibashi, MD; Takeo Goto,
MD; Kenji Ohata, MD (Osaka, Japan)
Introduction: Meningioma is mostly a benign tumor, but the
recurrence rate of tumor after treatment and the progression
rate during observation are not negligible. Currently, a definitive
method to predict recurrence or progression of this disease has
not yet been established. In this study, we used 11C methionine
(MET) positron emission tomography (PET) in patients with
meningioma to determine whether MET PET can be used to
predict tumor recurrence or progression.
Methods: A total of 37 patients newly diagnosed as intracranial
meningioma were examined using MET PET before treatment. The
lesion to normal tissue (L/N) ratios were generated by dividing
the mean MET uptake of the lesion by that of the contralateral
frontal lobe gray matter. Patient characteristics, location and
histopathology of tumor, extent of resection, Ki 67labeling indices,
and L/N ratios were analyzed especially with respect to tumor
recurrence and progression.
Conclusions: An endoscopic endonasal approach can be used to
expose the maxillary strut. The improved understanding of this
anatomy can extend the utility of the approach to the biopsy or
resection of lesions in the lateral sellar compartment, the
pterygopalatine fossa, and aspects of the middle cranial fossa.
175. The Clinicopathological Evaluation Of Cyclooxygenase 2
Cxpression In Meningioma
Results: Among 37 patients enrolled in this study, 33 patients
were surgically treated and four patients were followed without
surgery. Recurrence occurred in six of 33 surgically treated
patients and progression was seen in two of four observed
patients during a mean follow up period of 80 months. Multivariate
analysis found high L/N ratios, small extent of resection, and
high WHO grade to be significant risk factors for recurrence and
progression. Receiver operating characteristic curve analysis
indicated that an L/N ratio of greater than 3.18 provided the best
sensitivity and specificity for recurrence and progression, 63% and
79%, respectively.
Yasutaka Kato; Hiroshi Nishihara, MD, PhD; Hiroyuki Kobayashi,
MD, PhD; Shunsuke Terasaka, MD, PhD; Kiyohiro Houkin,
MD, PhD; Shinya Tanaka (Hokkaido, Sapporo, Japan)
Introduction: Tumorigenic activity of cyclooxygenase 2 (COX 2),
a rate limiting enzyme in the production of prostaglandins (PGs),
has been proved for some types of cancer, including brain tumors.
We evaluated expression of COX 2 in meningioma, one of the most
common intracranial tumors in adults.
Methods: We performed immunostaining for COX 2 and MIB 1 in
76 cases of meningioma consisting of 44 cases of low grade (WHO
Grade I) and 32 cases of high grade (29 cases of Grade II and 3
cases of Grade III) meningioma. Immunostaining ofCOX 2was
evaluated in terms of the proportion andstaining intensity of tumor
Conclusions: MET PET may provide quantitative values in
prediction of meningioma recurrence or progression, although
they are not absolute indicators.
55
177. Withdrawn
II, 16 grade III, and 4 grade IV) taken to surgery from 2010 2012.
Volumetric analysis of 3D T2 weighted imaging was completed
for 43 non enhancing and 13 minimally enhancing lesions using
IPlan software (BrainLAB). Pre operative, intra operative, and post
operative tumor volumes were used to calculate EOR.
178. Use Of Gliadel Wafers For Treatment Of Recurrent
Malignant Meningiomas: Case Series
Elena Fomchenko; Linda Liau, MD, PhD; Marvin Bergsneider, MD
(Los Angeles, CA)
Results: Median pre operative tumor volume was 22.38cc.
Complete resection was considered feasible in 27 patients based
on pre operative imaging alone. 24 of the other 29 patients
underwent intra operative electrocorticography, and 5 had
tumors involving deep functional structures. 26 of 56 patients
did not undergo further resection following IoMRI: 14 showed
complete resection at IoMRI and 12 evidenced critical structure
involvement. Median intra operative EOR for all patients was 88%
(intra operative median residual tumor volume (mRTV): 2.61cc),
and 46% of patients had EOR greater than 90%. In 30 patients
undergoing further resection, median intra operative EOR was
84% (intra operative mRTV: 3.93cc). Following further resection,
post operative EOR in these patients was 98.2% (post operative
mRTV: 0.41cc), and 90% had EOR greater than 90%.
Introduction: The prognosis for recurrent grade II/III meningiomas
failing radiotherapy is poor, associated with 60% progression at 8
months and 17% PFS at one year. Few alternatives exist, as prior
trials with chemotherapy, hormonal agents, and small molecule
inhibitors have largely been ineffective. Here, we investigate the
use of Gliadel BCNU wafers implanted during image complete
resection of grade II/III meningiomas.
Methods: Three patients ages 27 65 at first resection, diagnosed
with grade II/III meningiomas with15 30% Ki 67+ cells and 4
18 mitoses/10X field, having failed 1 4 cycles of stereotactic
radiosurgery and chemotherapy, KPS‹80%, were treated with
Gliadel wafer implantation during resection at 1st, 4th, and
8th meningioma recurrences. One patient was concurrently
treated with Temodar+Avastin. Patients were followed with serial
imaging and neurologic examinations, and assessed for toxicity,
complications, PFS and OS.
Conclusions: Use of high field IoMRI improves the extent of
resection in non enhancing gliomas that do not involve functional
structures.
Results: PFS after the last recurrence prior to Gliadel
implantation for all three patients ranged from 2 to 8 months.
After Gliadel implantation for recurrent atypical meningioma,
PFS was 21, 23 and 48 months in our three patients (30.6 months
average), indicating significant improvement in local tumor control
compared to prior stereotactic radiosurgery and chemotherapy.
Patient who had surgery + Gliadel at 8th recurrence remains
progression free for <23 months, the longest period of tumor
control during last 5 recurrences. There were no additional
toxicities/complications attributable directly to the use of Gliadel
in these patients that were unrelated to their underlying co
morbidities.
180. Valproic Acid Has Anti Tumor Action In A Primary In Vitro
Model Of Glioblastoma Multiforme
Abdel Nasser Hosein; Yi Chieh Lim, PhD; Bryan Day, PhD; Brett
Stringer, MD, PhD; Stephen Rose, PhD; Richard Head, PhD;
Andrew Boyd, MD; Leah Cosgrove, PhD; Michael Fay, MD; Jennifer
Martin, MD, PhD (Mississauga, Canada)
Introduction: Glioblastoma multiforme (GBM) has nearly a 100%
mortality rate and a median survival of less than two years. While
there has not been any novel anti GBM therapeutics for many
years, there has been the gradual accumulation of clinical data
suggesting that the anti convulsant agent, valproic acid (VPA), may
significantly prolong survival in GBM patients. Aim: To determine
if VPA treatment decreases the viability of GBM cell lines in a
primary in vitro model, both as monotherapy and in combination
with chemotherapy and irradiation.
Conclusions: Gliadel wafers may be safe and effective in
controlling local recurrence in selected patients with grade II/III
recurrent meningiomas that have failed radiation therapy. Further
randomized, controlled studies of Gliadel wafers for refractory
meningiomas may be warranted.
Methods: Our group has established numerous GBM primary
cell lines from patients at the Royal Brisbane and Women
Hospital. Primary GBM cell lines were plated and exposed to
increasing concentrations of VPA (1 15mM) in order to establish
a monotherapy dose response curve. VPA was then used as a pre
treatment modality in combination with temozolamide (TMZ) or
gamma irradiation. Cells were incubated for 72 hours and cell
numbers were quantified with the MTS colormetric assay.
179. Use Of High Field Intra Operative MRI Improves Extent Of
Resection In Non Enhancing Gliomas
T. Barrett Sullivan; Alireza Mohammadi, MD; Jason Schroeder,
MD; Gene Barnett, MD; Violette Recinos, MD; Lilyana Angelov, MD;
Michael Vogelbaum, MD, PhD (Cleveland, OH)
Introduction: Intra operative MRI (IoMRI) is used to improve the
extent of resection (EOR) of brain tumors. Prior studies of IoMRI
have focused on enhancing tumors, where the goal is resection
of all contrast enhancing tumor. Defining the surgical target is
different for non enhancing tumors and requires use of non T1
weighted MRI sequences.
Results: VPA as a monotherapy was effective, with nearly all
tested lines demonstrating at least 50% kill at a concentration of
15mM. Conversely, response to combination therapy varied across
the panel of primary GBM samples, although most did show a
synergistic effect with VPA in combination with either irradiation
or TMZ. Interestingly, a markedly additive effect was observed
when the three treatment modalities were combined.
Methods: An IRB approved retrospective review was performed on
56 patients with predominantly non enhancing gliomas (36 grade
56
Conclusions: VPA significantly decreased the viability of primary
GBM cell lines in vitro. These findings provide a significant
rationale for the investigation of VPA in GBM patients in the
clinical setting.
182. Withdrawn
183. miR 142 3p Modulates The M2 Macrophage Phenotype And
Exerts Therapeutic Efficacy Against Murine Glioma
Amy B. Heimberger, MD, FAANS; Shuo Xu, PhD; Jun Wei, PhD;
Ling Yuan King, PhD; Tiffany Doucette, PhD; Ganesh Rao, MD;
Greg Fuller, MD; George Calin, PhD (Houston, TX)
181. Velocity Of Tumor Spontaneous Expansion Predicts Long
Term Outcomes For Diffuse Low Grade Gliomas. A Multicentre
Analysis From 407 Cases
Introduction: The immune therapeutic potential of microRNAs
(miRNAs) in the context of tumor mediated immune suppression
has not been previously described for glioma associated
macrophages (derived from the peripheral blood monocyte),
which are the largest infiltrating immune cell population in
glioblastomas, are predominately M2 and facilitate gliomagenesis.
Johan Pallud, MD; Marie Blonski; Emmanuel Mandonnet; Etienne
Audureau; Denys Fontaine; Nader Sanai; Luc Bauchet; Philippe
Peruzzi; Jacques Guyotat; Luc Taillandier; Laurent Capelle;
Hugues Duffau (Paris, France)
Introduction: Supratentorial diffuse low grade gliomas present
a slow macroscopic tumor growth that can be quantified through
the measurement of their velocity of diametric expansion. We
assessed whether spontaneous velocity of diametric expansion
can predict long term outcomes.
Methods: On the basis of miRNA gene expression microarrays of
glioblastoma infiltrating macrophages and matched peripheral
monocytes, miR 142 3p was identified as the most significantly
down regulated miRNA candidate in the glioblastoma macrophage
population.
Methods: 407 adult patients with newly diagnosed supratentorial
diffuse low grade gliomas in adults were studied.
Results: Ex vivo human macrophage induction assays
confirmed the preferential down regulation of miR 142 3p
during macrophage differentiation in M CSF-derived immune
suppressive M2 macrophages relative to the GM CSF-derived pro
inflammatory M1. Forced over expression of miR 142 3p in M2
macrophages resulted in the down regulation of the M2 marker
CD163, induction of apoptosis, and diminished phagocytosis;
indicating miR 142 3p may induce a preferential elimination of
M2 macrophages and/or a M2 to M1 like phenotypic shift. This is
attributed to disruption of TGFBR1 autocrine signaling in the M2
population. In vivo local and systemic miR 142 3p administration
resulted in glioma growth inhibition and extended median
survival in immune competent GL261 glioma bearing mice and in
genetically engineered murine models of glioma with correlative
enhanced anti tumor immune responses.
Results: The mean spontaneous velocity of diametric expansion
before first line treatment was 5.8 ±6.3 mm/year. During the
follow up, 209 patients presented a malignant transformation and
87 died. The malignant progression free survival and the overall
survival were significantly longer in cases of slow velocity of
diametric expansion (median, 103 and 249 months, respectively)
than in cases of fast velocity of diametric expansion (median, 35
and 91 months, respectively) (p‹0.001). In multivariate analyzes,
spontaneous velocity of diametric expansion as a categorical
variable (‹4, ≥4 and ‹8, ≥8 and ‹12, ≥12 mm/year), was
an independent prognostic factors for malignant progression
free survival (p‹0.001; hazard ratio, 3.87; 95%CI, 2.67 5.52) and
for overall survival (p‹0.001; hazard ratio, 4.62; 95%CI, 2.58
7.97). Velocity of diametric expansion was also an independent
prognostic factor for overall survival as a continuous predictor,
showing a linear relationship between overall survival and
spontaneous velocity of diametric expansion (HR: 1.09 per one unit
increase; 95%CI, 1.06 1.12; p<0.001).
Conclusions: These data indicate a unique role of miR 142 3p in
glioma immunity by modulating glioma infiltrating macrophage
function, as well as a novel immunotherapeutic approach with
transitional potential in glioma treatment.
Conclusions: Independently to the molecular status, the
spontaneous velocity of diametric expansion allows the
identification of rapidly growing diffuse low grade gliomas (at
higher risk of worsened evolution) during the pre-therapeutic
period and without delaying treatment.
57
184. Catenin Signaling Initiates Astrocyte Activation And
Contributes To The Pathogenesis of Astrocytomas
185. Long Term Follow-up After Stereotactic Radiosurgery for
the Treatment of Meningiomas
Shervin Rahimpour; Chunzhang Yang, PhD; Russell Lonser, MD;
Zhengping Zhuang, MD, PhD (Bethesda, MD)
John M. McGregor, MD; John Grecula; Mario Ammirati;
Christopher Pelloski; Nina Mayr; Lanchun Lu; Nilendu Gupta;
Susan Bell
Introduction: Astrocyte injury results in disruption of intra/
extracellular contacts, loss of contact inhibition and subsequent
migration and proliferation. Dysregulation of pathways involved
in this response may be involved in the proliferative nature of
neoplasias.
Introduction: Complete surgical resection of intracranial
meningiomas including the dura of origin and infiltrated bone
remains the treatment of choice. Factors such as residual
disease, advanced tumor grade, location within the cranial
vault, or patient comorbidities may limit the success of surgery
alone. Stereotactic radiosurgery (SRS) expands the options for
treatment. We review the outcomes in patients with meningiomas
treated with SRS at our institution from 1999 – 2012.
Methods: Primary human and mouse astrocytes were
cultured and an in vitro scratch assay was used for injury.
Immunofluorescence staining, PCR array, and western blot
analysis were performed to identify the spatial and temporal
expression of molecular markers associated with astrocyte
activation. β catenin siRNA knockdown studies were also
performed in normal astrocytes and tumor sphere forming glioma
cultures. Finally, both frozen and paraffin embedded tumor
samples were stained for relevant markers.
Methods: A retrospective review was performed of 78 patients
with 82 presumed or confirmed meningiomas treated with SRS
over the 13 year period. The median age was 56 (range 17-84).
There were 19 males and 59 females. The median marginal dose
was 15.95 Gy (range 10 -31 Gy) to an averaged 51% isodose line
(range 47 – 70%). 39 patients had undergone surgery previous to
treatment (50%). 10 patients had undergone previous radiation
therapy prior to SRS (13%). The patients were followed clinically
and radiographically at 1, 3, 5 and ≥10 years after SRS.
Results: Following injury, GFAP and Nestin expression increased
at the margins of the wound. PCR array revealed increased
β catenin expression and an associated decrease in cadherin
expression. Western blot analysis further showed that membrane
bound β catenin decreased, while phosphorylated and
cytoplasmic levels increased. siRNA knockdown of β catenin
resulted in decreased expression of GFAP and nearly abolished
expression of Nestin and SOX2 while in glioma cells, siRNA
knockdown decreased tumor sphere size and S phase population.
Results: The majority (n = 53) of tumors (65%) were located in
the falx/parasagital or cerebral convexities while the others (n =
28) involved the skull base (34%). Tumor histology when available
included 21 WHO grade I, 15 WHO grade II and 1 WHO grade III
meningiomas. 45 patients had no definitive pathologic analysis.
In reviewing all 82 tumors, 7 lesions required further treatment
during the follow up period (9%), either further radiation or
surgery. Three of these progressive lesions were tumors at the
skull base, and 4 were convexity/parasagital in location. Four of
these tumors were known WHO grade ll. Two were WHO grade l,
and one did not have confirmatory pathology.
Conclusions: We discovered that the loss of contact inhibition
plays a critical role in the initiation and regulation of reactive
astrocytes in the healing of wounds. In particular, injury of
the astrocytes interrupts and destabilizes the - cadherin
catenincomplexes at the cell membrane leading to nuclear
translocation of β catenin and characteristic changes
associated with the activation of astrocytes. Similar signaling
pathways are not only found to be active, but also dysregulated, in
astrocytomas.
Conclusions: Radiosurgery is a reasonable adjunct to
management of patients with primary, residual or recurrent
meningiomas and presumed meningiomas. The control rates are
›90%. Longer follow up evaluations are still needed.
58
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geaux to booth 103
for the news
Gliadel® is manufactured by Eisai Inc. for Arbor Pharmaceuticals, LLC.
Gliadel® is a registered trademark of Eisai Inc. ©2013 Arbor Pharmaceuticals, LLC. All rights reserved. March 2013
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