Cole Eye Institute
S prin g 2013
Ophthalmology
Update
Jules and Doris Stein
Professorship Awarded for Study of
the Genetics of Retinal Ciliopathies
Cole Eye Institute, in partnership with Cleveland Clinic
develop correlations between specific human mutations
Lerner College of Medicine of Case Western Reserve
and the degree of visual loss in various ciliopathies, to
University, has been granted a Jules and Doris Stein
identify novel ciliopathy alleles that contribute to retinal
Professorship Award from Research to Prevent Blind-
pathology and to understand the cellular mechanisms
ness (RPB) to support the research efforts of Brian
regulating basal body migration.
Perkins, PhD, in ciliopathies in the eye.
Brian Perkins, PhD
“Our intention is to use the support from RPB to conduct
Genetic mutations that disrupt the assembly, structure
exciting additional work with zebrafish, which are al-
or function of basal bodies and/or cilia result in a spec-
ready established as reliable models for genetic testing,”
trum of diseases known as ciliopathies. These multi-
says Dr. Perkins. “As just a few examples, we will use
syndromic disorders cause retinal degeneration, kidney
zebrafish to test the in vivo mechanisms that position
disease, mental retardation and polydactyly.
Dr. Perkins will continue his work using zebrafish, members of the minnow family known for their regenerative ability, to characterize the molecular basis of cilia
basal bodies, including the role of cytoplasmic dynein
motors, the planar cell polarity (PCP) pathway, and the
interactions between PCP signaling and the Joubert
syndrome protein Arl13b.”
formation in photoreceptor cells. In collaboration with
The hope is that the research supported by RPB will en-
colleagues at Cole Eye Institute, Dr. Perkins plans to
able clinicians to better predict the outcomes of certain
Continued on next page
Strabismus Surgery in
Thyroid Eye Disease
Intraoperative Optical
Coherence Tomography
Looking Back at a
Decade in Publishing
Biomarkers in
Uveal Melanoma
Page 3
Page 4
Page 8
Page 10
Clinical Trials, Cole Eye
CME and Distinguished
Lecture Series
Page 11
mutations and improve genetic testing. The lab also
plans to develop zebrafish models of diabetic retinopathy
and age-related macular degeneration.
The award includes up to $1.025 million in grant support, payable over seven years.
“I am so pleased that the promise of Dr. Perkins’ re-
Third Frontier Grant
+ Building Campaign
= Big Future for CEI
Cleveland Clinic’s Cole Eye Institute is preparing to provide its
search is being recognized by an organization as distin-
superior care to tens of thousands of additional patients and become
guished as RPB,” says Daniel F. Martin, MD, Chairman
a premier site for research, development and commercialization of
of Cole Eye Institute. “I believe that his future work will
ophthalmic imaging technologies. The focal point of vision care at
continue to build on his notable accomplishments in
Cleveland Clinic was recently awarded a $3 million grant from the
this research area.”
Ohio Third Frontier Program at the same time it began a building
The research will add to Dr. Perkins’ work in zebrafish
campaign to more than double its size.
genetics and biochemistry. Dr. Perkins has been using
The grant and another $3 million in matching funds will help launch
zebrafish as a model system for retinal degeneration for
several new products and services being developed in the Ophthalmic
more than 10 years. As a National Institutes of Health
Imaging Center, a research, development and commercialization unit
(NIH)-funded postdoctoral fellow at Harvard University,
within Cole Eye Institute. Specifically, the monies will support the
he developed transgenic tools to analyze the photorecep-
development of an innovative intraoperative spectral domain optical
tor structure in zebrafish and identified several mutants
coherence tomography system, including:
affecting photoreceptor survival. As the principal inves-
• Novel surgical instruments that improve image-based analysis
tigator (PI) of two currently funded NIH grants and the
PI on a previous NIH subcontract, Dr. Perkins has also
conducted studies of zebrafish IFT mutants and other
and visualization of surgical sites
• Contrast dyes
genes that lead to photoreceptor degeneration.
• Surgical imaging software
RPB supports eye research directed at the prevention,
More innovations like this will be possible in the future expansion
treatment or eradication of all diseases that threaten
of the Cole Eye Institute. A planned additional 135,000-square-foot
vision. RPB has committed hundreds of millions of dol-
facility will:
lars in grant support to medical institutions across the
• Create a state-of-the-art ocular imaging research center
United States for research into all blinding eye diseases.
Jules and Doris Stein RPB Professorships, the highest
• Double the size and scope of our basic science research laboratory
• Increase education and training space, including an eye surgery
award bestowed by RPB, help attract exceptionally tal-
simulator, surgical wet lab and dedicated location for international
ented basic scientists to careers devoted to eye research.
activities
To date, the program has supported 45 scientists who
seek to devote their research careers to the field of
ophthalmology.
For more information, contact Dr. Perkins
at ophthalmologyupdate@ccf.org.
The new building along with renovations to the existing eye building
will:
• Accommodate an additional 100,000 patients per year
• Increase the number of operating rooms from five to eight, incorporating femtosecond laser and other innovative surgical devices
• Add more than 50 uniquely designed clinical lanes, with easy
navigation for patients with reduced vision
• Expand pediatric surgery space
• Increase the number of recovery beds, to keep operating rooms
at capacity
• Double the size and capability of the diagnostic center
• E xpand clinical services to include aesthetic surgery, trauma care
Adult zebrafish retina stained for cone photoreceptors (green) and
and an ophthalmology genetic center
the rod photoreceptors (red)
2
Ophthalmology Update | Spring 2013
Strabismus Surgery in Thyroid Eye Disease
The medial rectus muscle
in a patient with thyroid eye
disease has been detached
and rests against the globe.
Exposure is best obtained
with a Helveston Barbie
retractor. The muscle will
Elias Traboulsi, MD
be sutured where the end of
the tendon meets the globe
with the eye in primary
position.
Physicians at Cleveland Clinic’s Cole Eye
predictability of strabismus surgery. “This
is reinserted where it naturally lies. With
Institute have recently published 10-year
makes for a real challenge for the surgeon,”
traditional techniques, the muscle is at-
outcome data on a technique for improv-
says Dr. Traboulsi. “It is hard to predict how
tached to an adjustable suture that can
ing the outcomes of strabismus surgery
far you will need to move the insertions of
and does move over time, allowing for
in patients with Graves disease. Devel-
those extraocular muscles. The tables that
postoperative manipulation, and reop-
oped by Elias Traboulsi, MD, Head of the
inform the surgeon how many millimeters
eration rates vary from 8 to 27 percent.
Department of Pediatric Ophthalmology at
to adjust the muscles back according to
In the revised technique the muscle is
Cleveland Clinic, the surgery is intended for
the level of prism diopter deviation – which
attached directly to the sclera where it is
the approximately 5 percent of patients with
were developed for use on a pediatric popu-
more secure, preventing muscle slippage.
thyroid eye disease whose illness necessi-
lation - do not work because the muscles
tates strabismus surgery.
are abnormal.”
One of the complications of Graves disease
To improve the surgical outcomes, Dr.
physicians reported that the final outcome
is the development of an orbital inflam-
Traboulsi and colleagues developed an
after one surgery was good or excellent in
matory process involving the extraocular
intraoperative relaxed muscle positioning
52 patients (90 percent). “Our outcomes
muscles that move the eye, particularly the
technique that improves ocular alignment
also show that exact measurements of how
inferior rectus and medial rectus muscles.
and relieves diplopia in the majority of
much the eye has drifted one way or the
As the muscles become inflamed and
surgical patients.
other are not as important as previously
larger in volume, patients develop proptosis. Additionally, inflamed and stiff muscles
lead to restrictive strabismus, diplopia and
compression damage to the optic nerve.
Decompression surgery, wherein bones of
the floor of the orbit’s medial wall are surgically broken, provides more volume for the
eye to fall back and relieves pressure on
the optic nerve. However, this surgery can
consequently cause diplopia and strabismus if muscles are trapped or displaced in
newly created openings.
In contrast to traditional adjustable stra-
In the 10 years of experience on approximately 60 patients at Cleveland Clinic,
thought,” adds Dr. Traboulsi.
bismus surgery, where muscle position
Along with achieving very positive out-
changes are made when the patient is
comes, this approach removes much of
awake, this technique is performed while
the surgical estimation where to suture the
the patient is under general anesthe-
muscle. “I have been told many times that
sia. “In the traditional adjustable suture
surgeons are relieved to have a method that
technique, with the patient awake, we ask
is simple and predictable and that provides
them to look straight ahead; we adjust
such good results,” says Dr. Traboulsi. “It
the position of the muscle insertion so
takes away a lot of the anxiety about what
that they are not seeing double, and then
to do for their patients.”
we tie the suture at that time,” explains
Dr. Traboulsi. With the revised technique,
The inflammation-induced fibrosis and
the eye is placed straight forward with
thickened extraocular muscles limit the
the patient asleep and the muscle tendon
Contact Dr. Traboulsi at
ophthalmologyupdate@ccf.org.
clevelandclinic.org/OUSpring3
COle EYe Institute Corne al
Surgeons Ma ximize Use of
Intraoperative
4
Ophthalmology Update | Spring 2013
Cole Eye Institute anterior segment surgeons are incorporating intraoperative optical coherence tomography (OCT) into almost every aspect of their
work, from corneal grafting to LASIK and cataract surgery.
William J. Dupps Jr.,
MD, PhD
One procedure for which OCT has proven value is Descemet’s
OT HE R U S E S FO R IN T R AO PE R AT I V E O C T
stripping automated endothelial keratoplasty (DSAEK), in which
Another surgery in which intraoperative OCT is likely to prove
high-resolution visualization of the layers of corneal tissue is re-
valuable is deep anterior lamellar keratoplasty (DALK), in which
quired, says Cole Eye Institute surgeon William J. Dupps Jr., MD, PhD.
surgeons attempt to keep the endothelium but replace all other
“When you are looking through an operating microscope, you are
corneal layers, such as in keratoconus.
presented with the en face view,” he says. “You can differentiate
DALK is technically challenging and time-consuming as it requires
features along the x and y axes, but standard scopes do not provide
manual dissection of the stroma from Descemet’s membrane (DM).
good capabilities for resolving depth, which is the dimension in
About half the time, the surgeon perforates DM and has to convert
which so much of the progress in corneal surgery is concentrated.”
to a full-thickness transplant. With the native endothelial cells lost,
Accurately differentiating corneal layers is essential in treating
conditions such as Fuchs dystrophy, in which endothelial cells
deteriorate prematurely.
“Formerly, Fuchs was best treated by a full-thickness cornea
transplant. Now we selectively replace the endothelial cells,”
Dr. Dupps says. “One of the biggest technical challenges of this
surgery involves achieving adherence of the donor tissue to the
posterior surface of the recipient cornea. Early in the learning curve
and with more complex cases, surgeons often have to take the
patient back to the operating room the next day and rebubble the
the risk of rejection dramatically increases, and the surgeon has
invested an extra hour or more along the way.
“We have started to use OCT to visualize exactly how deep we are
during our initial dissection in DALK cases. The technique involves
putting a cannula tip deep in the cornea and injecting an air bubble
to separate the layers,” Dr. Dupps says. “If the cannula is not deep
enough, the bubble doesn’t get to the right plane and opacifies the
cornea, obscuring the view. Intraoperative OCT appears to improve
our ability to put the air bubble in the right place.”
“We think that intraoperative OCT — especially once it is integrated
graft to reposition it against the back of the cornea.”
into the surgical microscope — will lead to more successful DALK
To help prevent that problem and better understand the dynamics
procedures and improve the efficiency of the procedure,” he says.
of graft adherence, Dr. Dupps and his colleagues now routinely pause
He and his colleagues also are using intraoperative OCT in LASIK,
during surgery to perform OCT with a handheld FDA-approved unit
reviewing the flap before performing the ablation. The thin, tem-
that attaches to the operating microscope. The cross-sectional image
porary layer of bubbles produced by the femtosecond laser at the
clearly depicts the corneal layers, allowing the surgeons to assess
flap interface allows excellent visualization of the flap’s dimensions
graft position and the presence of interface fluid and make any
with OCT before it is lifted. If there is any concern about the flap
needed adjustments.
“We have incorporated a standardized scan routine so we can start
thickness or shape, the surgeon can make an informed decision
about whether to lift the flap and proceed with LASIK or modify the
to tease out the intraoperative factors that promote adherence and
surgical plan based on flap morphology.
those that don’t matter as much,” he says.
In cataract surgery, they are using intraoperative OCT to image fea-
Intraoperative OCT has led Dr. Dupps and his colleagues to
tures such as the lens capsule, the geometry of the capsulorrhexis
make changes in how they perform DSAEK. Since 2005, Cole Eye
and the position of the lens implant.
Institute surgeons have used an infusion technique during DSAEK in
Dr. Dupps and colleagues Justis Ehlers, MD, and Sunil Srivastava,
which a cannula is placed in the anterior chamber to increase pres-
MD, are working in their labs and collaborating with microscope and
sure in the eye, pushing the graft closer to the back of the cornea.
OCT manufacturers to develop a system that integrates the technolo-
Intraoperative OCT has shown that graft apposition improves during
gies. This work is one of the major focuses of a $3 million grant Cole
infusion, but also that sweeping the cornea with a cannula, moving
Eye Institute recently received from the Ohio Third Frontier Program
from the middle outward to evacuate fluid from the interface while
(story on page 2).
there is high pressure underneath the graft, has a dramatic effect
on reducing the space between graft and host tissue, he says.
For more information, contact Dr. Dupps at
ophthalmologyupdate@ccf.org.
clevelandclinic.org/OUSpring5
Intraoperative OCT for
Posterior Segment Surgery
1A
1B
Justis P. Ehlers, MD
Optical coherence tomography (OCT) has revolution-
A PIONEER IN E XPLORING POTENTIAL IN THE OR
ized the clinical care of patients across ophthalmology.
Many questions remain regarding intraoperative OCT,
OCT provides high-resolution cross-sectional ana-
including clinical validation of its utility and its ideal
tomic information at near histological quality and has
role in ophthalmic surgery. At the Ophthalmic Imaging
become the critical driver for treatment protocols and
Center of Cleveland Clinic Cole Eye Institute, our intraop-
patient management for numerous conditions. Perhaps
erative OCT research team is actively pursuing answers
more than any other area, the diagnosis and manage-
for many of these questions. Our PIONEER study is
ment of vitreoretinal diseases have been transformed
a multisurgeon prospective clinical study examining
by this technology.
intraoperative OCT across ophthalmic surgery utilizing a
The near biopsy-level detail provided by OCT is a natural
microscope-mounted SD-OCT probe (Figure 1). Our first
complement to the operating room. Intraoperative OCT
provides immediate feedback to the surgeon regarding
the impact of surgical maneuvers and the status of the
surgical objectives. It also is a novel tool for evaluating the pathophysiology and intraoperative dynamics
Sunil K. Srivastava, MD
associated with various vitreoretinal surgical diseases.
The field of intraoperative OCT continues to evolve and
is still in its infancy. Integrating OCT technology into the
operating room theater is still a limiting factor for many
surgeons. Currently, modified tabletop units or handheld
OCT probes are the most viable options for surgeons.
Microscope-integrated OCT systems have been developed
and are being tested; however, these systems are not currently commercially available in the United States.
6
year of enrollment recently ended with more than 250
patients enrolled.
V I T REO RE T IN A L A PPL I C AT I O N S A RE M A N Y
Vitreoretinal surgical conditions that may benefit from
intraoperative OCT include macular holes, epiretinal
membranes, proliferative diabetic retinopathy, retinal
detachment and vitreomacular traction syndrome.
Using intraoperative OCT for macular hole surgery,
we have found that significant architectural alterations
occur following internal limiting membrane peeling.
Utilizing novel software algorithms, we have been able
to calculate intraoperative geometric changes to the
macular hole following manipulation of the internal
Ophthalmology Update | Spring 2013
2A
3A
2B
Figure 1: Microscope-mounted OCT probe. The mount allows the system to be
utilized entirely draped (A) or left undraped (B).
Figure 2: Impact of intraoperative maneuvers on macular hole geometry. Significant changes are noted in macular hole geometry from the pre-peel scan (red) to
the post-internal limiting membrane peel scan (B) (yellow). Additionally, increased
subretinal hyporeflectivity is noted in the area of peeling (A) (white arrow).
Figure 3: Epiretinal membrane and intraoperative OCT. Pre-peel intraoperative
OCT scan (A) showing prominent epiretinal membrane (yellow arrow). Post-peel
scan (B) confirms removal of the epiretinal membrane (orange arrow) and reveals
areas of increased subretinal hyporeflectivity in the areas of peeling (red arrow).
limiting membrane, including increased macular
hole volume, changes in the base area and increased
subretinal hyporeflectivity (Figure 2). These findings
may be useful in predicting hole closure rate, an area
of active research at Cole Eye Institute.
3B
NEW TECHNOLOGIES UNDER DEVLOPMENT
The generalizable clinical utility of intraoperative OCT
remains unknown. We believe the PIONEER study will
begin to answer many of these questions and help
identify diseases/procedures that should be specifi-
Utilizing intraoperative OCT during retinal detachment
cally targeted for the application of intraoperative OCT
repair, novel changes to foveal architecture have been
technology. Areas of active development include optimal
noted, including occult full-thickness macular hole
microscope integration, enhanced OCT-friendly surgical
formation. The foveal configuration appears to have
instrumentation, intraoperative OCT software algorithms
prognostic significance for visual outcome and may
and optimized display systems. Advances in each of
also predict future macular hole formation in these
these areas are needed to facilitate truly seamless
eyes. For epiretinal membrane surgery, intraopera-
integration into the operating room theater. From our
tive OCT is proving to be useful in confirming both
preliminary research, it seems clear that intraoperative
completion of peeling and, conversely, the presence
OCT provides new and important information to the sur-
of residual membranes requiring attention. Addition-
geon in select cases. Identifying those areas of greatest
ally, areas of increased subretinal hyporeflectivity are
impact on patient care and surgical outcomes continues
common following membrane peeling (Figure 3), pos-
to be a major focus of the intraoperative OCT research
sibly indicating photoreceptor stretching or distortion.
team at Cole Eye Institute.
The functional significance of this remains unknown.
In vitreomacular traction syndrome, intraoperative
OCT can be used to confirm release of traction and
Contact Drs. Ehlers and Srivastava at
ophthalmologyupdate@ccf.org.
may reveal small occult unroofing of foveal cysts,
which would impact the surgical plan.
clevelandclinic.org/OUSpring7
Decade in Medical Publishing
Saw Beginning of New Era in
the Treatment of Retinal Dise ase
I n J a n u a r y 2013, A n d r e w S c h a c h a t , MD, Vice Chairman for Clinical Affairs at the Cole Eye Institute and Director
of Clinical Research, stepped down after 10 years of service
as Editor-in-Chief of one of the premier journals in the field of
ophthalmology, the American Academy of Ophthalmology’s
Ophthalmology.
During that time, Dr. Schachat has not only seen significant
medical changes within ophthalmology, but had helped to usher
in those changes. In addition to his own practice in clinical
research, his editorial position was critical to relaying those
changes to those practicing and performing research in the field.
“I had the good fortune to be editor of Ophthalmology during a
time of transition from paper publishing to a web-based manuscript management system,” says Dr. Schachat. The consequences
of that shift include reducing by 75 percent the time it takes to
review a submitted paper. The median time to decision-making
once a manuscript is received is now approximately 30 days.
“The journal, authors and readers have all benefited from that because we all want timely information,” he adds. “And not only has
production gone electronic, but so has digestion of the material.”
Although 30,000 copies of Ophthalmology are mailed monthly,
most of the articles are consumed online.
Since 2003, Dr. Schachat has overseen a significant transition to an increasingly international readership. Today, of the
approximately 1,800 manuscripts received yearly at the journal,
72 percent of them are from an international primary author,
compared with about half of the manuscripts submitted in 1999.
And about half of the journal’s readers are non-U.S. subscribers. “Much of ophthalmology has become very international, and
we are really learning much more from each other,” he says. “I
think electronic access is largely responsible for that, and it is
something that has been exciting to participate in as editor of
Ophthalmology.”
Advancements in the treatment of certain eye diseases have been
particularly striking. In the last three to four years, Dr. Schachat
noted tremendous strides related to new drugs and new treatments
in leading retinal diseases such as macular degeneration and
diabetic retinopathy. When Dr. Schachat became Editor-in-Chief,
8
Ophthalmology Update | Spring 2013
“Much of ophthalmology has become very international,
and we are really learning much more from each other.
I think electronic access is largely responsible for that,
and it is something that has been exciting to participate
in as editor of Ophthalmology.” – Andrew Schachat, MD
the field of ophthalmology lacked an anti-VEGF therapy. “When I became editor, 90
percent of patients with macular degeneration lost vision,” he recalls. “Now, anti-VEGF
therapy is the norm, and 90 percent of treated patients have stable disease.”
The surge in refractive surgery over the past decade has continued as more patients choose
elective laser surgery to eliminate the need to wear glasses. The results have been so successful that patients who are inconvenienced by eyewear now consider the treatment normative.
Similarly, Dr. Schachat has seen a great change in patient outcomes and expectations
for cataract surgery over the past 10 years. He comments that the expectation for fantastic outcomes in cataract surgery clearly has continued to increase tremendously. “The
expectation used to be to get back to better vision,” he adds. “Now the expectation is to
get back to better vision faster, with very high and specific patient demands for superb
outcomes that 10 years ago were not really possible but are today.”
Looking forward, Dr. Schachat embraces the “absolute revolution” in the number of papers
related to genetics of eye diseases. “We don’t have treatments yet but there has been a revolution in figuring out what the defect is or what has gone wrong,” he says. “I think in the next
10 to 20 years we should see an explosion in targeted therapies for genetic diseases.” He
is also encouraged by the engineering tour de force exhibited in artificial retina devices. “I
think in the next 10 years, if that moves ahead at a third or even a tenth of the pace that
computers moved ahead, there are going to be tremendous advances for patients.” He is also
hopeful that the increasingly large amount of data and promise in understanding the underlying mechanisms involved in glaucoma will result in significant leaps in glaucoma therapy.
“It has been a privilege to serve as the Editor-in-Chief of Ophthalmology,” says Dr. Schachat, who will remain on the journal’s editorial board and continue to manage retinarelated manuscripts. “It has been a fantastic opportunity to have been in a leadership
role at a time when both the business of medical publishing and the treatment of some
important eye diseases have changed so substantially.”
Retina , Fifth Edition, now available
Just released, Retina, Fifth Edition, published by Elsevier, is the most comprehensive reference to date about retinal diagnosis, treatment, development, structure,
function and pathophysiology. The three-volume set draws on the extensive knowledge and experience of editors Stephen J. Ryan, MD; Andrew P. Schachat, MD
(Vice Chairman of Cleveland Clinic Cole Eye Institute); Charles P. Wilkinson, MD;
David R. Hinton, MD; SriniVas R. Sadda, MD; and Peter Wiedemann, MD.
With insights from hundreds of world authorities across Europe, Asia, Australasia
and the Americas, Retina, Fifth Edition, will keep ophthalmologists on the leading edge of today’s
newest technologies, surgical approaches, and diagnostic and therapeutic options for retinal diseases and disorders.
clevelandclinic.org /OUSpring9
Blood Biomarkers to Guide Surveillance and
Treatment of Uveal Melanoma Being Explored
Overall mortality in uveal melanoma is high due to
Arun D. Singh, MD
metastatic disease that develops despite advances in its
E arly B iomarkers of
Micrometastases Needed
diagnosis and improvements in local tumor control. Several
The identification and validation of blood biomarkers may
lines of evidence indicate that micrometastases are pres-
permit early detection of uveal melanoma metastasis and
ent in many patients with uveal melanoma at the time of
could potentially allow for adoption of effective strategies
ophthalmic diagnosis. In partnership with Pierre Triozzi,
to suppress micrometastases before they progress, thereby
MD, of the Taussig Cancer Institute, we have explored new
improving prognosis. Cole Eye Institute is actively exploring
options to treating this challenging disease. An effective
the utility of immune regulation factors in the blood and
strategy to improve survival in uveal melanoma would be to
other new blood biomarkers in an effort to better define
identify patients with micrometastases and suppress those
prognosis and monitor disease progression in patients with
micrometastases before they progress to macrometastases.
uveal melanoma.
Chromosomal aberrations (monosomy-3 and others) and
gene expression profiling of tumors are superior to clinical
and histopathological factors in predicting metastasis.
Detection of circulating melanoma cells is a convenient test
that may be potentially useful for diagnosis, risk stratification, identification of metastasis and treatment monitor-
Fine-needle aspiration biopsy of tumors at the time of local
ing in uveal melanoma. The results of polymerase chain
therapy (plaque radiation), tumor resection and enucleation
reaction-based and immunomagnetic techniques tested to
are the methods applied to obtain material for molecular
date are controversial and cannot be interpreted reliably.
prognostication. The time from diagnosis of the primary
tumor to discovery of metastasis can range from weeks to
decades. Assessment of tumor tissue, however, does not
indicate whether tumor cells have actually been shed or
are forming metastasis, and whether adjuvant treatment is
reducing micrometastasis.
A variety of blood constituents, ranging from melanoma-associated mRNA, vascular endothelial growth factor, hepatocyte
growth factor, epidermal growth factor and insulin-like growth
factor-1 (IGF-1) have been implicated in progression of uveal
melanoma and are measurable in patient serum or in experimental models of uveal melanoma. For various biological and
technical reasons, these biomarkers have not demonstrated to
date the sensitivity, specificity and predictive values necessary
to monitor metastasis in patients with uveal melanoma.
Beta2-microglobulin (B2M) is a component of the HLA
class I molecule light chain. Like the HLA class I heavy
chain, tumor B2M expression by immunohistochemistry
has been associated with metastasis in uveal melanoma.
Because it is noncovalently associated, B2M can circulate.
We studied 76 patients, 47 treated by plaque brachytherapy and 29 treated by enucleation. Thirty-three (43 percent)
of the tumors manifested monosomy-3. Most tumors were
large, were located in the choroid and were of mixed cell
type. Blood was drawn in patients without metastatic
disease prior to fine-needle aspiration biopsy. Tumor chromosome 3 status was determined by fluorescence in situ
hybridization. Levels of B2M, IGF-1 and insulin-like growth
factor-binding protein-3 (IGFBP-3) were determined by enzyme-linked immunosorbent assays. Blood levels of IGF-1
Figure. Fundus photograph of a large choroidal melanoma
and IGFBP-3 were not associated with tumor monosomy-3.
In contrast, increases in blood B2M (p ≤ 0.02) were.
10
Ophthalmology Update | Spring 2013
CME Opportunitie s
The independent association of increased blood
level of B2M and tumor monosomy-3 status was
confirmed in multivariable analysis. Measuring
blood levels of B2M in patients with primary uveal
Mark your calendars for continuing medical education
melanoma may therefore have prognostic value and
symposia hosted by Cole Eye Institute. You’ll gain insights
may help guide surveillance and adjuvant therapy
recommendations.
For more information, contact Drs. Singh and
Triozzi at ophthalmologyupdate@ccf.org.
References
1. Schaller UC, Bosserhoff AK, Neubauer AS, et
al. Melanoma inhibitory activity: a novel serum
marker for uveal melanoma. Melanoma Res. 2002
Dec;12(6):593-599.
2. Missotten GS, Tang NE, Korse CM, et al. Prognostic value of S-100-beta serum concentration in
patients with uveal melanoma. Arch Ophthalmol.
2003 Aug;121(8):1117-1119.
3. Callejo SA, Antecka E, Blanco PL, Edelstein C,
Burnier MN, Jr. Identification of circulating malignant
cells and its correlation with prognostic factors and
treatment in uveal melanoma. A prospective longitudinal study. Eye (Lond). 2007 June; 21(6):752-759.
4. Ulmer A, Beutel J, Süsskind D, et al. Visualization
of circulating melanoma cells in peripheral blood of
patients with primary uveal melanoma. Clin Cancer
Res. 2008 Jul;14(14):4469-4474.
5. Triozzi PL, Singh AD. Blood biomarkers of uveal
melanoma metastasis. Br J Ophthalmol. 2011
Jan;95(1):3-4.
6. Crosby MB, Yang H, Gao W, Zhang L, Grossniklaus
HE. Serum VEGF levels correlate with number and
location of micrometastases in a murine model of uveal
melanoma. Br J Ophthalmol. 2011 Jan;95(1):112-117.
7. Torres V, Triozzi P, Eng C, Tubbs R, Schoenfiled
L, Crabb JW, Saunthararajah Y, Singh AD. Circulating tumor cells in uveal melanoma. Future Oncol.
2011;7:101-9.
8. Singh AD, Turell ME, Topham AK. Uveal melanoma: trends in incidence, treatment, and survival.
Ophthalmology. 2011 Sep;118(9):1881-1885.
9. Triozzi PL, Singh AD. Blood biomarkers for uveal
melanoma. Future Oncol. 2012 Feb;8(2):205-215.
10. Turell ME, Tubbs RR, Biscotti CV, Singh AD.
Uveal melanoma: prognostication. Monogr Clin Cytol.
2012 Oct;21:55-60.
11. Triozzi PL, Elson P, Aldrich W, Achberger S, Tubbs
R, Biscotti CV, Singh AD. Elevated blood beta-2
microglobulin is associated with tumor monosomy-3
in patients with primary uveal melanoma. Melanoma
Res. 2013;23:1-7.
into state-of-the-art diagnostic, medical and surgical
techniques and learn about the promise that research holds
for patients with ophthalmic conditions.
Ophthalmic Ultrasonography:
Practical Aspects
For ophthalmologists, optometrists,
nurses, technicians, photographers
and others
Friday-Saturday, March 15-16, 2013
Location: InterContinental Hotel and
Conference Center, Cleveland, Ohio
Activity Directors:
Arun D. Singh, MD
Brandy Hayden
Uveitis Update
For general ophthalmologists, uveitis
and vitreoretinal specialists, Internists,
rheumatologists, and pulmonary and
paramedical personnel
Saturday, April 20, 2013
Location: InterContinental and
Conference Center, Cleveland, Ohio
Activity Directors:
Careen Lowder, MD, PhD
Sunil K. Srivastava, MD
Retina Summit
For vitreoretinal specialists
North Coast Retina Symposium IV
For vitreoretinal specialists
Friday-Saturday, May 17-18, 2013
Location: Cole Eye Institute,
Cleveland, Ohio
Activity Directors:
Daniel F. Martin, MD
Sunil K. Srivastava, MD
Optical Coherence Tomography
& Imaging: Panel Experts Review
(OCTIPER)
For vitreoretinal specialists
Friday, August 23, 2013
Location: Toronto, Canada
Activity Directors:
Peter Kaiser, MD
Sunil K. Srivastava, MD
Justis P. Ehlers, MD
International Society of Ocular
Oncology (ISOO 2013) - NON-CME
For ophthalmic oncologists, ophthalmologists, medical students,
residents and fellows
Friday, May 3, 2013 (pre-ARVO)
Sunday-Thursday,
Sept. 29-Oct. 3, 2013
Location: The W Seattle Hotel
Seattle, Wash.
Location: InterContinental Hotel and
Conference Center, Cleveland, Ohio
Activity Directors:
Peter Kaiser, MD
Sunil K. Srivastava, MD
Activity Director:
Arun D. Singh, MD
For details, exact locations or to confirm dates for any of our 2013 CME
courses, please contact Jane
Sardelle at sardelj@ccf.org.
clevelandclinic.org/OUSpring11
Distinguished Lecture Series
Cole Eye Institute is proud to present the 2013 Distinguished Lecture Series, which provides a forum for
internationally renowned researchers in the visual sciences to present their latest findings on basic and clinical
ophthalmic research. Ample opportunity for questions and answers is provided after lectures.
Feb. 21, 2013
May 16, 2013
Nov. 21, 2013
Mitochondrial Dysfunction: A
Potential Mechanism for Age-Related
Macular Degeneration
Lerner Research Institute, NA1-140
Global Blindness: Can We Control It?
Lerner Research Institute, NA1-140
Leukocytes Take Directives from the
Extracellular Matrix in Ocular Infections
and Inflammation
Location: TBD
Deborah Ferrington, PhD
Associate Professor
Departments of Ophthalmology
and Visual Neurosciences
University of Minnesota
Minneapolis, Minn.
March 14, 2013
The Role of the Choriocapillaris
in Early AMD
Lerner Research Institute, NA1-140
Robert Mullins, PhD
Hansjoerg E.J.W. Kolder, MD, PhD
Associate Professor of Best Disease
Research, Department of
Ophthalmology & Visual Sciences
University of Iowa
Iowa City, Iowa
April 18, 2013
Genetic Control of Angiogenesis:
Implications for ARMD
Lerner Research Institute, NA1-140
Robert D’Amato, MD, PhD
Judah Folkman Chair in Surgery
Professor of Ophthalmology
Harvard Medical School
Vascular Biology Program
Boston Children’s Hospital
Boston, Mass.
12
Gullapalli Rao, MD
Chairman, LV Prasad Eye Institute
L V Prasad Marg Banjara Hills
Hyderabad, Andhra Pradesh
India
Sept. 19, 2013
Responding to Clinical Need:
Taking OCT Imaging Beyond
Standard Clinical Applications
Location:TBD
Cynthia A. Toth, MD
Professor of Ophthalmology
and Biomedical Engineering
Duke University Eye Center
Durham, N.C.
Oct. 17, 2013
The Hypoxic Response: Sought
and Dreaded by the Retina
Location:TBD
Shukti Chakravarti, PhD
Professor
Departments of Medicine,
Cell Biology and Ophthalmology
Johns Hopkins University
School of Medicine
Baltimore, Md.
Please join us for these insights into
ophthalmic research and the promises
they hold for patient care. No registration
is required; call 216.444.5832 with any
questions. The Distinguished Lecture Series
is held from 7 to 8 a.m., in the locations
listed; check our website for locations of
events that are listed as TBD. Attendees
should park in the East 102nd Street parking lot (facing the front of Cole Eye Institute)
or the visitor’s parking garage at East 100th
Street and Carnegie Avenue. We will validate your parking ticket.
Christian Grimm, PhD
Professor for Experimental
Ophthalmology
Department of Ophthalmology
University of Zurich
Schlieren, Zurich
Switzerland
Ophthalmology Update | Spring 2013
Clinical Trials
All studies have been approved by the Institutional Review
Board. The featured studies are currently enrolling.
Retinal Diseases
Uveitis
Ozurdex for Diabetic Macular Edema
Treated with Pars Plana Vitrectomy and
Membrane Removal (OPERA)
A Proof-of-Concept Study of Intravitreal
LFG316 in Patients with Multifocal
Choroiditis (MFC)
Objective: This study will evaluate the
use of Ozurdex in patients needing surgery
for epiretinal membrane with diabetic
macular edema.
Objective: The study is designed to
provide information on the safety, tolerability,
pharmacokinetics, pharmacodynamics and
efficacy of successive intravenous doses of
LFG316 in eligible patients with neovascular
age-related macular degeneration.
R
Contact: Sunil Srivastava, MD,
216.636.2286 or Kim Baynes,
216.444.2566
Investigator-Initiated Observational Study
of Intravitreal Aflibercept Injection for
Exudative Age-Related Macular Degeneration Previously Treated with Ranibizumab
or Bevacizumab
Objective: This observational study will
assess the efficacy of intravitreal aflibercept
injection in subjects previously treated with
ranibizumab or bevacizumab on central
retinal thickness as measured by spectral
domain optical coherence tomography
(SDOCT).
Contact: Rishi P. Singh, MD,
216.445.9497, or Stephanie Bennett,
216.445.6497
Fluocinolone Acetonide Intravitreal Inserts
for Vein Occlusion in Retina (FAVOR)
Objective: This study will assess the
safety and efficacy of fluocinolone acetonide
intravitreal inserts in subjects with macular
edema secondary to RVO.
Contact: Peter K. Kaiser, MD,
216.444.6702, or Gail Kolin, RN,
216.445.4086
Contact: Sunil Srivastava, MD,
216.636.2286, or Laura Holody,
216.445.3762
Pediatric Eye Disease
HTS1-Glasses vs. Observation for Moderate Hyperopia in Young Children
Objective: The purpose of this study is to
compare visual acuity outcomes and
development of strabismus after a three-year
follow-up period in children ages 12 to < 60
months with moderate hyperopia who are
prescribed glasses either immediately or only
after confirmation of prespecified deterioration criteria.
Contact: Elias Traboulsi, MD,
216.444.4363, or Sue Crowe,
216.445.3840
Bilateral Lateral Rectus Recession vs.
Unilateral Recess-Resect for Intermittent
Exotropia (IXT1)
Objective: The purpose of this study is
to evaluate the effectiveness of bilateral
lateral rectus muscle recession vs. unilateral
lateral rectus recession with medial rectus
resection procedures for the treatment of
strabismus.
Contact: Elias Traboulsi, MD,
216.444.4363, or Sue Crowe, RN,
216.445.3840
Increasing Patching for Amblyopia in
Children 3 to < 8 Years Old (ATS15)
Objective: This study is designed to
evaluate the effectiveness of increasing
prescribed patching treatment after visual
acuity has stabilized with initial treatment
and amblyopia is still present.
Contact: Elias Traboulsi, MD,
216.444.4363, or Sue Crowe, RN,
216.445.3840
Genetics
Molecular Genetics of Eye Diseases
Objective: The objective of this project is
to study the molecular genetics of ophthalmic disorders through the compilation of a
collection of DNA, plasma and eye tissue
samples from patients and from families
with a broad range of eye diseases and
malformations.
Contact: Elias Traboulsi, MD,
216.444.4363, or Sonal Uppal, PhD,
216.444.7137
Cornea/Refractive Surgery
LASIK Flap Thickness and Visual Outcomes Using the WaveLight FS200
Femtosecond Laser
Objective: To evaluate the visual outcome,
accuracy and predictability of LASIK flap
thickness using the new WaveLight®
FS200 femtosecond laser and compare
these results to those obtained using the
IntraLaseTM FS60 femtosecond laser.
Contact: Ronald Krueger, MD,
216.444.8158, or Laura Holody,
216.445.2264
Continued on next page
clevelandclinic.org/OUSpring13
Clinical Trials
continued from previous page
Ophthalmology Update, a publication
of Cleveland Clinic’s Cole Eye Institute,
provides information for ophthalmologists
about state-of-the-art diagnostic and management techniques and current research.
Please direct any correspondence to:
Long-Term Safety Follow-up for Subjects
Previously Implanted with the AcrySof
Cachet Phakic Lens in Clinical Studies
C-02-23, C-02-40, C-03-21 and C-05-57
Objective: To estimate the annualized endothelial cell loss rate (for up to 10 years
following date of implantation) of subjects
previously implanted with the L-series
AcrySof® Cachet™ Phakic Lens from
clinical studies.
Contact: Ronald Krueger, MD,
216.444.8158, or Laura Holody,
216.445.2264
Other Open Studies
Safety Study of a Single IVT Injection
of QPI-1007 in Chronic Optic Nerve
Atrophy and Recent-Onset NAION
Patients (NAION)
Contact: Rishi P. Singh, MD,
216.445.9497, or Laura Holody,
216.445.2264
The following studies have completed
patient enrollment in the past year at
Cole Eye Institute and are in follow-up:
Home Vision Monitoring Using the
ForseeHomeTM Device Following
Treatment of Neovascular Age-Related
Macular Degeneration
Comparing the Effectiveness of Treatment Strategies for Primary Open-Angle
Glaucoma
A Phase II Dose-Ranging Study of
Pazopanib to Treat Neovascular
Age-Related Macular Degeneration
(GSK AMD)
Objective: This is an open-label, dose
escalation, safety, tolerability and pharmacokinetic study, where the active study drug
(QPI-1007) will be given to all patients who
participate. This study will determine
whether QPI-1007 is safe when it is
injected into the eye. The study will also
reveal if there are any side effects of the
drug and how long it takes for the body to
clear the drug.
Cleveland Clinic E xecutive Education
Learn From Top Healthcare Executives
ophthalmologyupdate@ccf.org
Institute Chairman
Daniel F. Martin, MD
Managing Editor
Kimberley Sirk
Art Director
Michael Viars
Marketing Manager
Bill Sattin, PhD
Marketing Associate
Mary Anne Connor
Cole Eye Institute, one of 26 institutes at
Cleveland Clinic, is one of the few dedicated,
comprehensive eye institutes in the world. Our
internationally recognized staff diagnoses and
treats the entire spectrum of eye conditions, caring for more than 170,000 patients and performing more than 7,500 surgeries annually.
Cleveland Clinic is a nonprofit, multispecialty
academic medical center consistently ranked
among the top hospitals in America by U.S. News
& World Report. Founded in 1921, it is dedicated
to providing quality specialized care and includes
an outpatient clinic, a hospital with more than
1,300 staffed beds, an education institute and a
research institute.
Ophthalmology Update is written for physicians
and should be relied on for medical education
purposes only. It does not provide a complete
overview of the topics covered and should not
replace the independent judgment of a physician
about the appropriateness or risks of a procedure
for a given patient. Physicians who wish to share
this information with patients need to make them
aware of any risks or potential complications
associated with any procedures.
© 2013 The Cleveland Clinic Foundation
The competencies needed to lead and manage differ from those needed to be an
effective administrator, clinician or scientist. Take advantage of this opportunity
to acquire skills and insights into the business of healthcare excellence from top
executives at Cleveland Clinic.
Two-day and two-week programs are open to healthcare executives, including
physicians, nurses and administrators. Visit clevelandclinic.org/ExecutiveEducation
for details, including the opportunity to earn 72.5 CME credits.
14
Ophthalmology Update | Spring 2013
Cole Eye Institute Staff
Chairman, Cole Eye Institute
Daniel F. Martin, MD............................................ 216.444.0430
Institute Vice Chairman | Institute Quality Review Officer
Andrew P. Schachat, MD....................................... 216.444.7963
Institute Vice Chairman for Education
Elias I. Traboulsi, MD........................................... 216.444.2030
Comprehensive Ophthalmology
John Costin, MD.................................................. 440.988.4040
Richard E. Gans, MD, FACS.................................. 216.444.0848
Philip N. Goldberg, MD ....................................... 216.831.0120
Michael Gressel, MD............................................ 440.988.4040
Mohinder Gupta, MD............................................ 419.289.6466
Martin A. Markowitz, MD ..................................... 440.461.4733
Shari Martyn, MD ............................................... 216.831.0120
Peter McGannon, MD........................................... 216.529.5320
Michael E. Millstein, MD ...................................... 216.831.0120
Wynne Morley, MD............................................... 440.366.9444
Sheldon M. Oberfeld, MD .................................... 440.461.4733
Allen S. Roth, MD ............................................... 216.831.0120
David B. Sholiton, MD ......................................... 216.831.0120
Scott A. Wagenberg, MD ...................................... 440.461.4733
Cornea and External Disease
William J. Dupps Jr., MD, PhD.............................. 216.444.2020
Jeffrey M. Goshe, MD........................................... 216.444.0845
Roger H.S. Langston, MD ..................................... 216.444.5898
Martin A. Markowitz, MD ..................................... 440.461.4733
Peter McGannon, MD........................................... 440.529.5320
David M. Meisler, MD .......................................... 216.444.8102
Wynne Morley, MD............................................... 440.366.9444
Sheldon M. Oberfeld, MD .................................... 440.461.4733
Allen S. Roth, MD ............................................... 216.831.0120
Scott A. Wagenberg, MD ...................................... 440.461.4733
Steven E. Wilson, MD .......................................... 216.444.5887
Glaucoma
Jonathan A. Eisengart, MD ................................... 216.445.9429
Edward J. Rockwood, MD .................................... 216.444.1995
Shalini Sood-Mendiratta, MD................................ 216.445.5277
Keratorefractive Surgery
William J. Dupps Jr., MD, PhD.............................. 216.444.2020
Ronald R. Krueger, MD, MSE................................. 216.444.8158
Michael E. Millstein, MD ...................................... 216.831.0120
Allen S. Roth, MD ............................................... 216.831.0120
Steven E. Wilson, MD .......................................... 216.444.5887
Neuro-Ophthalmology
Gregory S. Kosmorsky, DO.................................... 216.444.2855
Lisa D. Lystad, MD ............................................. 216.445.2530
Oculoplastics and Orbital Surgery
Mark Levine, MD................................................. 440.988.4040
Julian D. Perry, MD ............................................. 216.444.3635
Ophthalmic Anesthesia
Marc A. Feldman, MD ......................................... 216.444.9088
M. Inton-Santos, MD............................................ 216.445.1016
J. Victor Ryckman, MD......................................... 216.444.6330
Sara Spagnuolo, MD ............................................ 216.444.6324
Ophthalmic Oncology
Arun D. Singh, MD .............................................. 216.445.9479
Ophthalmic Research
Bela Anand-Apte, MBBS, PhD............................... 216.445.9739
Vera Bonilha, PhD................................................ 216.445.7960
John W. Crabb, PhD............................................. 216.445.0425
William J. Dupps Jr., MD, PhD.............................. 216.444.2020
Stephanie Hagstrom, PhD..................................... 216.445.4133
Joe G. Hollyfield, PhD.......................................... 216.445.3252
Neal S. Peachey, PhD........................................... 216.445.1942
Brian Perkins, Ph.D.............................................. 216.444.9683
Pediatric Ophthalmology and Adult Strabismus
Fatema Ghasia, MD............................................. 216.444.0999
Andreas Marcotty, MD ......................................... 216.831.0120
Paul Rychwalski, MD .......................................... 216.444.4821
Elias I. Traboulsi, MD .......................................... 216.444.2030
Retina
Amy Babiuch, MD................................................ 440.366.9444
Ryan Deasy, MD.................................................. 440.695.4010
Justis P. Ehlers, MD ............................................. 216.636.0183
Peter K. Kaiser, MD ............................................. 216.444.6702
Daniel F. Martin, MD ........................................... 216.444.0430
Andrew P. Schachat, MD ...................................... 216.444.7963
Jonathan E. Sears, MD......................................... 216.444.8157
Rishi P. Singh, MD............................................... 216.445.9497
Sunil K. Srivastava, MD........................................ 216.636.2286
Richard Wyszynski, MD........................................ 440.988.4040
Alex Yuan, MD..................................................... 216.444.0079
Uveitis
Careen Y. Lowder, MD, PhD.................................. 216.444.3642
Sunil K. Srivastava, MD........................................ 216.636.2286
Patient Referrals
To refer a patient to Cole Eye Institute, please call 216.444.2020 or 800.223.2273, ext 42020.
clevelandclinic.org/OUSpring15
Cole Eye Institute
The Cleveland Clinic Foundation
9500 Euclid Avenue / AC311
Cleveland, OH 44195
Ophthalmology Update
24/7 Referrals
Referring Physician Hotline
855.REFER.123 (855.733.3712)
Physician Directory
View all Cleveland Clinic staff online at clevelandclinic.org/staff.
Track Your Patient’s Care Online
DrConnect is a secure online service providing real-time
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information about the treatment your patient receives
800.553.5056
at Cleveland Clinic. Establish a DrConnect account at
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Critical Care Transport Worldwide
Cleveland Clinic’s critical care transport teams and fleet
of vehicles are available to serve patients across the globe.
•T
o arrange for a critical care transfer, call 216.448.7000 or
866.547.1467 (see clevelandclinic.org/criticalcaretransport).
About Cleveland Clinic
Cleveland Clinic is an integrated healthcare delivery system
with local, national and international reach. At Cleveland
•F
or STEMI (ST elevated myocardial infarction), acute stroke,
ICH (intracerebral hemorrhage), SAH (subarachnoid hemorrhage)
or aortic syndrome transfers, call 877.379.CODE (2633).
Clinic, 2,800 physicians represent 120 medical specialties
Outcomes Data
and subspecialties. We are a main campus, 18 family health
View clinical Outcomes books from all Cleveland Clinic
centers, eight community hospitals, Cleveland Clinic Florida,
institutes at clevelandclinic.org/outcomes.
the Cleveland Clinic Lou Ruvo Center for Brain Health in Las
Vegas, Cleveland Clinic Canada, Sheikh Khalifa Medical City
and Cleveland Clinic Abu Dhabi.
In 2012, Cleveland Clinic was ranked one of America’s top 4
hospitals in U.S.News & World Report’s annual “America’s
Best Hospitals” survey. The survey ranks Cleveland Clinic
among the nation’s top 10 hospitals in 14 specialty areas, and
as the top hospital in three of those areas.
Clinical Trials
We offer thousands of clinical trials for qualifying patients.
Visit clevelandclinic.org/clinicaltrials.
CME Opportunities: Live and Online
The Cleveland Clinic Center for Continuing Education’s website offers
convenient, complimentary learning opportunities. Visit ccfcme.org to
learn more and use Cleveland Clinic’s myCME portal (available from
the site) to manage your CME credits.
Resources for Physicians
Executive Education
Referring Physician Center and Hotline
leaders — the Executive Visitors’ Program and the two-week Samson
Cleveland Clinic’s Referring Physician Center has established
Global Leadership Academy immersion program. Visit clevelandclinic.
a 24/7 hotline — 855.REFER.123 (855.733.3712) — to
org/executiveeducation.
streamline access to our array of medical services. Contact
the Referring Physician Hotline for information on our clinical
specialties and services, to schedule and confirm patient appointments, for assistance in resolving service-related issues,
and to connect with Cleveland Clinic specialists.
Cleveland Clinic has two education programs for healthcare executive
Same-Day Appointments
Cleveland Clinic offers same-day appointments to help your patients
get the care they need, right away. Have your patients call our sameday appointment line, 216.444.CARE (2273), or 800.223.CARE
(2273).