Ophthalmology Update

Continued on next page

Looking Back at a Decade in Publishing

Page 8

Strabismus Surgery in Thyroid Eye Disease

Page 3

Intraoperative Optical Coherence Tomography

Page 4

Biomarkers in Uveal Melanoma

Page 10

Clinical Trials, Cole Eye CME and Distinguished Lecture Series

Page 11

Brian Perkins, PhD

Cole Eye Institute SPring 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

Lerner College of Medicine of Case Western Reserve

University, has been granted a Jules and Doris Stein

Professorship Award from Research to Prevent Blind-

ness (RPB) to support the research efforts of Brian

Perkins, PhD, in ciliopathies in the eye.

Genetic mutations that disrupt the assembly, structure

or function of basal bodies and/or cilia result in a spec-

trum of diseases known as ciliopathies. These multi-

syndromic disorders cause retinal degeneration, kidney

disease, mental retardation and polydactyly.

Dr. Perkins will continue his work using zebrafish, mem-

bers of the minnow family known for their regenera-

tive ability, to characterize the molecular basis of cilia

formation in photoreceptor cells. In collaboration with

colleagues at Cole Eye Institute, Dr. Perkins plans to

develop correlations between specific human mutations

and the degree of visual loss in various ciliopathies, to

identify novel ciliopathy alleles that contribute to retinal

pathology and to understand the cellular mechanisms

regulating basal body migration.

“Our intention is to use the support from RPB to conduct

exciting additional work with zebrafish, which are al-

ready established as reliable models for genetic testing,”

says Dr. Perkins. “As just a few examples, we will use

zebrafish to test the in vivo mechanisms that position

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.”

The hope is that the research supported by RPB will en-

able clinicians to better predict the outcomes of certain

thIrd frOntIEr Grant + BUIldInG CamPaIGn = BIG fUtUrE fOr CEICleveland Clinic’s Cole Eye Institute is preparing to provide its

superior care to tens of thousands of additional patients and become

a premier site for research, development and commercialization of

ophthalmic imaging technologies. The focal point of vision care at

Cleveland Clinic was recently awarded a $3 million grant from the

Ohio Third Frontier Program at the same time it began a building

campaign to more than double its size.

The grant and another $3 million in matching funds will help launch

several new products and services being developed in the Ophthalmic

Imaging Center, a research, development and commercialization unit

within Cole Eye Institute. Specifically, the monies will support the

development of an innovative intraoperative spectral domain optical

coherence tomography system, including:

• Novel surgical instruments that improve image-based analysis

and visualization of surgical sites

• Contrast dyes

• Surgical imaging software

More innovations like this will be possible in the future expansion

of the Cole Eye Institute. A planned additional 135,000-square-foot

facility will:

• Create a state-of-the-art ocular imaging research center

• Double the size and scope of our basic science research laboratory

• Increase education and training space, including an eye surgery

simulator, surgical wet lab and dedicated location for international

activities

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, incorpo-

rating 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

• Expand clinical services to include aesthetic surgery, trauma care

and an ophthalmology genetic center

2 Ophthalmology Update | Spring 2013

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 sup-

port, payable over seven years.

“I am so pleased that the promise of Dr. Perkins’ re-

search is being recognized by an organization as distin-

guished as RPB,” says Daniel F. Martin, MD, Chairman

of Cole Eye Institute. “I believe that his future work will

continue to build on his notable accomplishments in

this research area.”

The research will add to Dr. Perkins’ work in zebrafish

genetics and biochemistry. Dr. Perkins has been using

zebrafish as a model system for retinal degeneration for

more than 10 years. As a National Institutes of Health

(NIH)-funded postdoctoral fellow at Harvard University,

he developed transgenic tools to analyze the photorecep-

tor structure in zebrafish and identified several mutants

affecting photoreceptor survival. As the principal inves-

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

genes that lead to photoreceptor degeneration.

RPB supports eye research directed at the prevention,

treatment or eradication of all diseases that threaten

vision. RPB has committed hundreds of millions of dol-

lars in grant support to medical institutions across the

United States for research into all blinding eye diseases.

Jules and Doris Stein RPB Professorships, the highest

award bestowed by RPB, help attract exceptionally tal-

ented basic scientists to careers devoted to eye research.

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 [email protected].

Adult zebrafish retina stained for cone photoreceptors (green) and

the rod photoreceptors (red)

2 Ophthalmology Update | Spring 2013 clevelandclinic.org/OUSpring 3

StraBiSmuS Surgery In thyrOId EyE dIsEasE

Physicians at Cleveland Clinic’s Cole Eye

Institute have recently published 10-year

outcome data on a technique for improv-

ing the outcomes of strabismus surgery

in patients with Graves disease. Devel-

oped by Elias Traboulsi, MD, Head of the

Department of Pediatric Ophthalmology at

Cleveland Clinic, the surgery is intended for

the approximately 5 percent of patients with

thyroid eye disease whose illness necessi-

tates strabismus surgery.

One of the complications of Graves disease

is the development of an orbital inflam-

matory process involving the extraocular

muscles that move the eye, particularly the

inferior rectus and medial rectus muscles.

As the muscles become inflamed and

larger in volume, patients develop propto-

sis. 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 surgi-

cally 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 strabis-

mus if muscles are trapped or displaced in

newly created openings.

The inflammation-induced fibrosis and

thickened extraocular muscles limit the

predictability of strabismus surgery. “This

makes for a real challenge for the surgeon,”

says Dr. Traboulsi. “It is hard to predict how

far you will need to move the insertions of

those extraocular muscles. The tables that

inform the surgeon how many millimeters

to adjust the muscles back according to

the level of prism diopter deviation – which

were developed for use on a pediatric popu-

lation - do not work because the muscles

are abnormal.”

To improve the surgical outcomes, Dr.

Traboulsi and colleagues developed an

intraoperative relaxed muscle positioning

technique that improves ocular alignment

and relieves diplopia in the majority of

surgical patients.

In contrast to traditional adjustable stra-

bismus surgery, where muscle position

changes are made when the patient is

awake, this technique is performed while

the patient is under general anesthe-

sia. “In the traditional adjustable suture

technique, with the patient awake, we ask

them to look straight ahead; we adjust

the position of the muscle insertion so

that they are not seeing double, and then

we tie the suture at that time,” explains

Dr. Traboulsi. With the revised technique,

the eye is placed straight forward with

the patient asleep and the muscle tendon

is reinserted where it naturally lies. With

traditional techniques, the muscle is at-

tached to an adjustable suture that can

and does move over time, allowing for

postoperative manipulation, and reop-

eration rates vary from 8 to 27 percent.

In the revised technique the muscle is

attached directly to the sclera where it is

more secure, preventing muscle slippage.

In the 10 years of experience on approxi-

mately 60 patients at Cleveland Clinic,

physicians reported that the final outcome

after one surgery was good or excellent in

52 patients (90 percent). “Our outcomes

also show that exact measurements of how

much the eye has drifted one way or the

other are not as important as previously

thought,” adds Dr. Traboulsi.

Along with achieving very positive out-

comes, this approach removes much of

the surgical estimation where to suture the

muscle. “I have been told many times that

surgeons are relieved to have a method that

is simple and predictable and that provides

such good results,” says Dr. Traboulsi. “It

takes away a lot of the anxiety about what

to do for their patients.”

Contact Dr. Traboulsi at

[email protected].

elias traboulsi, mD

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

be sutured where the end of

the tendon meets the globe

with the eye in primary

position.


COlE EyE InstItUtE COrnEal sUrGEOns maxImIzE UsE Of

intraoPerative


One procedure for which OCT has proven value is Descemet’s

stripping automated endothelial keratoplasty (DSAEK), in which

high-resolution visualization of the layers of corneal tissue is re-

quired, says Cole Eye Institute surgeon William J. Dupps Jr., MD, PhD.

“When you are looking through an operating microscope, you are

presented with the en face view,” he says. “You can differentiate

features along the x and y axes, but standard scopes do not provide

good capabilities for resolving depth, which is the dimension in

which so much of the progress in corneal surgery is concentrated.”

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

graft to reposition it against the back of the cornea.”

To help prevent that problem and better understand the dynamics

of graft adherence, Dr. Dupps and his colleagues now routinely pause

during surgery to perform OCT with a handheld FDA-approved unit

that attaches to the operating microscope. The cross-sectional image

clearly depicts the corneal layers, allowing the surgeons to assess

graft position and the presence of interface fluid and make any

needed adjustments.

“We have incorporated a standardized scan routine so we can start

to tease out the intraoperative factors that promote adherence and

those that don’t matter as much,” he says.

Intraoperative OCT has led Dr. Dupps and his colleagues to

make changes in how they perform DSAEK. Since 2005, Cole Eye

Institute surgeons have used an infusion technique during DSAEK in

which a cannula is placed in the anterior chamber to increase pres-

sure in the eye, pushing the graft closer to the back of the cornea.

Intraoperative OCT has shown that graft apposition improves during

infusion, but also that sweeping the cornea with a cannula, moving

from the middle outward to evacuate fluid from the interface while

there is high pressure underneath the graft, has a dramatic effect

on reducing the space between graft and host tissue, he says.

OTHER USES FOR INTRAOPERATIVE OCT

Another surgery in which intraoperative OCT is likely to prove

valuable is deep anterior lamellar keratoplasty (DALK), in which

surgeons attempt to keep the endothelium but replace all other

corneal layers, such as in keratoconus.

DALK is technically challenging and time-consuming as it requires

manual dissection of the stroma from Descemet’s membrane (DM).

About half the time, the surgeon perforates DM and has to convert

to a full-thickness transplant. With the native endothelial cells lost,

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

into the surgical microscope — will lead to more successful DALK

procedures and improve the efficiency of the procedure,” he says.

He and his colleagues also are using intraoperative OCT in LASIK,

reviewing the flap before performing the ablation. The thin, tem-

porary layer of bubbles produced by the femtosecond laser at the

flap interface allows excellent visualization of the flap’s dimensions

with OCT before it is lifted. If there is any concern about the flap

thickness or shape, the surgeon can make an informed decision

about whether to lift the flap and proceed with LASIK or modify the

surgical plan based on flap morphology.

In cataract surgery, they are using intraoperative OCT to image fea-

tures such as the lens capsule, the geometry of the capsulorrhexis

and the position of the lens implant.

Dr. Dupps and colleagues Justis Ehlers, MD, and Sunil Srivastava,

MD, are working in their labs and collaborating with microscope and

OCT manufacturers to develop a system that integrates the technolo-

gies. This work is one of the major focuses of a $3 million grant Cole

Eye Institute recently received from the Ohio Third Frontier Program

(story on page 2).

For more information, contact Dr. Dupps at

[email protected].

William J. Dupps Jr., mD, PhD

Cole Eye Institute anterior segment surgeons are incorporating intraopera-

tive optical coherence tomography (OCT) into almost every aspect of their

work, from corneal grafting to LASIK and cataract surgery.


intraoPerative oCt fOr POstErIOr sEGmEnt sUrGEry

Optical coherence tomography (OCT) has revolution-

ized the clinical care of patients across ophthalmology.

OCT provides high-resolution cross-sectional ana-

tomic information at near histological quality and has

become the critical driver for treatment protocols and

patient management for numerous conditions. Perhaps

more than any other area, the diagnosis and manage-

ment of vitreoretinal diseases have been transformed

by this technology.

The near biopsy-level detail provided by OCT is a natural

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 evaluat-

ing the pathophysiology and intraoperative dynamics

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 cur-

rently commercially available in the United States.

A PIONEER IN EXPLORING POTENTIAL IN THE OR

Many questions remain regarding intraoperative OCT,

including clinical validation of its utility and its ideal

role in ophthalmic surgery. At the Ophthalmic Imaging

Center of Cleveland Clinic Cole Eye Institute, our intraop-

erative OCT research team is actively pursuing answers

for many of these questions. Our PIONEER study is

a multisurgeon prospective clinical study examining

intraoperative OCT across ophthalmic surgery utilizing a

microscope-mounted SD-OCT probe (Figure 1). Our first

year of enrollment recently ended with more than 250

patients enrolled.

VITREORETINAL APPLICATIONS ARE MANY

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

Justis P. ehlers, mD

Sunil K. Srivastava, mD

1a

1B


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.

Utilizing intraoperative OCT during retinal detachment

repair, novel changes to foveal architecture have been

noted, including occult full-thickness macular hole

formation. The foveal configuration appears to have

prognostic significance for visual outcome and may

also predict future macular hole formation in these

eyes. For epiretinal membrane surgery, intraopera-

tive OCT is proving to be useful in confirming both

completion of peeling and, conversely, the presence

of residual membranes requiring attention. Addition-

ally, areas of increased subretinal hyporeflectivity are

common following membrane peeling (Figure 3), pos-

sibly indicating photoreceptor stretching or distortion.

The functional significance of this remains unknown.

In vitreomacular traction syndrome, intraoperative

OCT can be used to confirm release of traction and

may reveal small occult unroofing of foveal cysts,

which would impact the surgical plan.

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. Signifi-cant 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).

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-

cally targeted for the application of intraoperative OCT

technology. Areas of active development include optimal

microscope integration, enhanced OCT-friendly surgical

instrumentation, intraoperative OCT software algorithms

and optimized display systems. Advances in each of

these areas are needed to facilitate truly seamless

integration into the operating room theater. From our

preliminary research, it seems clear that intraoperative

OCT provides new and important information to the sur-

geon in select cases. Identifying those areas of greatest

impact on patient care and surgical outcomes continues

to be a major focus of the intraoperative OCT research

team at Cole Eye Institute.

Contact Drs. Ehlers and Srivastava at

[email protected].

2a

3a

3B

2B


DeCaDe in meDiCal PuBliShing saw BEGInnInG Of nEw Era In thE trEatmEnt Of rEtInal dIsEasE

I n Ja n u a r y 2013, a n d r e w S c h a c h a t, M d, Vice Chair-

man 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 manu-

script 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 be-

cause 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 transi-

tion 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. subscrib-

ers. “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,

RETINA, FIFTH EDITION, NOW AVAILABLEJust released, Retina, Fifth Edition, published by Elsevier, is the most comprehen-

sive reference to date about retinal diagnosis, treatment, development, structure,

function and pathophysiology. The three-volume set draws on the extensive knowl-

edge 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 dis-

eases and disorders.clevelandclinic.org/OUSpring 98 Ophthalmology Update | Spring 2013

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 success-

ful 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 fan-

tastic 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 revolu-

tion 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 under-

lying 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. Scha-

chat, who will remain on the journal’s editorial board and continue to manage retina-

related 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.”

“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


BlOOd BIOmarkErs tO GUIdE sUrvEIllanCE and trEatmEnt Of UvEal mElanOma BEInG ExPlOrEd

Overall mortality in uveal melanoma is high due to

metastatic disease that develops despite advances in its

diagnosis and improvements in local tumor control. Several

lines of evidence indicate that micrometastases are pres-

ent in many patients with uveal melanoma at the time of

ophthalmic diagnosis. In partnership with Pierre Triozzi,

MD, of the Taussig Cancer Institute, we have explored new

options to treating this challenging disease. An effective

strategy to improve survival in uveal melanoma would be to

identify patients with micrometastases and suppress those

micrometastases before they progress to macrometastases.

Chromosomal aberrations (monosomy-3 and others) and

gene expression profiling of tumors are superior to clinical

and histopathological factors in predicting metastasis.

Fine-needle aspiration biopsy of tumors at the time of local

therapy (plaque radiation), tumor resection and enucleation

are the methods applied to obtain material for molecular

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.

EARLY BIOMARKERS OF MICROMETASTASES NEEDED

The identification and validation of blood biomarkers may

permit early detection of uveal melanoma metastasis and

could potentially allow for adoption of effective strategies

to suppress micrometastases before they progress, thereby

improving prognosis. Cole Eye Institute is actively exploring

the utility of immune regulation factors in the blood and

other new blood biomarkers in an effort to better define

prognosis and monitor disease progression in patients with

uveal melanoma.

Detection of circulating melanoma cells is a convenient test

that may be potentially useful for diagnosis, risk stratifica-

tion, identification of metastasis and treatment monitor-

ing in uveal melanoma. The results of polymerase chain

reaction-based and immunomagnetic techniques tested to

date are controversial and cannot be interpreted reliably.

A variety of blood constituents, ranging from melanoma-asso-

ciated 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 experi-

mental 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 brachythera-

py 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 chro-

mosome 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 en-

zyme-linked immunosorbent assays. Blood levels of IGF-1

and IGFBP-3 were not associated with tumor monosomy-3.

In contrast, increases in blood B2M (p ≤ 0.02) were. Figure. Fundus photograph of a large choroidal melanoma

arun D. Singh, mD


Cme oPPortunitieS

Mark your calendars for continuing medical education

symposia hosted by Cole Eye Institute. You’ll gain insights

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 aspectsFor 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 updateFor 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

Friday, may 3, 2013 (pre-arvo)

Location: The W Seattle Hotel Seattle, Wash.

Activity Directors: Peter Kaiser, MD Sunil K. Srivastava, MD

north Coast retina Symposium ivFor 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, oph-thalmologists, medical students, residents and fellows

Sunday-thursday, Sept. 29-oct. 3, 2013

Location: InterContinental Hotel and Conference Center, Cleveland, Ohio

Activity Director: Arun D. Singh, MD

For details, exact locations or to con-firm dates for any of our 2013 CME courses, please contact Jane Sardelle at [email protected].

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. Prog-nostic 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 longitu-dinal 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. Circulat-ing tumor cells in uveal melanoma. Future Oncol. 2011;7:101-9.

8. Singh AD, Turell ME, Topham AK. Uveal mela-noma: 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.

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

melanoma may therefore have prognostic value and

may help guide surveillance and adjuvant therapy

recommendations.

For more information, contact Drs. Singh and

Triozzi at [email protected].


dIstInGUIshEd lECtUrE SerieS

Feb. 21, 2013

mitochondrial Dysfunction: a Potential mechanism for age-related macular Degeneration lerner research institute, na1-140

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.

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.

may 16, 2013

global Blindness: Can We Control it? lerner research institute, na1-140

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

Christian Grimm, PhD

Professor for Experimental Ophthalmology Department of Ophthalmology University of Zurich Schlieren, Zurich Switzerland

nov. 21, 2013

leukocytes take Directives from the extracellular matrix in ocular infections and Inflammation 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 park-ing lot (facing the front of Cole Eye Institute) or the visitor’s parking garage at East 100th Street and Carnegie Avenue. We will vali-date your parking ticket.

CliniCal trIalsAll studies have been approved by the Institutional Review Board. the featured studies are currently enrolling.


retinal Diseases

ozurdexr for Diabetic macular edema treated with Pars Plana vitrectomy and membrane removal (oPera)

objective: This study will evaluate the use of Ozurdex in patients needing surgery for epiretinal membrane with diabetic macular edema.

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 Degenera-tion 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

uveitis

a Proof-of-Concept Study of intravitreal lFg316 in Patients with multifocal Choroiditis (mFC)

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.

Contact: Sunil Srivastava, MD, 216.636.2286, or Laura Holody, 216.445.3762

Pediatric eye Disease

htS1-glasses vs. observation for moder-ate 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 deteriora-tion 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 ophthal-mic 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 out-comes 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

CliniCal trIalscontinued from previous page

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 endo-thelial 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)

objective: This is an open-label, dose escalation, safety, tolerability and pharma-cokinetic 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.

Ophthalmology Update, a publication of Cleveland Clinic’s Cole Eye Institute, provides information for ophthalmologists about state-of-the-art diagnostic and man-agement techniques and current research.

Please direct any correspondence to:

[email protected] 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, car-ing for more than 170,000 patients and perform-ing 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


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 treat-ment Strategies for Primary open-angle glaucoma

a Phase ii Dose-ranging Study of Pazopanib to treat neovascular age-related macular Degeneration (gSK amD)

CLEVELAND CLINIC EXECUTIVE EDUCATION

learn From top healthcare executives

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.

COlE EyE InstItUtE StaFFChairman, Cole eye instituteDaniel 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 ophthalmologyJohn Costin, MD ................................................. 440.988.4040Richard E. Gans, MD, FACS ................................. 216.444.0848Philip N. Goldberg, MD ...................................... 216.831.0120Michael Gressel, MD ........................................... 440.988.4040Mohinder Gupta, MD ........................................... 419.289.6466Martin A. Markowitz, MD .................................... 440.461.4733Shari Martyn, MD .............................................. 216.831.0120Peter McGannon, MD .......................................... 216.529.5320Michael E. Millstein, MD ..................................... 216.831.0120Wynne Morley, MD .............................................. 440.366.9444Sheldon M. Oberfeld, MD ................................... 440.461.4733Allen S. Roth, MD .............................................. 216.831.0120David B. Sholiton, MD ........................................ 216.831.0120Scott A. Wagenberg, MD ..................................... 440.461.4733

Cornea and external DiseaseWilliam J. Dupps Jr., MD, PhD ............................. 216.444.2020Jeffrey M. Goshe, MD .......................................... 216.444.0845Roger H.S. Langston, MD .................................... 216.444.5898Martin A. Markowitz, MD .................................... 440.461.4733Peter McGannon, MD .......................................... 440.529.5320David M. Meisler, MD ......................................... 216.444.8102Wynne Morley, MD .............................................. 440.366.9444Sheldon M. Oberfeld, MD ................................... 440.461.4733Allen S. Roth, MD .............................................. 216.831.0120Scott A. Wagenberg, MD ..................................... 440.461.4733Steven E. Wilson, MD ......................................... 216.444.5887

glaucomaJonathan A. Eisengart, MD .................................. 216.445.9429Edward J. Rockwood, MD ................................... 216.444.1995Shalini Sood-Mendiratta, MD................................ 216.445.5277

Keratorefractive SurgeryWilliam J. Dupps Jr., MD, PhD ............................. 216.444.2020Ronald R. Krueger, MD, MSE ................................ 216.444.8158Michael E. Millstein, MD ..................................... 216.831.0120Allen S. Roth, MD .............................................. 216.831.0120Steven E. Wilson, MD ......................................... 216.444.5887

neuro-ophthalmologyGregory S. Kosmorsky, DO ................................... 216.444.2855Lisa D. Lystad, MD ............................................ 216.445.2530

oculoplastics and orbital SurgeryMark Levine, MD ................................................ 440.988.4040Julian D. Perry, MD ............................................ 216.444.3635

ophthalmic anesthesiaMarc A. Feldman, MD ........................................ 216.444.9088M. Inton-Santos, MD ........................................... 216.445.1016J. Victor Ryckman, MD ........................................ 216.444.6330Sara Spagnuolo, MD ........................................... 216.444.6324

ophthalmic oncologyArun D. Singh, MD ............................................. 216.445.9479

ophthalmic researchBela Anand-Apte, MBBS, PhD .............................. 216.445.9739Vera Bonilha, PhD ............................................... 216.445.7960John W. Crabb, PhD ............................................ 216.445.0425William J. Dupps Jr., MD, PhD ............................. 216.444.2020Stephanie Hagstrom, PhD .................................... 216.445.4133Joe G. Hollyfield, PhD ......................................... 216.445.3252Neal S. Peachey, PhD .......................................... 216.445.1942Brian Perkins, Ph.D ............................................. 216.444.9683

Pediatric ophthalmology and adult StrabismusFatema Ghasia, MD............................................. 216.444.0999Andreas Marcotty, MD ........................................ 216.831.0120Paul Rychwalski, MD ......................................... 216.444.4821Elias I. Traboulsi, MD ......................................... 216.444.2030

retinaAmy Babiuch, MD ............................................... 440.366.9444Ryan Deasy, MD ................................................. 440.695.4010Justis P. Ehlers, MD ............................................ 216.636.0183Peter K. Kaiser, MD ............................................ 216.444.6702Daniel F. Martin, MD .......................................... 216.444.0430Andrew P. Schachat, MD ..................................... 216.444.7963Jonathan E. Sears, MD ........................................ 216.444.8157Rishi P. Singh, MD .............................................. 216.445.9497Sunil K. Srivastava, MD ....................................... 216.636.2286Richard Wyszynski, MD ....................................... 440.988.4040Alex Yuan, MD .................................................... 216.444.0079

uveitisCareen Y. Lowder, MD, PhD ................................. 216.444.3642Sunil K. Srivastava, MD ....................................... 216.636.2286

clevelandclinic.org/OUSpring 15

PatIEnt reFerralSTo refer a patient to Cole Eye Institute, please call 216.444.2020 or 800.223.2273, ext 42020.


24/7 referralsreferring Physician hotline

855.REFER.123 (855.733.3712)

hospital transfers

800.553.5056

On the Web at clevelandclinic.org/refer123

Stay connected with us on …

Twitter/YouTube/Facebook

About Cleveland ClinicCleveland Clinic is an integrated healthcare delivery system

with local, national and international reach. At Cleveland

Clinic, 2,800 physicians represent 120 medical specialties

and subspecialties. We are a main campus, 18 family health

centers, eight community hospitals, Cleveland Clinic Florida,

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.

resources for Physiciansreferring Physician Center and hotline

Cleveland Clinic’s Referring Physician Center has established

a 24/7 hotline — 855.REFER.123 (855.733.3712) — to

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 ap-

pointments, for assistance in resolving service-related issues,

and to connect with Cleveland Clinic specialists.

Cole Eye Institute

The Cleveland Clinic Foundation

9500 Euclid Avenue / AC311

Cleveland, OH 44195

Ophthalmology Update

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

information about the treatment your patient receives

at Cleveland Clinic. Establish a DrConnect account at

clevelandclinic.org/drconnect.

Critical Care transport Worldwide

Cleveland Clinic’s critical care transport teams and fleet

of vehicles are available to serve patients across the globe.

• To arrange for a critical care transfer, call 216.448.7000 or

866.547.1467 (see clevelandclinic.org/criticalcaretransport).

• For STEMI (ST elevated myocardial infarction), acute stroke,

ICH (intracerebral hemorrhage), SAH (subarachnoid hemorrhage)

or aortic syndrome transfers, call 877.379.CODE (2633).

outcomes Data

View clinical Outcomes books from all Cleveland Clinic

institutes at clevelandclinic.org/outcomes.

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.

executive education

Cleveland Clinic has two education programs for healthcare executive

leaders — the Executive Visitors’ Program and the two-week Samson

Global Leadership Academy immersion program. Visit clevelandclinic.

org/executiveeducation.

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 same-

day appointment line, 216.444.CARE (2273), or 800.223.CARE

(2273).

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