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February 2007

News in Review
A Look at Today's Ideas and Trends
By Linda Roach, Contributing Writer
Edited by Brian A. Francis, MD

• Web: Rapid Feedback on Avastin’s Safety
• Stem Cell Transplant: It’s All About Timing
• Eye Exam for Malaria Can Save Kids From Death
• Controversial Treatment for ROP to Be Studied

Web: Rapid Feedback on Avastin’s Safety

The World Wide Web helped spread news of the use of cancer drug bevacizumab (Avastin) for ocular disease quickly around the globe. More recently, the Web hastened the answer to the nagging question of the short-term riskiness of this treatment. And the news is good.

Based on responses from ophthalmologists in 12 countries, an Internet-based survey found few ocular and systemic adverse events during the first few months following intravitreal injection of the antiangiogenic drug. The systemic event rates included: 0.01 percent for transient ischemic attack, 0.07 percent for cerebrovascular accident, 0 percent for myocardial infarction and 0.03 percent for death (one from pneumonia and the other in a patient with atrial fibrillation who insisted on bevacizumab injection despite the cardiovascular risk).

“In the short term, Avastin appeared to be safe, and no alarming rates of systemic or ocular events were discovered. It was reassuring to learn that despite different dosages and injection techniques among our colleagues worldwide, no real concerns have emerged yet,” said Anne E. Fung, MD, a San Francisco retina specialist and study coauthor.

A rush of bevacizumab injections around the world followed the publication in late 2005 of reports of the drug’s possible effectiveness in the treatment of choroidal neovascularization.1 As enthusiasm for the treatment snowballed, Dr. Fung and a coauthor of those early reports, together with a third colleague, appealed by e-mail to retina specialists to report side effects associated with intravitreal bevacizumab through a survey Web site.

The survey, the results of which were printed in the British Journal of Ophthalmology,2 documented 7,113 injections in 5,228 patients from November 2005 through April 2006. Doctors reported on 30 prespecified adverse events that could be treatment-related and 54 that could be drug-related—25 ocular and 29 systemic.

Dr. Fung said there are no plans to extend the survey to cover the long-term safety or efficacy of bevacizumab because of the statistical limitations of the self-reporting method. “What we really wanted to know with our survey was whether there were any acutely dangerous events occurring that we wouldn’t be able to detect quickly,” she said. “Now, a year later, prospective, long-term efficacy and safety information is important.”

For these longer-term answers, a retrospective voluntary survey isn’t enough. So she and others will be looking instead to the prospective clinical trial in which the NEI plans to compare the effectiveness of bevacizumab to that of its ophthalmic cousin, ranibizumab (Lucentis).

1 Rosenfeld, P. J. et al. Ophthalmic Surg Lasers Imaging 2005;36:331–335 and 336–339.
2 Fung, A. E. et al. Br J Ophthalmol 2006;90;1344–1349.


Research Report

Stem Cell Transplant: It’s All About Timing

The three blind mice might stand a chance of seeing again if they run into the ophthalmic-research labs of the University of Michigan and the London Institute of Ophthalmology.

It is there that teams led by Anand Swaroop, PhD, of Michigan, and Robin R. Ali, PhD, professor of molecular therapy, Institute of Ophthalmology in London, have discovered how to coax transplanted stem cells to grow into rod photoreceptors, to line up correctly in the host retina and to form light-transmitting connections to retinal ganglion cells.

At the end of the experiment, formerly blind mice showed pupillary responses to light, and their retinal ganglion cells showed responses to light stimuli.

The paper, published in Nature,1 follows years of basic research on the steps that stem cells take in their long road to becoming functioning neurons.

“This provides a clear example of how basic fundamental research can contribute to treatment of blinding diseases,” said Dr. Swaroop, who is professor of ophthalmology and visual sciences at the University of Michigan. “We now have proof of principle that our approach to repairing damaged retina by transplantation of appropriate cells can be successful.”

In their mouse experiments, the team confirmed in vivo that the secret to a perfect match between transplant and host lies in the timing. Taken from the fetal mouse’s retina too early, the stem cells continued to develop but wouldn’t line up correctly in the retina and wouldn’t form synaptic connections. They needed to be moved at the peak time of rod genesis, after the stem cells had become committed as rod “precursor cells” by expressing the transcription factor NRL.

This confirmation of a hypothesis that Dr. Swaroop has been testing, bit by bit, over several years, is adding complexity to the stem cell story that cell biologists have been telling.

There has been a fundamental belief that stem cells could differentiate into any type of cell in the body. Though that might prove true, it also has become apparent that for each ultimate type of cell there is likely a different path of precisely timed molecular signals.

If those signals had to begin in a fetus instead of a petri dish, the ethical and legal roadblocks—such as the United States’ federal ban on using fetal tissue for research—would be daunting.

Dr. Swaroop said he anticipates several years’ more research on animals and in cell culture before photoreceptor transplants might be ready for human testing. “Perhaps within the next five years we will begin to see the first steps toward retinal cell transplants for people with blinding eye disease,” he said.

1 MacLaren, R. E. et al. Nature 2006;444:203–207.


Ophthalmology World News

Eye Exam for Malaria Can Save Kids From Death

Two retinal abnormalities unique to cerebral malaria could help clinicians in the tropics quickly distinguish children made comatose by malaria from those who need treatment for other life-threatening illnesses, ophthalmic researchers in Africa have concluded.

These signs—white retinal patches commonly surrounding the foveola, and vessels discolored orange or white, mainly in the peripheral fundus—were first described in 1993. They and other nonspecific retinal features of malaria since have been documented in more than 1,000 African children, according to a study, published in the American Journal of Tropical Medicine and Hygiene.1

Nevertheless, as recently as 2004, a prospective study of Malawian children who died after a diagnosis of cerebral malaria found that 23 percent had another cause of death. The study’s authors attributed misdiagnosis to the fact that malaria is so common in Africa that it can be incidental to another serious illness.

Malarial retinopathy shows up best on a dilated funduscopic exam with an indirect ophthalmoscope, and its presence confirms that malaria is the primary illness in a comatose child. A Gambian study found that, even in the hands of an ophthalmologist, a direct ophthalmoscope showed malarial retinopathy with a sensitivity of only 73 percent, and this fell to 37 percent in physicians with no special training. With dilation and training, sensitivity rises to 95 percent.

General clinicians are reluctant to use dilating drops and lose the ability to monitor the pupil response for about two hours.

But study leader Nicholas A. V. Beare, FRCOphth, of the Malawi-Liverpool-Wellcome Trust clinical research program, said he believes that overcoming these challenges is important. “Our research demonstrates that the detection of malarial retinopathy is a much needed diagnostic tool in cerebral malaria, and can identify those children at most risk of death.”

1 Beare, N. V. et al. Am J Trop Med Hyg 2006;75(5):790–797.


Pediatrics Update

Controversial Treatment for ROP to Be Studied

Anti-VEGF molecules might not be just for adults anymore. Indeed, the early case reports are so encouraging that a small ad hoc group of North American ophthalmologists is planning a multicenter, controlled clinical trial of Genentech’s two antiangiogenic drugs against retinopathy of prematurity.

Nine centers in the United States and one in Canada will participate in the study of unilateral intravitreal injections of bevacizumab (Avastin) and ranibizumab (Lucentis), said study leader Michael T. Trese, MD, chief of pediatric and adult vitreoretinal surgery at Beaumont Hospital, Royal Oak, Mich. The study is likely to begin during the second quarter of this year, he said.

The trial grew from a trickle of case reports and small clinical studies over the last year, which reported sometimes dramatic regression of neovascularization in premature babies after bevacizumab injections. However, it still isn’t known if this would reduce retinal detachments compared with laser treatment, Dr. Trese noted.

In addition, pediatric therapy with antiangiogenic drugs must move cautiously because of safety concerns when treating children, said Philip J. Rosenfeld, MD, PhD, professor of ophthalmology at the University of Miami. Dr. Rosenfeld is cochairing a symposium in Key Biscayne this month at which researchers from Portugal and Mexico will report on bevacizumab in ROP.

“Based on the anecdotal data, I don’t think there’s any doubt that this approach works to cause regression of the neovascularization. The preliminary data that I’ve seen look very encouraging,” said Dr. Rosenfeld.

“But with children the risk/benefit calculation is different. There’s a heightened concern regarding the safety of these drugs in premature infants. It’s a very different equation when you are dealing with babies, but one that needs to be studied and understood.”