Spring/Summer 2002

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Medical Updates

Repairing a Deadly Deformity in a Five-day-old

Philippe Gailloud points to the abnormal blood vessels in the brain that threatened the life of Joshua Holley.
Philippe Gailloud points to the abnormal blood vessels in the brain that threatened the life of Joshua Holley.

Sharese Holley was 36 weeks into her pregnancy when a sonogram detected a tangled web of abnormal blood vessels deep in her baby's brain. The condition had a name that sounded more biblical than medical. It was called the Vein of Galen Malformation. Left untreated, doctors told Holley, these snarled vessels steal vital blood and oxygen meant for the heart and lungs, making it likely the baby will develop pulmonary hypertension and heart failure and die soon after birth. Surgeons could try to clip the malformation and restore normal blood flow, but the operation requires retracting the newborn's tiny, jello-like brain. And that poses a high risk of death from bleeding.

"It's a devastating disease," acknowledges interventional neuroradiologist Philippe Gailloud. "If you do nothing, 95 percent of these babies die. If you operate, you only reduce the mortality to 85 percent."

Holley heard only one piece of news that gave her hope. A new, less-invasive catheter approach at Hopkins—which embolizes (clots) these malformations—now brings the chance of survival for these babies up to 50 percent. Her team of doctors however, agreed they wanted to wait as long as they could after the baby was born so it would be strong enough to withstand the procedure. An infant's arteries are so tiny and fragile and its blood supply so minuscule that even this catheter approach poses risks of bleeding, clotting, stroke and death.

Sharese Holley gave birth to a baby boy on a gray morning last November and named him Joshua. He came out with the worst case of pulmonary hypertension neonatal specialist Chris Lehmann had ever seen.

"We were in a bind," Lehmann says, "because this child was very sick, very unstable and on maximum ventilator support. We decided we had to do something, but even the trip to the cath lab was going to be risky."

Joshua was just five days old when he was wheeled into the cath lab. But because his umbilical vein was still intact, Gailloud saw a way to make the procedure a bit less perilous. Rather than inserting the catheter through the femoral artery in the leg, which can easily cause a clot and the loss of the leg in newborns, Gailloud inserted the tiny catheter through Joshua's belly button and into the vein. He then threaded the catheter to the aorta and carotid arteries up to the choroid-branch artery in the brain that feeds the malformation. Then, he injected a fast-drying super-glue that would clot quickly and block most of the blood flow into the Vein of Galen.

"If you completely close off the artery, the baby will die from a massive stroke because of an enormous increase of pressure on blood vessels in the brain," Gailloud explains. "The safe approach is to do this in stages."

Stage one stabilized Joshua, for a week. Then, his pulmonary hypertension worsened again, causing tremendous swelling in his lungs and body. "I pretty much told Mom that we didn't expect him to live," Lehmann remembers.

But Gailloud wouldn't give up. Once more, he inserted the catheter, this time through the femoral artery in Joshua's leg. Again, he embolized the artery, leaving one feeder vessel into the Vein of Galen to minimize blood pressure. And this time, within 48 hours, Joshua's swelling faded and his blood pressure plummeted. A week later, there were no signs of pulmonary hypertension, and he was taken off the ventilator.

Pediatric neurosurgeon Tony Avellino is unequivocal about what saved Joshua Holley's life. "What Philippe did," he says, "was remarkable. If we hadn't had access to this approach, the child would have died."

Gary Logan

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The Next Wave in LASIK

Wavefront LASIK, says Terrence O'Brien, removes the subtlest of aberrations on the eye's surface.
Wavefront LASIK, says Terrence O'Brien, removes the subtlest of aberrations on the eye's surface.

In the years since LASIK surgery first hit the national scene as a way for people to reduce their dependence on glasses, Terrence P. O'Brien has become an expert in performing the laser procedure. These days, though, the ophthalmologist is getting better results than ever in improving people's vision. A new technique called wavefront custom-guided corneal ablation, that's still in an experimental stage, is allowing him to detect and reshape the surface of the cornea to correct variations which conventional lasers miss. The wavefront procedure compared with the earlier technique, O'Brien says, is like painting spots on a wall with a fine brush instead of a paint roller.

As remarkable as the human eye is, subtle aberrations like astigmatism still produce blurred vision. But beyond these easy-to-spot anomalies, even people with near-perfect vision can have flaws that are nearly impossible to detect. With the new technique, O'Brien captures these patterns, obtaining a precise map of the wavefront pattern of the eye and even distinguishes "good" waves from "bad" ones. He then programs the patient's own prescription into the laser and applies a new computerized component called variable spot scanning—his paintbrush—to carry out the customized surgery.

"Rather than just treating a shape, the laser can now carve a lens into the cornea that's customized to an individual wavefront pattern," O'Brien explains. "It gives us the potential to achieve super-normal vision."


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When an Autopsy Makes Sense

When a 79-year-old Baltimore County woman died a few months ago, her doctor had no doubt that the cause was acute peritonitis. But the woman's family wanted to know more. Precisely where had the lethal inflammation of the lining of the abdomen originated? Had Alzheimer's, which can be hereditary, caused the dementia she'd suffered from over the past decade? And what had years of heavy smoking done to her lungs?

Brain tissue specimens, says pathologist Barbara Crain, can reveal whether a patient's dementia was related to a hereditary form of Alzheimer's disease.
Brain tissue specimens, says pathologist Barbara Crain, can reveal whether a patient's dementia was related to a hereditary form of Alzheimer's disease.

The woman had died at home, but because she had been an inpatient at Hopkins within the past year, her family was able to have an autopsy performed there free of charge. The examination produced quick answers. Pathologists found that the peritonitis had developed from an inflammation of a diverticulum, or abnormal outpouching, of the colon just above the rectum. The lungs, surprisingly, showed no signs of bronchitis or emphysema. And almost unexpectedly, the patient had significant coronary artery disease and a gallstone. The dementia, according to microscopic examinations of slices of atrophied brain tissue, indeed appeared to be Alzheimer's.

"Alzheimer's has a hereditary component, and families are tremendously worried they're going to get it," says pathologist Barbara Crain, director of Hopkins' autopsy service. They want to know when a relative has the condition. But Crain says relatives request autopsies for all sorts of reasons. Some need "closure" by finding out the exact cause of death. Others want to learn which conditions beside the obvious their loved one was afflicted with. They also want to understand the complications caused by the terminal disease, or even if treatment may have contributed to death.

But autopsies also have an educational component, Crain stresses. "The examination can reveal conditions like cancer, thyroid disease or more heart disease than anyone realized. Such knowledge helps both the family and the physicians who are managing their care."

And yet, because patients today tend to die at home or in a hospice rather than in a hospital, many families aren't even aware they can request an autopsy. Across the nation, the number performed each year has plummeted, depriving both families and physicians of often-vital information.


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A New Approach to a Rare Blood Cancer

Oncologists generally use a fairly standard approach to prolong life in patients stricken with the rare but lethal blood cancer multiple myeloma—in which plasma cells grow out of control and produce tumors in the bone marrow. High doses of chemotherapy kill the cancer cells and a subsequent stem cell transplant replenishes the damaged bone marrow. But as any oncologist knows, stem-cell transplants pose their own threats. The allogeneic variety, which use stem cells from a donor, come with the risk of graft vs. host disease. Autologous transplants, in which patients receive cleansed marrow that they themselves have donated earlier, don't pack the same punch.

When Ralph Walker learned, therefore, that he had this usually fatal cancer, he approached the problem systematically, just as he would a project in his managerial position at the International Monetary Fund in Washington, D.C. Walker collected information, then implemented a plan that looked like it would get results and also minimize risk. The method led him straight to Johns Hopkins, where two oncologists, Ivan Borrello and Hyam Levitsky, had recently added a new twist to conventional multiple myeloma treatment.

The method uses an autologous transplant to help the transplanted stem cells kill cancer cells. Additionally, both before and after bone marrow transplant, patients receive an injection of an anti-tumor vaccine. Animal studies by Borrello have shown that the vaccine—which actually consists of a mix of the patient's own tumor cells retrieved from a bone marrow harvest, and a cell line that produces GM-CSF, a protein known to stimulate the immune system—offers better anti-tumor protection.*

"The protocol was tailor-made for the kind of procedure I was looking for," Walker says. "It wasn't like I was putting all my eggs in one basket. And the risk seemed low."

While it may take years to see the net results of their vaccine therapy, Borrello and Levitsky will begin measuring the "tumor responsiveness" of new cells in patients like Walker. "Our main focus is to show that patients' immune cells that initially were dormant are suddenly responsive," Borrello says. "If we can increase the therapeutic benefit of the autologous transplant, we can potentially make an impact on this disease."

* Some of this research has corporate ties. For full disclosure information, call the Office of Policy Coordination, 410-223-1608.


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Constructing the Vaccine

When Ivan Borrello joined Hyam Levitsky's lab in 1996, his immediate goal was to try to come up with a vaccine for multiple myeloma. He decided to take a different tack from what other researchers were using. Rather than give the preparation to patients as an individual therapy separate from their chemotherapy/bone-marrow-transplant treatment, he would add the vaccine to the transplant regimen. He accomplished this by harvesting cells directly from the tumor site, irradiating them so they wouldn't cause further harm, and then mixed them with the cells from the protein GM-CSF that stimulates the immune system to make the vaccine. Other researchers had been inserting the GM-CSF gene directly into patients' tumors.

Using mouse models, the method worked. Mice injected with the vaccine responded by producing a "massive expansion and activation" of tumor-killing cells early after bone marrow transplant.

A lot of people had their doubts about the technique, Levitsky admits. "They'd say 'You're going to try and raise an immune response in someone who has just had their entire immune system wiped out? There's not a chance.'"

"We shared that concern," Levitsky says. "But at least in animals, Ivan has shown us that when the immune system is being reconstituted is actually a good time to generate and enhance immune responses. That idea is now catching on."

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Does Cardiac Bypass Induce a Cognitive Slump?

Ola Selnes documented troubling neurologic changes in some patients.
Ola Selnes documented troubling neurologic changes in some patients.

My life was suddenly changed by unanticipated coronary bypass surgery." So writes David Metcalf, an articulate physician from Montana who, at age 80, went for a routine stress test following mild shortness of breath, then learned his coronary arteries were partially blocked. A week later, Metcalf underwent coronary artery bypass grafting (CABG).

"My medical intuition and good sense led to the surgery... but now I am brain-damaged!" he wrote in a letter to Hopkins neurologist Ola A. Selnes.

Selnes and his colleague Guy McKhann have devoted nearly a decade to finding if CABG is linked to the cognitive changes Metcalf and others report.

"I'm just not the same!" is a common cry. Metcalf's letter describes "vague, difficult-to-specify neurological and perceptual alterations." He turns the wrong way en route to his bedroom. He cracks dishes in putting them away: "My aim seems to have left me," he says.

Nearly a third of CABG patients experience a cognitive slump right after surgery, the two neurologists have shown, with short-term changes in perception and memory. Most gradually improve in the ensuing year. But in their Archives of Neurology study reported last spring, Selnes and McKhann documented troubling longer term changes. Using a battery of tests sensitive to different brain regions, they followed 102 patients prior to CABG and then at 1 month, 1 year and 5 years post op. A decline in performance between one and five years suggests some bypass patients do experience late-developing cognitive problems. Is it the CABG? Anesthesia? Aging? Selnes talks about the findings:

Your study has no controls. Is that a problem?

Yes. Definitely. Our patients' decline five years after surgery was intriguing, but we couldn't say if that's from the procedure itself or normal aging in a population saddled with the hypertension, diabetes or high cholesterol typical of bypass patients. These things by themselves can hurt cognition.

So we've moved on to a new study—one using newer "off pump" bypass surgery as a control. The heart keeps beating: there's no heart-lung machine. We're also following patients with coronary artery disease who've had no surgery. That may help us pinpoint what's amiss."

A recent Duke University study also followed patients for five years, using cognitive tests. It, too, showed a later decline. But your work teased out the nature of that loss. Why's that important?

We'd hoped the breadth of our cognitive testing would shed light on the mechanism of the decline. And the results are suggestive. Visuo-spatial ability—a sense of direction, for example—and speed of processing declined significantly. It turns out these cognitive areas are also vulnerable in patients with hypertension, diabetes or other risks for cerebrovascular disease—surgery or not.

Does vascular disease underlie the late cognitive decline in CABG patients? If that's the case, you'd expect to see that patients without cerebrovascular risk factors have few cognitive problems.

Some recent studies seem to confirm this. So the explanation for later decline may not be so simple as we'd thought: you can't just say, for example, 'It's the heart-lung machine.'"

Do you have a "take-home" message for physicians?

No! It's too early to recommend anything different. My personal fear in publishing our study was that people would say, "I don't want this surgery because I don't want to lose my mental abilities." But, really, the incidence of late cognitive change after cardiac surgery is relatively low. The Duke study says it's 40 percent, but our estimates are much lower."

To say Dr. Metcalf felt unprepared for the changes is an understatement. An air of betrayal lingers in his letter. Comment?

As patients become more educated, they need realistic discussions with their clinicians about benefits and potential problems. Look at Dick Cheney with his choice of angioplasty, varieties of stenting, off-pump surgery. At some point, however, a patient's decision will probably boil down to a quality-of-life issue. These decisions are tough.

Marjorie Centofanti

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The Eureka Facilitator

Deep in the bowels of the Physiology Building, scientists witness what they have only suspected.

Doug Murphy packed up his own cellular biology lab to become full-time director of the Microscope Facility.
Doug Murphy packed up his own cellular biology lab to become full-time director of the Microscope Facility.

The idea of resounding yelps coming from the somber basement corridors of the Physiology Building may seem peculiar, but such outbursts don't surprise Doug Murphy. In his three years as director of a School of Medicine service known as the Microscope Facility, located in a special nook down in those subterranean parts, he's heard a good many triumphant Eurekas! "Important discoveries take place here all the time," Murphy says, because in this lab, with its armament of microscope technology, scientists frequently witness in front of their eyes what they only suspected was taking place in a test tube.

Here, for instance, psychiatrist Christopher Ross's lab confirmed exactly where in a cell the critical proteins that cause Huntington's disease could be found. (That discovery was announced first in Science.) One of oncologist Stephen Baylin's graduate students also left the Microscope Facility last year with a new piece of knowledge: "It was the first time," Baylin says, "we began to understand how key proteins interact to silence genes abnormally in cancer cells. We knew we were onto something big."

The fact is, the technology in this isolated corner of the basic sciences complex goes far beyond anything that many scientists might even imagine. The site boasts two confocal microscopes that offer rare views of an interior layer of a specimen without destroying any of the surroundings. There are two scanning electron microscopes, a transmission electron microscope and a fluorescence imaging laboratory, all essential tools for tracking down the whereabouts of elusive molecules. The techniques keep getting smarter: This winter, the facility acquired a deconvolution microscope. Like a standard confocal microscope, this piece of equipment can home in on a tiny slice within a specimen and then, through a series of computerized calculations, re-construct a view of surrounding layers that would otherwise be out of focus.

The Microscope Facility is a core resource, where scientists share equipment that would be far too expensive for any one lab to afford. This kind of pooling happened as far back as 1989, but three years ago, with funding from the basic science directors and the dean's office, the facility expanded to 2,000 square feet and began vaunting its technological capabilities. It earned NIH grants to purchase the latest, most sought-after equipment. Meanwhile, Murphy, a cellular biologist, packed his own lab into cardboard boxes and put his research in limbo in order to become the full-time director.

"I saw it as a challenge," he says, "to provide a site for the entire School of Medicine that would be absolutely cutting-edge."

Today, the Microscope Facility is used by researchers from more than 150 labs, as many as half of whom are from clinical departments. Scientists sign up in advance for a time-slot on a particular machine and pay by the hour.

Getting a good view of a biological phenomenon, however, is a learned craft. Murphy, who's recently published a textbook on the fundamentals of microscopy, offers graduate students, fellows and faculty three eight-week courses in using the 'scopes. He covers everything from choosing the appropriate technique to interpreting the images. The course even touches on the ethics of microscopy.

"It's possible," Murphy cautions, "to enhance an image in such a way that you're overstating what you think you see."

But the real punch behind the facility is the staff: Mike Delannoy, Carol Cooke and Brad Harris. Working with researchers individually, these microscopy specialists show them how to puzzle through their imaging problems. Even some of the best wet-lab scientists have botched the preparation of a specimen by using a fixative that happens to destroy the structure they want to see or a less-than-optimal antibody-tagging technique to mark a particular protein.

Cooke, an immuno-electron microscopy expert, says that each investigation comes with a new twist. Jeremy Nathans' molecular biology lab, for instance, had cloned a protein but struggled to get a good look at how it affected a layer of photoreceptor cells in the retina. The images weren't definitive. But Cooke had heard about a light-weight gold-tagging formula and found that it bonded well to the protein and created the appropriate shadow effect necessary to make the molecules visible. Suddenly, the distribution of protein across the cells was visible. Those images were published in Neuron.

The facility is still developing. The hottest, new programs for fluorescence microscopes (known as FRET and FRAP) are currently being installed. Meanwhile, an NIH grant that hangs in the balance may provide funding for an additional transmission electron microscope with highly specialized capabilities.

"We have to stay on top of the technology," Murphy says. "I'm constantly thinking, "Are we cutting-edge? Do our scientists have state-of-the-art equipment? A topnotch facility can really catapult research."

Kate Ledger

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Ferreting out the Hidden Tumors of a Rare Bone Disease

People with the rare bone disease oncogenic osteomalacia have the worst of both worlds. It may take years before their condition—marked by tiny, noncancerous tumors that hide out and wreak havoc on the skeletal system—is correctly diagnosed. Then more years can go by before physicians can precisely locate the tumors and remove them. Meanwhile, patients suffer debilitating bone pain, fractures and muscle weakness."Removing the tumors completely reverses the condition," says endocrinologist Suzanne M. Jan de Beur, "but because they are small, slow-growing and frequently located in unusual sites, conventional imaging techniques often fail to detect them."

Suzanne Jan de Beur has come up with an imaging technique for diagnosing patients with oncogenic osteomalacia.
Suzanne Jan de Beur has come up with an imaging technique for diagnosing patients with oncogenic osteomalacia.

Now, in a study supported by the National Institutes of Health, Jan de Beur and colleagues have found a way to smoke out most tumors from their hiding places. Knowing that the tumors express the receptor for the hormone somatostatin, they injected patients with a radioactive agent called pentetreotide, which binds to the same receptor. After 48 to 72 hours, they used gamma X-rays on each patient, looking for signs of radioactivity. The technique correctly pinpointed the tumors' locations in five of seven patients studied.

"Our findings suggest that pentetreotide imaging is a good initial test to assess people with oncogenic osteomalacia, and also can be used as a diagnostic screening tool for patients with similar symptoms," Jan de Beur says.

Oncogenic osteomalacia disrupts metabolism when the tiny tumors secrete a chemical that prevents kidneys from absorbing phosphate, a major component of bones. There are only 100 or so cases reported in the medical literature, but Jan de Beur thinks the condition is underdiagnosed. She personally has seen nine patients in the past four or five years. Too often, she says, the condition is missed or mistaken for arthritis, bone cancer or even emotional stress. Patients are left to endure pain that could have been prevented.

In the study, pentetreotide imaging identified tumors in such varied places as the sinus cavity, the groin and the arm. One patient plagued with bone fractures for years was found to have a tumor between the thumb and forefinger of his left hand. It was removed in an outpatient procedure, and he felt better within weeks.

Karen Blum

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