Spring/Summer 2002

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Elliot Fishman's Newest Image-maker

Elliot Fishman
Using 16-slice CT, Elliot Fishman picks up narrowing in arteries that conventional imaging could miss.

Watching radiologist Elliot Fishman manipulate 3-D images of the human ana-tomy on a computer screen is kind of like seeing a 9-year-old navigate the latest Nintendo game. He's into it, deeply. "Look at the detail, the resolution, the volume of the organ," Fishman enthuses as he points at the screen. "This is spectacular."

Fishman's apparatus, however, is no video game. It's a $1.5 million, 16-slice CT, the newest scanner in computed tomography, and it provides images of organ systems and their arteries and blood vessels, never before seen. Indeed, so sharp and illuminating are these images that Hopkins radiologists now are using them to make better decisions about treatment for every bodily organ.

With cardiac patients, for instance, the images can provide a better diagnostic tool than conventional angiography in looking for plaque or obstruction in the coronary arteries. The new scanner proves superior for several key reasons: The technology is faster, non-invasive, safer and less expensive, and provides more views from which to detect the disease.

"See how sharp the vessels are?" Fishman asks. "That's due to two advantages: the thin sections, which 16-slice CT gives you, and the infinite views. With conventional angiography, you only get one or two different projections."

Fishman uses a mouse to rotate, slice and travel through the 3-D images of vessels and organs, which allows him to detect the very earliest signs of disease. He can pick up narrowing in arteries around the heart, kidney and other organs, and also stage malignant tumors and their spread more accurately. That in turn helps surgeons make better decisions about treatment.

"In every pancreas, every liver, the surgeon wants to know if there's vessel invasion," Fishman says. "So we do CT angiographic maps of all these kinds of patients. The maps are key in determining whether they should have surgery, what type of surgery, and whether they should have chemotherapy at the end."

-Gary Logan

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Robots Can Help Diagnose Kidney Disease

Robotics are not new to needle biopsy procedures. Using a joy stick to deftly manipulate a robotic arm under X-ray guidance, surgeons have been able to obtain tissue specimens they often miss in conventional biopsy techniques. That works fine for fixed organs like the prostate or spine, but target a tiny tumor deep inside a moving organ like the kidney and it's like trying to thread a needle, blindfolded.

"You image the kidney and say, Put the needle here," says endourologist Thomas Jarrett, "and by the time the robotic arm carries out the task, the organ may have moved."

No more. By linking a robotic device developed at Hopkins with real-time CT imaging, Jarrett and other surgeons are able to do a biopsy on the smallest lesions in a moving organ. That's because the device, called PAKY, or percutaneous access to the kidney, is able to lock on a moving target, much like a laser-guided missile.

"The robotic arm moves with the kidney, following the tumor no matter where it goes," Jarrett says. "It makes sense that if you can deliver your needle more accurately, you'll have better sensitivity and better results."

And that means more accurate staging of the tumor and the most appropriate treatment plan for the patient. Also, patients experience less bleeding with this biopsy approach, and less risk of injury to adjacent organs. While PAKY is currently limited to use in biopsies, in the future it may be used in ablative therapies to destroy cancer cells, or even in high-dose radiation therapies.

-Gary Logan

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Growing Cartilage for Injured Knees

Lauren Dulay
Lauren Dulay, all mended, is back on the team.

As softball pitchers go, the Dulay girls were luminaries. Kristin, the oldest, starred for Seton Keough High School in Catonsville, Md., and it earned her a college scholarship. Lauren, her younger sister, looked every bit as good by the time she was 14 and hoped for the same payoff. Then, during a game in September 2001, Lauren's left knee locked in place and she was hit with pain so severe she was certain she'd broken her leg. An MRI showed a much more complicated problem.

Lauren had damaged the thin layer of cartilage that decreases friction and weight-stress on the knee joint and acts as a sort of shock absorber. But because cartilage has no direct blood supply, this kind of injury can't heal itself. What's more, although conventional surgery can temporarily relieve the pain, about 60 percent of these patients need additional surgery within five years.

Lauren's physician held out one hope. He'd heard that a Hopkins orthopedic surgeon named James Wenz was using a new approach for Lauren's problem. It went by the rather unwieldy name of "autologous chondrocyte transplantation." Wenz would harvest cartilage cells (chondrocytes) from a patient's knee and use them to grow new cells that he would then implant into the damaged knee. The procedure had given relief to about 80 percent of people with this problem.

"We were nervous and scared," admits Lauren's mother, Kathleen, "until Dr. Wenz told us about the procedure."

Lauren would first undergo a standard arthroscopy, in which Wenz would insert a tube with a tiny camera into her knee to examine the defect. If she was a candidate for the transplantation, he'd use the same tube to extract healthy cartilage cells and send them for cultivation to an outside laboratory for two or three weeks until they'd produce up to 15 million chondrocytes. At that point, in surgery, he'd trim Lauren's existing knee cartilage, patch it with a section of the fibrous periosteum tissue that covers bone, and suture a pouch onto the patch. He'd then inject the harvested cells into the pouch, and over the next few months they would grow new cartilage.

Lauren turned out to be the perfect candidate for autologous chondrocyte transplantation. She underwent the procedure in March 2002, and then spent six months rehabilitating. Today, she's in her uniform at Seton Keough training for the spring softball season. "There's no pain at all," the teenager says nonchalantly.

Her mother is less blasé. "Remarkable!" exudes Kathleen Dulay. "Looking at X-rays, you can't even tell there was a defect. It's absolutely unbelievable."

- Gary Logan

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Spacing the Knee

At age 44, Curtis Taylor didn't know what to do about his knee. He'd injured it years before playing football, and now it had an unfortunate tendency to pop painfully out of place, often while he was driving. Taylor would have to stop the car, get out and stand there until the knee slid back into place. Surgery hadn't fixed the problem, and an artificial knee wasn't an option for younger patients like him. Those devices have to be replaced every 10 or 15 years, each time with more complex surgery because of the repeated cutting of bone. "It was either live with it or have something else done," Taylor says.

Then, while driving one day in June 2002, Taylor turned on the radio and heard orthopedic surgeon Marc Hungerford talking about a device, called the UniSpace. Hungerford portrayed it as an alternative to knee replacement. The chrome, dishlike device floats in the space between the two main bones in the knee, stretching damaged ligaments back to their normal position, and providing a smooth surface on which the bones in the knee can glide painlessly. Inserting the device required only a 3-inch incision. Existing bone wouldn't have to be cut, so future knee-replacement surgery wouldn't be compromised.

A month later, Taylor had the device implanted. Today, his knee has stopped popping, and he's also back playing sports, for the first time in years.

- Gary Logan

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How a Turned-on Protein Triggers Breast Cancer

One phone call from a colleague at a pharmaceutical company a couple of years ago was all it took for Dan Leahy to embark on a laboratory project that's now yielded a bunch of successes. Leahy's colleague was trying to understand the workings of HER2, a protein involved in 20 percent to 30 percent of breast cancers. He'd called Leahy, a School of Medicine structural biologist, with a question. Would he be interested in giving researchers an image of the potentially lethal protein-in other words, in solving its structure? Like any scientist with insatiable curiosity about how things function, Leahy's response was, "Why not?"

HER2 is an unusual member of the family of epidermal growth factor (EGF) receptors found in the tissues in every adult human body. And like all EGF receptors, it plays a vital role in embryonic development. Normally, such receptors become active when a signal from the cell's exterior releases their safety catch and partners them up with another family member. But what's long bewildered scientists is why HER2 activates without a signal. And why a simple overabundance of HER2 leads to breast cancer.

Today, the Leahy lab in Biophysics and Biophysical Chemistry not only has analyzed a large chunk of HER2's structure, it can explain how the protein causes breast cancer. HER2, it seems, unlike all other EGF receptors, is missing its safety catch. That one deficiency leaves it perpetually turned on and ready to pair up with other receptors. Normally, such a characteristic wouldn't present a problem because only limited amounts of HER2 are available. It's when there is an overproduction that the trouble-breast cancer-occurs. In excess, HER2 promiscuously pairs up with other receptors and also with itself, causing everything to misfire chaotically and create the malignancy.

Besides learning all this, the Leahy lab has determined one more thing: the structure of HER2 when it binds with a drug called Herceptin, used annually by approximately 30,000 breast cancer patients. That contribution alone has been manna to pharmaceutical companies. For the first time, drug manufacturers see exactly how Herceptin is able to combat breast cancer and can begin to identify other parts of HER2 that might be targets. As for Leahy, when he speculates on all that's resulted from a casual phone call, he's, well, quite pleased.

- Raj Mukhopadhyay

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Opening Sinuses through the Nose

When Julia Yablonski's doctor told her she needed major surgery to unblock her frontal sinus, what bothered her was that the incision would be through her face. The 66-year-old Gainesville, Va., woman shuddered at the thought of how she might look afterward. An Internet search for another opinion led Yablonski to Andrew Lane, a head and neck surgeon at Johns Hopkins.

Lane agreed that the passageway into Yablonski's sinus needed enlarging and bottlenecks removing. But he could do the job without opening Yablonski's face. He would thread an endoscopic tube through her nose to the sinus.

A high-tech mapping system that lets him see sinus structures that normally could be viewed only in open surgery is what allows Lane to use this approach. Called stereotactic computer-assisted surgical navigation, the system is like a global positioning system. Stray too close to the thin layer of bone between the frontal sinus and the brain with an endoscopic tool and warning lights on a computer screen put the surgeon safely back on course.

"The frontal sinuses are considered high-price real estate," Lane observes. "You've got the brain above and the eyes to the side. It's very important to know precisely where you are."

But the real bonus of the endoscopic approach is that it reduces the risk of internal scarring--the enemy of sinus surgeons. Tear the lining of a sinus or expose bone and the scarring that results can clog sinus passageways as soon as they've been reopened. "It pays to get the surgery done right the first time," Lane emphasizes. "Once you start this process of scarring, it's impossible to undo."

Left untreated, Lane says, Yablonski's sinuses would have continued to drain improperly and would probably have resulted in a buildup of bacteria and recurring infections. Today, her problem is gone. And with the enlarged opening, antibiotics can now reach Yablonski's sinuses and combat her underlying tendency toward sinusitis.

-Gary Logan

Help for the Most Disfiguring Cancer of All

Patrick Byrne
Patrick Byrne with his 3-D polymer model of the patient's skull.

The 32-year-old patient had suffered a devastating malignancy in her nasal septum. What the cancer had not disfigured, repeated operations to rid her of the disease had. One of her cheekbones and one eye socket were missing. So was a significant portion of her nasal bone. With nothing to support them, her eye and nose flopped down to her mouth.

"Many of the options that you would normally use to reconstruct the face couldn't work here," says head and neck surgeon Patrick Byrne, "because we had nothing on the face with which to hold up the nose and eye."

Fortunately for this patient, new materials and surgical techniques are now making it possible for a surgeon like Byrne to reconstruct even as severely damaged a face as hers. Byrne first created a three-dimensional CT plastic polymer model of the wo-man's skull and used it to discern the exact topography of her facial bone and cartilage. The model provided him with precise landmarks as he performed microvascular surgery, transferring bone, muscle and tissue from rib grafts to fill the erosions. "It gave us a much more accurate idea of the defect we were dealing with," Byrne explains. "It also allowed us to select the best bone graft for restoring the face."

In such cases, though, the risk that the cancer will return is high, and Byrne normally waits a year before rebuilding a patient's septum with rib grafts. But that lapse means leaving the person with the terrible facial disfigurement for that time. Now, a new approach using a dissolving facial sheath is making it possible for Byrne to reconstruct the septum while the patient is being monitored and treated for any cancer spread.

The technique works like this: In the initial surgery, Byrne replaces the septum with a novel polymer plastic sheath that will be absorbed by the body in 12 to 18 months. By heating the sheath, he is able to mold it into the shape of the patient's natural septum. He then attaches bone chips to the scaffold, which slowly bond to the sheath, replacing the sheath as it is absorbed. To feed blood to the bone, he tunnels forehead muscle beneath the skin to the inside of the nose.

Using this approach, Byrne recently was able to allow a 32-year-old woman to undergo a full course of radiation therapy after her face had been reconstructed. "These disfiguring cancers are incredibly depressing for patients," Byrne says. "This new method of reconstruction prevents one more year of horror."

-Gary Logan

FDA Gives Chemo-Wafers the Go-Ahead for Brain Tumors

Henry Brem
Henry Brem and the dime-size wafer.

The FDA has just given its much-awaited OK to localized chemotherapy as a "first crack" at malignant brain tumors. The method relies on a dime-size polymer wafer-laced with the chemotherapeutic agent BCNU-that releases the drug onto malignant cells.

"When you apply therapy directly where it's needed, you minimize whole-body side effects that would otherwise keep you from using something so potent," says Neurosurgeon in Chief Henry Brem, who developed the technique. "We've seen that quality of life improves when we can combine the implants with surgery," adds Alessandro Olivi, head of neurosurgical oncology.

Surgeons using the Gliadel wafer first remove a tumor, then blanket the newly exposed brain surface with several of the slender disks. This area is often a "gray zone," still hiding cancer cells beyond surgery's reach.

A recent Phase III study of 240 patients showed the wafers plus follow-up radiation do indeed extend life. Five times more patients cross the three-year survival mark with wafer treatment than without it.

Gliadel technology for brain tumors has been available for some patients since 1996. But until February, the FDA had given its stamp only for recurring, highly invasive glioblastoma multiforme tumors following surgery. Now its use is expanded to all patients with primary malignant brain tumors.

And, most important, patients can get the therapy when they're first diagnosed.

-Marjorie Centofanti

Big News for the Hay fever Crowd

Instead of going through years of shots that can only marginally reduce their runny noses, sneezing, nasal congestion and itchy, watery eyes, hay fever victims may soon be able to receive just six shots in six weeks to gain relief from their allergy problems.

Last year during peak ragweed season, School of Medicine asthma/allergy specialist Peter Creticos led a clinical study of a new drug called AIC (Amb a 1 - ISS Conjugate)* and found that 25 adults with chronic, severe ragweed allergy showed a dramatic reduction in their hay fever symptoms and their need for allergy medication compared with patients who received a placebo. The new treatment nearly eliminated the need for antihistamines and decongestants.
For those who like a scientific explanation of how a medication works, the treatment was created by attaching immune-boosting molecules, or oligonucleotides, to the major ragweed protein responsible for allergic reactions (Amb 1 a).

Creticos was especially pleased when he did a second-year follow-up of the patients who'd been in the original trial. He found that their initial six-injection course of treatment appeared to be effective through more than one allergy season. Now, on to FDA approval of the drug, a step that usually takes several years.

- Trent Stockton

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

A Roadblock to Autoimmune Diseases

Lynn Castro pulls her weight; Dan Drachman verifies
Lynn Castro pulls her weight; Dan Drachman verifies

Since her early 30s, Lynn Castro, now 38, has lived under an autoimmune cloud. "I could cope with the rheumatoid arthritis or lupus," she says. "But I thought the myasthenia gravis might kill me." Castro had an intense, focused form of MG that so diminished her ability to breathe she'd faint from low oxygen. Ambulance crews knew her; she was on monthly plasmapheresis, IVIg therapy, a nighttime ventilator and such a steroid regimen she had cataracts. "I worry you might not make it to the ER in time," her Alabama neurologist confided.

So Castro jumped at a suggestion from neuroimmunologist Daniel Drachman, to "reboot" her immune system. It's an experimental approach that, in theory, cures or mitigates the disease by erasing immune instructions gone awry. Specifically, it knocks out the mature immune system, including theB cells that create MG's hallmark antibodies against nerve cell receptors.

"We call it a 'clean-slate therapy,'" says Drachman.

Earlier, Drachman had cleared the way for the therapy with studies on rat MG models. Rats received the drug cytoxan to destroy immune cells in bone marrow, then tissue was renewed via a bone marrow transplant (BMT). The animals became healthy, by all measures.

"But we thought that therapy too drastic," says Drachman, "and let it sit." Recently, however, oncologists here discovered that-thanks to a protective enzyme-cytoxan can't destroy the very hematopoietic stem cells that regenerate the immune system. There's no need for higher-risk BMT.

Clinicians here have successfully treated aplastic and hemolytic anemia and, recently, lupus with the rebooting technique. Drachman's patients-he's now done four under experimental protocol-are the first for myasthenia gravis. "The beauty of MG," he explains, "is that it's mostly reversible if you can get rid of the antibodies."

Within three months of Castro's cytoxan infusion, her symptoms disappeared. She began kickboxing lessons and took her family to Disney World.

Rebooting the immune system doesn't necessarily eliminate all autoantibodies, Drachman cautions. Patients still produce some. And because of risks, mostly of infection, the technique's only for serious cases that resist conventional treatment. But several years out, muscle strength and function are vastly improved. The need for immunosuppressive drugs is minimal, and all four patients are active again. Says Castro, "I'd lost even my sense of what a normal life was. Now everything's back."

-Marjorie Centofanti

Consultation with Arthur Burnett

Arthur Burnett

A urologist who has studied erectile dysfunction for almost a decade talks about treatments and his search for a cure.

What's the most exciting development?
New oral agents, that will probably receive FDA approval imminently. Some are already available. They're basically in
the same class as Viagra.

How are they different?
Some are staying in the body much longer than Viagra. One study shows that patients were still getting a pretty good response 24 to 36 hours after taking the drug. So there's a little more opportunity to have some romance. You don't have to be rushed.

If they're in the body longer, doesn't that mean any side effects will be stronger, too?
With Viagra, about 16 percent of men experience headaches, 10 percent facial flushing, another 10 percent indigestion, and 4 percent visual disturbances. It's puzzling, but studies of the new longer-lasting agents show that these side effects aren't any more significant.

The new oral therapies are better?
Whether they're more effective or not, we'll have to see. Also, you have to remember, these agents are not a cure. Restoring normal function is not what these pills do. They are still just temporary interventions.

So what's the answer?
The cure may lie in nerve and tissue regeneration. We now know that a whole host of neurotransmitters, growth factors, ions, intercellular proteins and hormones are involved in the complex physiology of erection function.

-Interviewed by Gary Logan

Pacing the Heart Out of Failure

David Kass, with the pacemaker that's now helping heart-failure patients, too.
David Kass, with the pacemaker that's now helping heart-failure patients, too.

The human heart operates much like an automobile engine. Cells in the upper chamber, or atrium, of the heart emit an electrical impulse that travels along a track that divides into the right and left lower ventricles. As the impulse descends into the two branches at the same speed, the muscle contracts almost simultaneously. But in some people there is a block in one branch that causes a delay in contraction, forcing the electrical impulse to detour slowly through the heart muscle itself. The heart struggles to send blood out to the body, much like a car constantly stalling due to poorly timed pistons.

But just as a car engine can be tuned-up, so can an out-of-sync heart-thanks to the pacemaker. Originally used to fix electrical abnormalities in people with irregular heart rhythms, notes cardiologist David Kass, the pacemaker is now successfully resynchronizing weak hearts in heart failure patients, whose previous treatment options were only drugs or surgery.

"It doesn't require open-heart surgery. It's not a ventricular assist, it's not a transplant," says Kass. "It's an electrical stimulator that coordinates contraction."

In a Circulation study of 22 patients with a potentially fatal form of heart failure known as dilated cardiomyopathy, Hopkins researchers led by Kass found that the therapy improved the heart's ability to contract and pump out blood by an average of 35 percent. Those patients whose hearts have the largest amount of timing discord, and whose hearts are often weakest, were the ones who seemed to benefit most from a pacemaker.

"These devices are costly, and must be placed inside the body," Kass says. "So we want to be sure we select patients who will respond."

- Gary Logan