One New Shinbone Later

For three years at Glenelg High School in Maryland, Eric Elmer, the 6-foot-1-inch, 190-pound tight end on the football team, played every game in pain. The gnawing discomfort, which kept Elmer up at night and on Tylenol all day, stemmed not from a gridiron injury but from a pea-size growth on his shinbone. By last fall, when the 19-year-old met Frank Frassica and Kieran Murphy at Hopkins, he despaired of ever being pain-free.

The two specialists quickly gave the culprit a name: a bone lesion called an osteoid osteoma that strikes mostly in children and young adults. Though benign, these tiny tumors can be painful and difficult to get rid of. They typically require complex surgery to remove. But Elmer was in luck. Frassica, chair of orthopedic surgery, and Murphy, director of neurointerventional radiology, belong to a small cadre of surgeons nationwide who can now do the job with a one-hour outpatient procedure.

The key to the advance in treatment is CT fluoroscopy, a high-tech imaging technique that makes it possible to scan simultaneously in three places at 13 frames per second. That capability allowed Murphy to pinpoint the growth exactly and then insert electrode-tipped probes through the skin into the core of the osteoma. He then used radiofrequency energy to produce heat strong enough to destroy the growth.

Today, Elmer, who’s just finished his freshman year at West Virginia University, is pain-free for the first time in years. “It’s like having a new leg,” he says.

Michael Levin-Epstein

Behold the Zebra Fish

> Steve Leach and his striped swimmers.

As schools of zebra fish dart across their tanks, Steve Leach’s research team is learning to understand one of mankind’s deadliest killers—pancreatic cancer. Thanks to technologies like immunofluorescent staining—which makes each fish’s pancreas look like a tiny neon squiggle—the group is unraveling the mysteries of early pancreatic development by taking a close look at the growth and movement of the cells in this large gland in their earliest stages.

This year 30,000 people will die from pancreatic cancer. It’s the fifth leading cause of cancer death in the United States and has only a 5 percent five-year survival rate. Leach, who’s the Paul K. Neumann Professor in pancreatic cancer and chief of surgical oncology, is on a mission to improve those numbers by identifying the genes that regulate the development of the exocrine pancreas, the part that makes the digestive enzymes that organ secretes. “We already know exocrine cells are involved in pancreatic cancer,” he says. “And we’ve shown that genes regulating the development of these cells in the embryo also regulate the development of cancer in the adult.”

So, why study zebrafish? They offer two undeniable virtues: Because the tiny, striped swimmers lay hundreds of eggs, researchers gain immediate access to hordes of embryos at the one-cell stage. And, since their eggs are transparent, it’s possible to evaluate developmental events as they take place. Every day, Leach’s group injects the fish with candidate genes and watches how their cells develop. Even at one and a half hours old, the fish embryos show their worth. Already, the scientists have found that a major developmental gene (the Notch pathway gene) is a critical regulator of exocrine pancreatic development and is also abnormally activated in human pancreatic cancer. Early findings suggest that when the gene behaves normally it acts to delay the “flowering” of the exocrine pancreas. And that’s something that would be impossible to see in a mouse, Leach says.

But mouse studies are an important next step, Leach says. As they move forward, his team is using a mouse model to investigate how inhibiting the Notch gene might alter the course of pancreatic cancer. “It’s amazing how similar embryonic development is between species,” he says.

Judith Minkove

Consultation with Jeff Geschwind

It’s dramatic how rapidly your specialty is offering new treatments for so many conditions. What about that?

It’s true, there’s been an explosive growth and interest in minimally invasive image-guided therapeutic techniques. In fact, some of these techniques have totally replaced more traumatic surgical procedures. We interventional radiologists use high-tech imaging to tell us the story about what’s going on in the patient’s body, and then we move right in with a treatment. We’ve learned to shrink tumors and to treat aneurysms. We’ve given patients easier procedures for draining fluid and for shrinking fibroids.

For which kinds of conditions would you say your capabilities have made the most difference?

The areas that stand out are gynecology, specifically fibroid disease, and some cancer treatments. We’ve made a world of difference in the length of recovery and severity of what patients have to go through. Many of our new procedures can be done on an outpatient basis.

What procedures would you say you’re performing most?

We’re treating more patients for advanced liver cancer using chemoembolization and radiofrequency ablation. This is a catheter-driven treatment that kills liver tumors by delivering chemotherapy drugs directly to the site. Then, we’re using embolization to get rid of uterine fibroids. And we’re using embolotherapy to break up the dangerous blood clots known as arterio-venous malformations. And, of course, we’re handling more everyday problems like varicose veins with endovenous laser therapy. That interests a lot of people.

What do you see as the field’s biggest challenge?

Well—training remains insufficient. Residents need to have more exposure to the latest interventional techniques. But that should start happening. The increase in physicians going into the field is astounding.

Any other obstacles?

I’d have to say the toughest thing is being accepted by clinicians in other specialties. They’re not used to thinking of radiologists as clinicians. That’s less a problem in academic centers like ours, where relations with colleagues are excellent, but in private practice things may not be as collegial. That’s going to have to change. We all need to keep in mind our common goal: treating patients with the most effective procedures.

JM

Gastric Bypass Bonus

> Riley Wymer after dropping 80 pounds.

Today, Schweitzer has done more than 500 of the minimally invasive gastric procedures, and the numbers are in. More than 85 percent who undergo the operation lose an average of 70 percent of excess body weight after a year and a half. The change improves their overall health in ways they never imagined: blood pressure drops and conditions like sleep apnea disappear. But the most stark difference has occurred among patients with type II diabetes: Some 80 percent no longer experience any symptoms of the disease. “Most go off their meds completely,” Schweitzer reports. “and the other 20 percent usually go from heavy doses of insulin injections down to just one low-dose pill a day.”

For truck driver Riley Wymer, those results literally meant his livelihood. Before the surgery, he weighed 315 pounds and took four different kinds of medication to avoid insulin injections, which would prohibit him from truck driving professionally. Five months after his bypass, Wymer weighed 235 pounds, was off all medication and hauling an 18-wheeler between Maryland and Michigan. “If it weren’t for Dr. Schweitzer and the bypass, I probably wouldn’t have my job right now,” he says.

Animal Kingdom

> Kathy Gabrielson checks one of her furry creatures.

As one of four veterinary pathologists in the Department of Comparative Medicine, Gabrielson, who earned her Ph.D. in toxicology at the School of Public Health, helps maintain the health of the thousands of laboratory animals, from mice to pigs to monkeys, that are housed on campus. Over the course of her career, the assistant professor has indeed worked with her share of jumbo species, including an elephant at the San Diego Zoo and a beluga whale from the National Aquarium that was brought here for a necropsy to determine why it had died unexpectedly.

But today, Gabrielson also makes time for one more group of animals—the rats and mice in her own lab. Working with the little furry creatures, she’s created the only known animal model geared to explain, and perhaps one day circumvent, the severe and sometimes fatal heart problems that can occur when two potent anticancer drugs are used together.

“I was interested in brain neurodegeneration,” says Gabrielson, “and one toxin I studied also causes cardiac degeneration. So I began looking at other things that injure the heart. One is chemotherapy. The cancer gets treated but the patient dies of heart failure.”

Doxorubicin, a drug widely used for breast cancer, has long been known to carry this risk. Then in 1998, a new promising agent called Herceptin was approved for a highly aggressive form of breast cancer. Problem is, 30 percent of patients given both drugs in clinical trials got heart disease. Since Herceptin isn’t cardiotoxic in animals, probably because it binds only to a human protein, the challenge Gabrielson successfully took on was to produce the same heart effects in rats that Herceptin plus doxorubicin cause in patients. Furthermore, needing to monitor her animals’ cardiac status over time, her lab developed a way to do echocardiography in awake, unsedated rats.

Gabrielson’s aim is to find out why the two drugs together don’t result in dire consequences all the time. Answers to that question could kill the cancer but save the heart.

MAA

For Heart Failure Patients,
A Change in the Picture

> John Conte: One of a handful of cardiac surgeons who does ventricular remodeling.

Treatments present problems of their own. Medication may not work; a heart transplant puts patients on immunosuppressive drugs for the rest of their lives; and the new mechanical pumping devices, while promising, won’t be ready for widespread use until the question of mechanical failure can be resolved.

Now, John Conte, director of heart and lung transplant programs here, has another approach. Called ventricular restoration, the procedure is part of a four- to six-hour operation that typically also includes a coronary artery bypass and/or mitral valve repair. Conte actually reshapes the patient’s enlarged heart to its normal and more elliptical form to restore its ability to contract. The key is a plastic shaper, which he inserts into the left ventricle, the main pumping chamber, and then inflates to the patient’s ideal ventricular size, based on body measurements. Conte remodels the heart around the shaper and removes the device. Many of the nearly 800 patients who have had the procedure, say it gives them back their vigor.

“It’s a far safer and more economical treatment than a heart transplant or putting in a mechanical device,” Conte says, of the new device, which the FDA approved just two years ago, But he makes clear that only a careful evaluation can determine if a patient is actually a candidate for the procedure.

Although the ventricular restoration was initially designed for patients with damage only in one “territory” of the heart involving the anterior wall, Conte says, “I’m looking for people with one-, two- or three-territory damage to their hearts who may not have many alternatives at this point. I’m pushing the envelope, so to speak.”

Hopkins is now the only training ground in the nation for the innovative technique.

MLE

Understandings in Aneurysm Surgery

Rafael, you don’t put in as many shunts as everybody else!” This offhand remark to neurosurgeon Rafael Tamargo began a flurry of record examining that has lessened a hazard of surgery for ruptured brain aneurysms.

“When an aneurysm ruptures and patients come in with a subarachnoid hemorrhage,” says Tamargo, “wayward blood gums up drainage of cerebrospinal fluid. They can develop hydrocephalus.” Sometimes “water on the brain” resolves, but 15 percent of patients need implantation of a fluid-draining shunt. That’s unfortunate because shunts typically require replacement surgery down the road.

Tamargo was perplexed, though. His 2 percent shunting rate was five times lower than colleagues’. Was he under-shunting? Scanning a decade of neurosurgical records showed him he was fine in recommending shunting. But why did his patients need it less? A chance reading of a small study and discussions with fellow surgeons gave the answer. Following a mentor’s advice, Tamargo routinely punctured the membrane that borders one of the brain’s spinal fluid reservoirs. “It helps deflate a turgid brain,” he says. No one else at Hopkins was taking this “quick and simple” step as a matter of course. Now, he says, it’s become standard and the Hospital’s rate matches his.

The practice is one of several Tamargo initiated that has dramatically changed outcomes for danger-fraught aneurysm surgery. His research team has also devised a way to tackle giant aneurysms that previously defied care. “We’ve chipped away at the problem,” he says. “And our progress is real.”

One Smart Surgeon Saves Two Lives

> Omayma Ahmad, now mother of one infant and twin toddlers.

Testing confirmed Ahmad’s worst fears: She needed emergency surgery to correct an aortic valve stuck wide open because of a blood clot. During the operation, the cardiopulmonary bypass (CPB) pump circuit would take over the job of circulating her blood, and that would threaten the fetus she was carrying. Every physician Ahmad talked to advised ending the pregnancy first. She and her husband decided to take their chances.

They were in luck. The cardiac surgeon assigned to Ahmad’s case knew a lot about this particular problem. David Yuh had arrived at Hopkins recently, fresh from a year of learning the intricacies of performing open heart surgery on pregnant patients.

Moments after Yuh began this emergency valve replacement, his team initiated full CPB, cross-clamped the ascending aorta and stopped Ahmad’s heart. Worried that scarring from the earlier surgery might present complications, Yuh immediately dissected the heart and aorta away from the adherent scar tissue, then removed the clotted valve and inserted an identical mechanical one. Meanwhile, the anesthesiologists monitored the two sets of vital signs like hawks.

“The hardest part, Yuh says, “was hastening the procedure to avoid circulatory damage to the mother and the child. Things also were pretty tense because usually we cool the patient on bypass to preserve organ function. But in a case like this you have to maintain higher pump rates at warmer temperatures while the heart is stopped. Otherwise, all that cooling and the insufficient flow rates might cause irreversible harm to the placenta or kill the fetus.”

In the end, the operation took about three hours, and Ahmad spent 99 minutes on CPB. But the fetal heart tones remained strong throughout. “That baby’s heartbeat was like beautiful music,” Yuh says. In March, Ahmad gave birth to a healthy baby boy.

JM

Hold the Gel, Pass the Salt

> Brody and Kern with their new concoction.

It all began when Kern’s postdoctoral fellow Jonathan Brody, searching for a cancer gene, found his experiments going awry after following a simple recipe to make an electrophoresis gel. Researchers use these gel concoctions to separate strands of molecularly snipped genetic material (they call it running a gel). The scientist directs an electrical current across a slab of the dense jelly, and the current pulls segments of DNA across the gelatinous medium. The shortest, lightest pieces drift the farthest, the longer pieces lag behind. When Brody’s gels didn’t produce results, he quickly realized it was botched by a mistyped decimal in the recipe he’d inherited.

But instead of getting annoyed, Kern and Brody got curious. They started reading up to find out about the chemicals that make up a gel, especially the two essential ingredients: Tris-acetate EDTA (or TAE) and tris-borate EDTA (or TBE) act as “buffers” for balancing the acidic genetic molecules and increasing the gel’s conductivity. But nothing the two researchers found justified those ingredients.

Electrophoresis, they found, dates back to the 1950s when it was introduced for protein separation, but the recipe for the gel has been conserved from mentor to student since the 1970s when it was brought into use for studying genes. Nobody thought to question it, Kern says. Today, for companies that produce the pre-made gels for laboratories worldwide, the age-old recipe has added up to a multimillion dollar business.

Brody was so fascinated he took a two-month leave from his cancer research to try making gels with other ingredients. Within weeks, he’d discovered that TAE and TBE not only were ineffective buffers but were actually detrimental to the study of DNA. The chemicals created so much heat during conductivity that both the gel and the genetic material can melt.

Furthermore, buffering proved not to be necessary at all in DNA separation. The optimal conductor proved to be simple sodium boric acid—a salt that sends a quick current without raising the temperature. The salt produced crisper, easier-to-read, staggered lines in the final snapshot and was such an efficient conductor it cut the time for running the gel from more than an hour to 15 minutes. It also cut production costs from 27 cents to 7 cents, a potential national savings of more than $30 million. For Hopkins alone, using the salt could shave as much as $40,000 from the budget.

Brody published his findings in the February issue of BioTechniques and patented the sodium boric acid with Kern, but their main interest is alerting the research community that a speedier medium outperforms the old standard.

He and Brody recently cooked up samples and offered a public seminar to explain the new recipe. Several high-power labs—including that of famed colon cancer researcher Bert Vogelstein—aleady have made the switch to the new recipe.

“The only complaint we’ve received,” Brody reports, “is that the gels are so efficient, we’ve ruined what used to be researchers’ lunch break.”

Kate Ledger

Extracting Molly’s Brain Tumor

Do you think Molly has a limp?” Kody Taylor asked her husband, Gary, as they watched their 3-year-old walking to the car. “Nah, it’s just the way she walks.” But when an orthopedist suggested Molly have an MRI, the South Carolina couple learned their daughter had a brainstem tumor, possibly a pontine glioma, a usually inoperable cancer, located at the seat of functions like breathing and heartbeat. The Taylors’ search for the right neurologist led them to Hopkins’ George Jallo.

“Brainstem tumors aren’t common in children,” Jallo says, “and they’re not something you want to see. They’re delicate, intricate growths. Many consider them inoperable, even when benign, because of the real estate they’re in.” But, in Molly’s case, Jallo was fairly certain her tumor wasn’t malignant and he could tackle her problem. And, amazingly, he could do it endoscopically. He’d arrived at Hopkins last year with more than 100 such surgeries to his credit.

Jallo made a small opening in Molly’s skull, gently feeding in the laser and necessary surgical tools. The prune-size tumor he teased free turned out definitely to be a low-grade astrocytoma, a benign growth. Now Molly’s getting light physical therapy for temporary arm weakness, but, says Jallo, “she should be right as rain.”

Marjorie Centofanti