Spring/Summer 2002

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Recognizing Mysterious Thoracic Outlet Syndrome

Julie Freischlag is a master of the delicate procedure for the painful
condition of the arm.

Some patients describe pain and swelling in their arm so severe that all they can do is sit and hold it. Others say the constant tingling and numbness makes their arm feel like a deadweight. So confusing can the symptoms sound that even doctors can have trouble making sense of them.

"Thoracic outlet syndrome is a disease of varied distinctions in the medical community," admits anesthesiologist Peter Staats. "Some physicians believe everyone with a sore arm has it; others think it doesn't exist at all." Indeed, TOS may be one of the most difficult-to-diagnose conditions.

But there's no doubt, says Julie Freischlag, an expert in the condition that it does exist. The syndrome occurs when the artery, vein and nerves that run down the arm from the thoracic outlet behind the collarbone become compressed. One time the condition might result from an accident, another it may be caused by a repetitive motion like brushing hair. Even being born with an extra rib can trigger the anguishing problem. Still, if you can't determine whether a patient's symptoms are biological or psychological, how do you treat them?

That's the critical question, says vascular surgeon Freischlag, who arrived at Hopkins this year to become head of surgery. Previously, as part of a team at UCLA that evaluated some 800 cases a year, she had developed an improved surgery for TOS. "Selecting the right patients for the procedure," Freischlag says, "is more important than the surgery itself. If you pick people improperly, they'll continue to have pain, and their emotional symptoms will become even more devastating, because they were looking forward to getting better."

Thanks to what she's learned about preoperative assessment, Freischlag achieves a 90 percent success rate in treating this problem. To identify the best candidates, she asks pain specialists like Staats to numb the patient's nerves. By watching what happens when a small amount of botulinum toxin is injected between certain nerves and muscles, she can determine whether someone will benefit from surgery and exactly what structures she should operate on (meanwhile, the therapy can temporarily alleviate the spasms caused by the condition). "What's key," Freischlag says, "is that if the nerve block works, you know what kind of operation will work best for the patient."

- Gary Logan

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No More Wait and See in the Brain

Jon Weingart in the OR

Neurosurgeons here have entered an era in which they receive instant feedback as they operate. The technology that allows this to happen is a new high-end intraoperative MRI scanner. Jon Weingart, a brain tumor specialist, describes its capabilities this way: "We can now see if we've missed a sliver of tumor and go back and clean it up before the patient even leaves the opera-ting table."

The scanner also gives neurosurgeons constant, real-time updates as they operate, allowing them to compensate for small shifts the brain may make. "It means we can do our jobs with more precision, more completely and in a way that is much safer for our patients," Weingart says. The new $1.1 million machine gives Hopkins capabilities available at only a handful of institutions in the United States.

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The Saga of a Horrible Birth Defect

Sponseller and Gearhart with Sasha, one more success story.

Blue-eyed and blond Sasha Blomstrom looks the picture of calm as he lies smiling in a hospital bed, holding his surgeon's hand. But the 12-year-old Russian boy's appearance belies his past. Born with the rare birth defect bladder exstrophy, Sasha spent the early part of his life with his bladder protruding outside his body, so he never learned to walk correctly. Several failed surgeries in the former Soviet Union ended with his bladder being removed and left him with scars across his abdomen. Worse, his ureters were placed in the lower portion of his large intestine, forcing him to pass both urine and feces through one canal. Sasha lived with chronic kidney infections and kidney stones and spent approximately half his life in a hospital.

"It also meant eight bowel movements per day, diapers at night and a social nightmare," says John P. Gearhart, chief of Pediatric Urology. "There's a tremendously high incidence of rectal cancer in these patients 15 to 20 years after their operation."

Gearhart and pediatric orthopedic surgeon Paul Sponseller have treated more than 700 bladder exstrophy patients from 13 different countries, many after botched earlier surgeries. To repair the defect they reconstruct the bladder, genitalia and pelvis. In Sasha's initial 15-hour operation, they used an osteotomy technique developed by Sponseller himself and now practiced around the world.

Aided by never-before-seen CT pictures of the boy's pelvic floor, the surgeons first closed the pubic bones to correct Sasha's gait. They then used his large intestine to construct a new bladder and reroute his appendix so his kidneys would have a way to drain. To erase the stomach scars, Gearhart rotated new tissue from the outer part of his abdomen to the middle.
"In this case, we had to remove his ureters from his colon and make a complete new bladder from a portion of his colon," Gearhart explains. "We had to protect his kidneys from further damage and render him continent, too."

It was a horrendous surgery, but like most Gearhart/Sponseller stories, it ended well. Today, Sasha is a healthy Minnesotan, living with his adopted American family. He walks freely, doesn't need diapers. He's also free from kidney infections and kidney stones, and other children no longer laugh at him.

Commenting on his and Sponseller's ability to create a new life for these bladder exstrophy cases, Gearhart sums it up this way: "What's so satisfying is being able to finally give these kids success with body functions that you and I take for granted everyday."

Sasha's mother agrees that Gearhart and Sponseller gave the boy success with his body functions. But more importantly, she says, they gave Sasha a future free from life-threatening illnesses. He rarely misses school, goes to camp, plays sports, has friends, fits in socially, and finally has the family he longed for.

- Gary Logan

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Defying Early Menopause

Because most women already have had their children when going through menopause, they're ready for the transition. Yet, sometimes, notes Jairo Garcia, director of Hopkins' in vitro fertilization (IVF) program, menopause can act as a brick wall. "Many women today put off having a child, until their late 30s or early 40s. Then they find themselves having menopausal symptoms and realize their delayed dream may not come true." Two conditions that will trigger onset even before age 40, he says, are autoimmune disease and cancer treatment.

Garcia now assesses all of his infertility patients for signs of early menopause. He's developed a protocol that can still offer those with the problem a chance to conceive through in vitro fertilization. First he uses blood tests and ultrasound to check estrogen levels and follicle-stimulating hormones (FSH) on day two of the menstrual cycle. In women past 35, a higher secretion of FSH hormone can mean that ovulation is occurring in six days. Eggs left in the ovaries in those cases tend to be damaged, so the pool that can be retrieved for IVF varies tremendously month to month.

Garcia identifies these patients and determines when to begin medical stimulation of the ovaries and follicles "so we can retrieve good eggs for IVF." If the estrogen and FSH levels are in line, he begins stimulation on day three of the menstrual cycle. On day seven, with levels still good, he'll continue stimulation and watch the patient until the follicles are larger than 18 mm. Thirty-six hours later, he'll retrieve the eggs. What's most important about this program, Garcia says, is that it can offer women who have begun menopause early a chance to give birth to a child. "Typically they don't believe they can get help, so they don't even participate in fertility programs."

- Gary Logan

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Consultation with John Freeman

The pediatric neurologist who demonstrated that high-fat foods can cure intractable epilepsy talks about the ketogenic diet he's revived.

How would anyone think up such a diet for epilepsy?

In the 1920s, an osteopathic physician believed epilepsy was due to irritation of the intestine. He reasoned that if the intestine was rested by fasting, that would control the epilepsy. He then fasted patients for 10 to 20 days and found that indeed the epilepsy was controlled -- for weeks, even years. The ketogenic diet, which is very high in fat and low in carbohydrates, mimics the effect of starvation. It brings the body into a fat-burning state of ketosis. Ketones, which are the "ashes" of incompletely burned fats, appear to inhibit the brain's electrical seizures. How or why this happens is still unknown.

So, the diet is loaded with fat.

That's true. The ketogenic diet is 90 percent fat with only four to eight grams of carbohydrate and one gram per kilogram of protein. It sounds terrible to those who have been brainwashed that fat is bad, but the diet is very palatable: Mushroom omelets with bacon, broccoli with cheese sauce, whipped cream sundaes. There is great variety.

Why don't more clinicians use the diet?

It's mainly been studied in children. Many pediatric neurologists don't have trained dietitians, who are key to the diet's success. The dietitian teaches parents to weigh and measure the foods and to read labels carefully. The teaching and the maintenance of the diet is very labor intensive.

How effective is the diet?

Our studies show that in children with uncontrollable seizures, half will stick with the diet for one year -- if it is effective. Half of those eventually come off the diet, and off their medications. They have few or no seizures three to six years later.

Why don't you see adults on the diet?

It hasn't been adequately studied in adults, but it will probably be equally effective if they stick to it.

- Interviewed by Marjorie Centofanti

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Is It a Heart Problem? It May Soon be Easier to Find Out

David Bush and Edward Shapiro are testing a new way to evaluate chest pain.

Each year, nearly 6 million people come into U.S. emergency rooms with chest pain. To determine if their symptoms are heart-related -- usually they're not -- doctors order an array of expensive lab and imaging tests, including blood work, electrocardiogram and echocardiogram. The results may then signal the need for an angiogram, so dye injected into the arteries can show any narrowing in the vessels.

"But at the end of the day, we often still don't know whether the patient has coronary artery disease," says interventional cardiologist David Bush. "The result is high utilization of hospital services and high anxiety for the patient," adds cardiologist Jaoa Lima.

Now, using a new CT scanner, Bush and Lima are part of a team that's testing whether an advanced form of CT multislice imaging can cut through the tests and rapidly and accurately assess chest pain. The 16-slice CT scans provide high-resolution, three-dimensional images of coronary arteries and transparent views through different layers of the vessels, allowing doctors to detect obstructions and also to evaluate the actual pathology of the arterial wall.

"We'll be able to judge the density of the plaque and infer whether it's a plaque that may rupture," says cardiologist Edward Shapiro. "That's something that even angiography can't do."

So, does that mean the multislicer CT can replace angiography, the gold standard for diagnosing coronary artery disease? Bush, Lima and Shapiro will determine that by using both methods to evaluate the same chest-pain patients in the emergency department at Johns Hopkins Bayview Medical Center. Then, they'll compare the results.

"We're looking at a revolution in how we treat patients with cardiovascular disease," Lima says. "This could completely change the way we screen for heart disease."

-Gary Logan

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Improving the Powerful Bone Marrow Transplant
The new protocol makes the treatment available to older, more vulnerable patients.

Richard Rhinehart no longer shows any signs of lympoma after undergoing the new kind of transplant.

In 1990, life was looking pretty good for Richard Rhinehart. He had a successful railroad construction company, a nice home in suburban Maryland and two sons he played basketball with. Then, he began experiencing night sweats and severe shooting pains in his leg and learned what he didn't have -- his health.

Non-Hodgkins lymphoma was Rhinehart's diagnosis. Twice in less than a decade he endured a regimen of chemotherapy and radiation to keep the cancer in his body's lymphatic tissue at bay. But the disease surfaced again in the late 1990s, and this time doctors told him they'd run out of options. They could offer a bone marrow transplant to replace stem cells damaged by yet another round of chemotherapy and radiation, but like 65 percent of leukemia and lymphoma patients, Rhinehart didn't have a family member with a complete tissue match. A partial match would put him at risk for rejecting the donor marrow or developing dangerous graft-versus-host disease -- GVHD. With the transplant, Rhinehart would have a 50 percent chance of dying; left untreated, he'd be dead in a year.

"If a patient receives high doses of chemotherapy or radiation to destroy his own marrow and ends up rejecting the donor's marrow, then he has no marrow to provide red cells, white cells and platelets," explains oncologist Ephraim Fuchs. "That's a fatal condition."

Rhinehart had one chance, though. At Hopkins, Fuchs and oncologist Leo Luznik had developed a new protocol in which donor marrow with at least a 50 percent tissue type match could be used for the transplant without the strong risk of GVHD. The trick involved administering high doses of cyclophosphamide three days after the transplant. The drug had been shown to attack T cells in the immune system that try to reject the graft, but not vital stems cells in the donor marrow. "It leaves untouched those cells that can prevent infections and kill the cancer," Fuchs explains.

The two physicians were offering the treatment through a clinical trial (Biology of Blood and Marrow Transplantation, July 2002). Of the 30 patients with fatal cancers who had gone through the protocol, 30 percent had lived beyond a year, and 20 percent no longer showed signs of disease in the blood or marrow or enlarged lymph nodes. Today, Rhinehart belongs to that latter group of patients.

"There's always a possibility of relapse," Fuchs says, "but as time goes by, that diminishes." The new protocol appears to have several more benefits too: the half-match allows patients to receive lower amounts of chemotherapy and radiation, making bone marrow transplant available to older, more vulnerable people. It also allows patients to find a donor match more quickly. Fuchs and Luznik believe, in fact, that the method could become standard treatment. And that would speed up transplants for all patients.

-Gary Logan

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Dan Lane Gets to the Bottom of Fat Bodies

It's funny how people sometimes find themselves right back where they started. Take Dan Lane. This long-time member of the Department of Biological Chemistry is amused by the loop his research has taken. Some 30 years ago, Lane became interested in a molecule called acetyl CoA carboxylase, because he was curious to know how it started the whole process of making body fat. That early work became a launch pad, and soon Lane was engrossed in other aspects of bodily fat manufacturing (a process known as adipogenesis). As the years went by, some 150 graduate students and 100 postdoctoral fellows working under Lane's mentorship moved his lab steadily forward in understanding that process. Then, along came C75.

Lane holds up a photograph of two lab mice to explain why C75 is such a remarkable molecule. The mouse on the left is overwhelmingly corpulent, the one on the right supermodel-thin. What's amazing, Lane says, is that the svelte mouse was as rotund as its neighbor until the research team started giving it C75. Immediately, the mouse cut back on its food intake and began losing weight.

C75's effect was actually first discovered in the late '90s in the laboratory of Hopkins pathologist Francis Kuhajda. Suspicious that the molecule had something to do with adipogenesis, Kuhajda suggested to Lane that they work together to figure out exactly what. That collaboration brought Lane right back to his old friend: acetyl CoA carboxylase.

From his earlier work Lane knew that acetyl CoA carboxylase makes a substance called malonyl, which is then picked up by another enzyme called fatty acid synthase and turned into long chains of fat. When C75 was fed to mice it stopped fatty acid synthase in its tracks. But at the same time, the acetyl CoA carboxylase continued to make malonyl CoA. It was the rising level of malonyl CoA, Lane's research team figured out, that triggered the mouse brain to stop eating. It seemed the signals released by the rodents' brains were the same ones that normally send out the alert that they'd eaten enough. In other words, the C75 fooled the brain into thinking the body was well fed.

Now, Lane wants to test the C75 reaction on cells grown in the lab instead of on mice. He wants also to know if stem cells can be tweaked to form fat tissue. The point is, though, that in the United States, where $100 billion is spent each year in treating obesity and related illnesses, the implications for what he's already discovered are immense.

-Raj Mukhopadhyay

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Surgeons Improve the Outlook for Liver Cancer Patients

With an ultrasound probe Michael Choti detects liver lesions and removes them before they become inoperable.

By using updated technology and new approaches to treatment, Hopkins surgeons are prolonging the lives of patients with liver cancer. The improved outcomes, says surgeon Michael Choti, are due in part to advances in CT and MRI imaging that show more precisely which patients are the best candidates for surgery. But additionally, ultrasound can now be used aggressively to draw a map to a lesion, and new high-tech surgical tools can be maneuvered to reach and remove the tumor.

"Our outcomes are getting better and better," Choti says of patients who have undergone surgery to remove tumors that have spread from colon cancer. "Historically, 30 percent of these people would have been alive five years after surgery. In our most recent experience, 50 percent were still alive at that point" (Annals of Surgery, June 2002).

Choti also adds a step as he operates that's not typical. To minimize damage to healthy tissue, he runs an ultrasound probe over the exposed liver as he plans his pathway to the tumors. Then, using new surgical dividing and stapling tools, he cauterizes blood vessels and tissues before cutting through them. "These steps allow us to go through the liver relatively bloodlessly," he explains. "We can map out our lines and operate more aggressively and more safely."

Choti makes two more points about why liver cancer patients here are living longer: Surgery is more typically being combined with chemotherapy or chemoembolization, and surgeons are doing more repeat operations.

Finally, for patients who aren't surgery candidates because of the spread of their cancer or their general health is too poor, Choti often uses radio-frequency ablation therapy to destroy smaller lesions. Inserting a thin probe into each lesion, he'll pass an electrical current through the probe and heat the tumor to about 100 degrees centigrade. The result is a slow but deadly burn that destroys the malignant tissue. One of the benefits of the ablation, Choti says, "is that it can convert the inoperable patient into a surgical candidate, by destroying the smaller lesions."

- Gary Logan

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For Heart Failure, Remodeling Could Be the Answer

Marcel Rauch with John Conte, his surgeon, who inserted a plastic mold (below) into his heart to restore its natural shape.

Marcel Rauch likes to tell people that he used to date women in every country he visited during the two decades he worked for the U.N. His second obsession was swimming. After a night on the town, Rauch liked to head for the nearest pool. But earlier this year, he began noticing that he couldn't finish his laps. And because he'd suffered a heart attack 15 years ago, Rauch, who by now had settled down in New York City, worried that a second one was on the way.

The problem turned out to be more sobering. Doctors told Rauch that his earlier attack had left him with a severely damaged heart, and that had led to heart failure. His condition was so serious, in fact, that he needed a heart transplant.

It was a devastating scenario for a vigorous man in love with life.

Desperate to discover if there was any way he could avoid a transplant, Rauch began gathering information. At Johns Hopkins, he found a potential answer. Cardiac surgeon John Conte was using a new technique that might make transplantation unnecessary. He could reshape damaged hearts to make them pump more efficiently and more powerfully.

When Rauch met Conte, the cardiac surgeon explained what he would do. Rauch's heart had undergone significant scarring as it healed from the earlier attack. That had thinned and elongated the protective layer of myocardium that envelopes his heart. Now, the heart's four chambers were so enlarged they no longer could contract as they were meant to. In the remodeling procedure -- ventricular restoration -- Conte would remove the non-functioning, scarred tissue and reconstruct the heart to its normal size. Then he'd do something quite uncommon medically -- insert a plastic mold into the ventricle, fill it with saline until he achieved the desired shape.

"By getting rid of tissue that's not working and giving the ventricle a more elliptical shape, we get better contraction," Conte explained. "The mold makes it easier to do that." Whether or not the procedure succeeded would be revealed by Rauch's ejection fraction, a measurement of his heart's pumping function. Today, the answer is in. Rauch's ejection fraction was below 35 before he had the procedure. Now it's closer to 60, the normal range. It's still too early to tell if he can avoid a transplant, but his breathing has improved and his fluid overload has decreased. In fact, Rauch exuded soon after his surgery, "I feel like I could swim like a 20-year-old."

- Gary Logan

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