Johns Hopkins Magazine - April 1994 Issue

Health & Medicine

Research Findings and News: Memorable imaging, etc.

Knowing when to operate for prostate cancer

Since the advent of the PSA test (which measures blood levels of prostate specific antigen), urologists can now detect even the smallest of prostate cancers. There has been concern, however, that some men with very small cancers (not detectable on a rectal exam) might undergo surgery unnecessarily: maybe their cancers would always remain small and innocuous. Now, physicians at the Johns Hopkins Medical Institutions report that a set of pre-operative screening tests can predict which small prostate cancers are likely to grow larger and more menacing, and which are not.

It is common knowledge among urologists that many prostate cancers lie indolent for years, possibly forever. "The trick," says pathologist Jonathan Epstein, "is to try to identify the more aggressive ones from the more indolent. If you are going to operate on everyone over age 70 who has prostate cancer, you would have to line up almost every man in that age group." But the vast majority would die of heart attacks or stroke or some other cause before the prostate cancer harmed them, Epstein says. The new guidelines may help limit prostate surgery to those men who really need it.

Urologists now screen patients for prostate cancer with a rectal exam and the PSA test. Elevated levels of PSA can indicate cancer. But a healthy man or a man with an insignificant tumor can also have an elevated level. In the February 2 Journal of the American Medical Association, Epstein, director of urology Patrick Walsh, MarnŽ Carmichael, and Charles Brendler report that the use of three tests--the PSA, along with the PSA density test (which compares the concentration of PSA to the size of the prostate) and a needle biopsy of the prostate--can distinguish significant from insignificant tumors.

The guidelines were based on a study of 157 men with nonpalpable prostate cancer who had surgery to remove the prostate. Epstein and his colleagues examined the pathology of the tumors that had been removed. Sixteen percent were insignificant. The team then asked whether, by analyzing the pre-operative screening tests (the PSA tests and needle biopsy) alone, without direct tumor analysis, they could have predicted which patients would have significant tumors.

The trio of tests picked out about 70 percent of the men who had significant tumors. Of the 30 percent the tests missed, says Epstein, "only two men had a fair amount of tumor." The rest had just enough to put them over the borderline of what is considered significant. "But none of these patients is going to be lost [without immediate treatment]," says Epstein, because the patients can be followed via "watchful waiting," a strategy that includes PSA tests every six months and a biopsy every year. Even for the two men with more advanced tumors, the disease would be caught in time.

Men in their 70s and older are not likely to benefit from aggressive treatment, say the doctors. Men in their late 60s who have small, incidental cancers are good candidates for watchful waiting, while those younger than 60 are good candidates for surgery. --MH

After a stroke, what kills the brain cells?

The most likely cause of brain cell death after a stroke is an enzyme that helps repair DNA, Johns Hopkins researchers report in a February 4 article in Science. They are beginning animal studies to prevent stroke injury by inhibiting the enzyme, after successful tests in vitro.

It had been known that large quantities of the neurotransmitter nitric oxide are lethal to brain cells, but not precisely how. Now, using cultured rat neurons to reproduce "a stroke in a dish," a research team led by post-doctoral fellow Jie Zhang teased out a key detail of the process, which is serpentine: After a stroke, a flood of nitric oxide in the form of free radicals is released. These attack brain cells, particularly the DNA.

The cells begin to repair their DNA by producing the enzyme PARS--poly (adeno-sine 5'-diphosphoribose) synthetase. So far, so good. PARS, however, is unusual in that it prepares DNA for repair by taking energy from the cell. When PARS is activated for a long period, the cell becomes depleted of energy and dies.

In the research, cultured brain cells treated with nitric oxide showed high death rates. But when PARS was shut down in these cultures, by using drugs such as benzamide, cell death was significantly reduced--sometimes by almost half. The more PARS was inhibited, the less cell death took place.

"Other situations where nerve cells are injured, such as Alzheimer's, may also involve DNA damage and too much PARS," says co-researcher Ted Dawson, assistant professor of neurology. "This could be the pathway, for example, for amphetamine toxicity." The federally supported research took place in the laboratory of neuroscientist Sol Snyder. --EH

Neuroscientists visualize neural communication

Using a technique called calcium imaging, Hopkins neuroscientists have developed a way to see the independent functioning of synapses--the junctions between neurons that transmit information. "We can use this technique to investigate mechanisms of learning and memory," says Timothy Murphy, a post-doc at the School of Medicine.

In the technique, the scientists grow rat neurons in culture and perfuse them with a calcium-binding dye. Calcium, which is found in regions of activity in neurons, binds to the dye, thus highlighting active regions. In the photo above, the light blue threads are the dendritic processes of a neuron. Each small finger-like nub along a thread is reaching out to make a synaptic connection with another (unhigh- lighted, thus unseen) neuron. Bright pink indicates an active region: the large bump in the center of the pink area appears to be the site of a synapse, says Murphy.

The scientists did not evoke the activity. Rather, the pink active region is the result of spontaneous "idling" of the neuron that is thought to occur naturally. Certain regions probably idle more than others, says Murphy. When a nerve cell is stimulated (by neurotransmitters from a neighboring neuron, for example), these regions may be the ones that respond with a great burst of activity.

"Maybe certain synapses are capable of responding to a stimulus and others are set up for just conveying information," says Murphy. "The ones that preferentially respond to a stimulus may be the ones the brain uses in learning and memory." Calcium imaging, he says, "allows us for the first time to pinpoint synaptic activity at each of the thousands of synaptic sites along a neuron."

Murphy, Hopkins neuroscientist Jay Baraban, and physiologists from the University of Maryland report their findings in the January 28 Science. --MH

Cutting costs of surgery

Here's a health-care change that requires no new money, no new staff, no new bureaucracies; it helps both patients and providers; and if put into nationwide use, it could cut medical costs by $1 to $3 billion each year.

It's also easy to do: stop unnecessary testing before surgery, by following a set of guidelines recently established in the Department of Anesthesiology and Critical Care Medicine at Hopkins. The guidelines were developed in association with the Maryland Society of Anesthesiology, and they are already in use at Hopkins Hospital and elsewhere.

The major issues, says L. Reuven Pasternak, medical director of outpatient surgery at the Hopkins Hospital, have been liability and habit. In recent years, physicians have tended to order every pre-op test of even marginal relevance, just in case of a malpractice suit. In addition, many tests have remained routine because, well, because they were routine.

Yet there was scientific evidence, reports Pasternak, "that much of the testing was unwarranted." It was testing run amok. He says the new guidelines shrink pre-op testing back to "procedures we do because there's a reason for it."

Under the new standards (available in detail from Pasternak), a test should go forward only if the patient's history shows a specific need for it; or if the patient is in a high-risk group for the surgery; or if the specific test is needed to ensure the safety of the surgery.

Pre-op EKGs, for instance, under this new system, are now routine only for patients over age 50; or those who have hypertension or diabetes; or those with a history of problems with the heart, circulation, or metabolism; or patients who are vulnerable because they are so very ill. Surgeons can order whatever tests they think desirable, but the ones anesthetists routinely do will no longer include EKGs for healthy 20-year-olds having knee surgery.

Is there any increased risk to patients? No, says Pasternak. The full range of tests remains available as needed, and the criteria are medical- and patient-based, not cost-based. Pasternak says what's being eliminated is wasted time and effort for both patient and medical staff. And he points out that some tests do occasionally cause complications--serum chemistries, for instance--which is especially regrettable if the test was unnecessary. In fact, Pasternak thinks the new guidelines will improve service, by enabling "health-care providers to focus attention on patients who have significant medical problems," which "may also prevent complications."

Pasternak also hopes for a gain in halting both nuisance lawsuits and genuine malpractice. He developed the guidelines in part at the request of the Maryland Legislature, basing the work on research and the experience of Hopkins physicians and nurses. The Legislature is expected to enact them into law in the near future as a rational basis for defense against malpractice--or for its prosecution.

Implementing the new standards is straightforward, in the experience of Brian Rosenfeld, medical director of the pre-operative evaluation unit at Hopkins. "We simply changed our guidelines, and staff are expected to follow them." If the need for a test is unclear, "we err on the side of caution."

Rosenfeld sees the system's primary benefit as economic. He doubts, from the patient's point of view, that any change will be obvious. Yes, some patients will no longer be inconvenienced by tests before the day of surgery, but these people have no way to know that's new. "And when we take a tube of blood," says Rosenfeld, "patients don't know if it's for one test or 101." He adds, "Until they get the bill." --EH

Muller chairs NIH panel on human embryo research

In the Reagan-Bush years, federal funds could not be used to support research with embryos, so such research dwindled to occasional studies by commercial firms performing in vitro fertilization (IVF). Now the ban has been lifted, and the National Institutes of Health has assembled a panel to review current research, suggest new guidelines, and ponder the ethical issues. Chaired by Steven Muller, president emeritus of Johns Hopkins University, the panel will report in June.

In its first hearing in early February, the 19-member panel heard testimony on current U.S. research, which consists largely of attempts to improve the IVF procedure. "I am told it's pretty low-quality work," said Muller, speaking from his office at Hopkins's Nitze School of Advanced International Studies. Research in Great Britain, Poland, and Czechoslovakia is generally agreed to be far more advanced.

Yet the work is important. One eventual application, known to work in animals, could be implanting "stem cells" --embryonic cells that retain the flexibility to develop into many kinds of specialized cells--to treat diseases including Parkinson's. Another possibility is genetic screening for high-risk couples. For instance, if a couple were at risk for cystic fibrosis or Tay-Sachs, sperm and egg would join in the test tube. After a few cells had developed, one cell would be removed and tested. Only if all were well would the embryo be placed in the mother. (Animal studies have shown that this procedure does not harm fetal development.)

Of the ethical issues, one problem clusters around the source of embryos. Is it ethical to create embryos in vitro explicitly for research? Is it more ethical to use "surplus" embryos, embryos developed for use in IVF but not needed? If so, is it ethical to purchase embryos? If embryos are purchased from parents in financial need, does the need make their informed consent less than free?

Muller emphasizes that the panel is contemplating only those embryos produced in the test tube, "in the period from what I will refer to as conception to 14 days, because embryo implants would take place after 14 days." An embryo before implant is not "singularized," said Muller. "That is, quite aside from not knowing whether the implant will succeed in terms of a pregnancy, you don't know whether you're dealing with a single future being or twins or triplets. The embryo is not sentient, either."

An embryo is clearly human tissue, said the president emeritus--but at what point does it become a human being? That's one of the questions his committee will ponder, to help the director of NIH make decisions as to whether and how NIH-funded embryo research should resume.

Muller is pleased that the hearings are taking place under the federal sunshine laws: everything is open to the public, and members of the public may testify. "I think one of the services we render is to bring this to the public's attention so people can develop their own views, perhaps with a little new knowledge of the issues." --EH

Coping with a stressfulevent on the job

Last winter, a rowhouse fire sent six children from a single Baltimore family to Hopkins's pediatric emergency room. Despite the best efforts of physicians and nurses, none of the children could be saved.

For those who work in emergency and intensive care, coping with the loss of patients is often part of the job. Yet a loss this extraordinary can be too much even for the most seasoned ER worker to cope with, and those involved in this case grieved, alone, for days.

Rosalie Parker, a clinical social worker in emergency care who was involved in the case, watched each staff member break down in his or her own way: through tears, anger, or inability to eat and sleep. She believed that talking about it as a group could help them to recover together. So she helped launch the Critical Incident Stress Service, a one-time debriefing service for groups that endure a painful situation on the job at Hopkins.

"We get people to talk about the incident," explains RenŽe Demski, a senior clinical social worker who helped Parker set up the program. "We share similar experiences, whether they're physical or psychological problems, loss of sleep or appetite. We teach that these are normal responses to abnormal events."

The debriefing team is comprised of physicians, nurses, social workers, and a chaplain, and is available to meet with a group of Hopkins staff members within 72 hours of a traumatic incident. Demski has found that a great deal of stress reduction can be accomplished in a one-time session. "We can't eliminate the trauma," she says, "but we can reduce it. The team members try to get a sense of how everyone is doing, and we can give individual referrals if necessary."

She says that the service has a "trickle-down effect." If staffers take care of themselves, they will be better equipped to take care of patients. --EB

Written by student intern Erin Bohensky '94, Elise Hancock, and Melissa Hendricks.

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