Volume 16 Number 3, SPRING 1999

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A QUICK LOOK AT THE LATEST DEVELOPMENTS FROM STANFORD UNIVERSITY MEDICAL CENTER

HMOs drive physicians to reduce care for all patients – not only those in HMOs

DOCTORS WHO ALTER or reduce their services to meet HMO requirements for their managed-care patients tend to make the same changes for everyone they treat .

"HMOs are fundamentally changing the way doctors practice medicine for all of their patients," says Laurence C. Baker, PhD, assistant professor of health, research and policy. "Physicians conditioned to function in a managed-care environment may find themselves treating even fee-for-service patients with a managed-care mind-set," Baker writes in the Feb. 3, 1999, Journal of the American Medical Association. Baker's research found that Medicare fee-for-service expenditures declined in proportion to increases in market share of HMOs. Specifically, Medicare paid out less per beneficiary in those parts of the country where HMOs had the largest share of the market. Baker says it seems that the decrease was due to a drop in the number and intensity of services, not changes in prices.

"For example, if physicians are told by HMOs that they should never run an MRI scan on patients on a first visit for certain symptoms, they may adapt their practice styles so that they hold off ordering such scans even for patients whose insurance would pay for such a test on a first visit," he says.

Baker, a health economist, speculated that there might be several reasons for this consistency in behavior:

* SOME PRACTITIONERS find it too complex and burdensome to keep track of insurance rules for each patient, so they try to pick the solution that works for most of their patients and stick to that scenario when they can.

* PHYSICIANS OFTEN are philosophically opposed to changing their practices to conform with how they're being paid.

* PHYSICIANS MAY agree with some of the standards set by HMOs, feeling that the recommendations are prudent for medical as well as economic reasons, and should be used for all patients.

* DOCTORS WHO do not treat many HMO patients, but who interact with others who do, may absorb HMO practice styles from their colleagues who take care of HMO patients.

Baker also notes that the availability of services would eventually begin to match the market. For example, if HMOs refuse to pay for a certain diagnostic test, that test may be harder for doctors to find or secure for their patients.

Baker says Medicare was used for the comparison because it is not directly influenced by competitive market forces and it subjects its patients to fewer limitations than do most managed-care plans.

In his research, Baker finds that the average decline in expenditure per patient on both parts A (hospitalization insurance) and B (medical insurance) of Medicare in markets with the highest HMO penetration was small -- about $34 per beneficiary on part A in 1994. But he calls the decline statistically significant, noting that it was "enough to suggest that we should pay more attention to the effects managed care can have on non-managed-care patients." -- MG

Gene therapy helps mice grow new blood vessels

STANFORD RESEARCHERS HAVE taken an important step toward successful gene therapy aimed at growing healthy new blood vessels. They've developed a technique that allows the large quantity of protein produced by their introduced gene -- in this case a cellular growth factor -- to create blood vessel structures similar to those formed during embryonic development.

The scientists inserted a gene for the protein, called vascular endothelial growth factor (VEGF), into the leg muscles of adult mice. The muscle cells then began churning out high levels of VEGF, which attracted new cell types to the site. The new cells included what appeared to be stem cells -- primitive cells in the bone marrow that multiply and give rise to specific blood cells, says principal investigator Helen Blau, PhD, professor and chair of molecular pharmacology and co-director of gene therapy technology at Stanford. The experiment led to the formation of major new blood vessel structures previously thought to exist only during the mouse's embryonic stage, she says.

"It suggests that embryonic-like stem cells in the circulation of adults can be recruited to build new structures -- vascular structures and blood vessels," Blau says. "This could have applications to heart disease -- growing new vessels instead of a bypass -- and to diabetes, where limb amputations are common due to lack of blood vessels; and to enhanced wound healing."

Understanding this vessel-building process also might help prevent the growth of tumors, which rely on VEGF to develop their own blood supplies. "If you understand this process, you could think about how to block it, which would be a way to block tumors and possibly metastases," says Blau, whose findings were reported in the Nov. 20, 1998, issue of Molecular Cell.

VEGF, first isolated in 1985, is found throughout the body, where its function is to help create new blood vessels for wound healing and other purposes. In recent years, scientists have been trying various methods of gene therapy to insert VEGF into different tissues. In most experiments, however, VEGF has been found to be present only at low levels or for short periods of time, limiting the extent to which new vessels could be grown.

The Stanford group used a different gene therapy approach, that allowed VEGF to be expressed continuously at relatively high levels, says Matthew Springer, PhD, a senior postdoctoral fellow in molecular pharmacology and lead author of the latest report. The researchers packaged the gene for VEGF inside a retrovirus. They then extracted muscle cells from laboratory mice, infected the cells with the VEGF-containing retrovirus and injected the altered cells back into the legs of other mice.

By the third week, the injected legs began to swell and there were signs that cells from elsewhere had begun to gravitate to the swollen area, Springer says. By the sixth week, the researchers were surprised to find that the injected legs had turned dark and huge, more than twice the normal size, as a result of the formation of a whole new system of blood vessels, he says. Control mice that received only non-VEGF-producing cells showed no changes at all.

In most gene therapy experiments, the problem is getting enough of a gene product to the target area. In this case, the researchers are in the unusual position of having to figure out how to turn off the gene or modulate its expression, which is a lot easier to do, Springer says. "The method we used to deliver genes is quite successful in delivering genes that induce the growth of new blood vessels. We're in the unusually good position of having to figure out how to deliver less."

Blau says the researchers have recently developed what appear to be ideal methods for achieving that regulation. They are now following up with experiments to help control the VEGF production.

"There are many clinical applications to growing new vessels, and we have a very robust system for doing it," Springer says. "We feel this will allow us to turn this into a very applicable clinical technique," he adds. -- RR

Food Bar to Soothe the Heartache of Angina

A COMPANY FOUNDED by a Stanford cardiologist has begun selling the first food designed to ease the symptoms of cardiovascular disease.

Modeled on the energy bars favored by athletes, the HeartBar helps patients by relaxing arteries and increasing blood flow, according to John Cooke, MD, PhD, founder of Cooke Pharma Inc., the bar's manufacturer. Improved circulation reduces angina pain, gives patients more stamina, and strengthens blood flow to the extremities. "It's about as good as anything we have for improving symptoms," says Cooke, an associate professor of medicine and director of the vascular medicine section.

The HeartBar works by boosting blood levels of nitric oxide, a vasodilator that relaxes the muscles that surround blood vessels. The bar can't do this directly, though, because nitric oxide is a gas. Instead, each HeartBar provides 3.5 g of the amino acid L-arginine, which the body transforms into nitric oxide.

Last fall, a study by the Mayo Clinic confirmed that large doses of L-arginine -- 9 g per day -- gave impressive results against cardiovascular disease. The treatment increased blood flow in coronary arteries by 150 percent and reduced the severity of angina by 70 percent.

To get these effects, however, patients had to pop 18 big, bitter pills a day. The HeartBar is a more palatable way to get the same results, Cooke says. In his recent studies, patients who took the recommended dose of two bars per day reported a 66 percent increase in the distance they could walk without pain.

Cooke says that recent interest in L-arginine research reflects a growing realization that cardiovascular disease involves villains besides cholesterol. One likely culprit is a defect in nitric oxide regulation. Low levels of nitric oxide likely contribute to the narrowing of arteries caused by cholesterol, he says.

Cooke adds that preliminary evidence suggests nitric oxide may also function as a kind of cellular Teflon, preventing globs of cholesterol from collecting on the lining of vessels.

Available in raspberry or vanilla flavor, the HeartBar is now on sale at pharmacies throughout the Bay Area. Cooke says that he expects nationwide sales of the bars -- Cooke Pharma's first product -- to begin in May. Since the bar is a spinoff of Cooke's Stanford research, the university will receive a share of the profits, Cooke says.

Is the HeartBar a drug, a food, or something else? That's a sticky issue. Cooke Pharma markets the bar as a medical food, a somewhat nebulous category between drug and dietary supplement. Sellers of medical foods are allowed to make specific health claims about their products, but unlike drug manufacturers, they need not submit to a long and expensive review process to gain FDA approval.

Cooke Pharma's decision to opt for this rarely used designation raised some eyebrows, most notably at the Wall Street Journal, which published a critical article in December. Defending the move, Cooke says the company has worked closely with Washington, D.C., lawyer Peter Hutt to ensure that the HeartBar meets the requirements of the 1988 Orphan Drug Act covering medical foods. Hutt wrote the relevant sections of the act.

"We were very disappointed that the writer [at the Wall Street Journal] took the slant that we were trying to minimize regulatory oversight by utilizing the medical food category," Cooke says. "The medical food category is most appropriate for a product that is a food directed at a specific disease."

The HeartBar is sold over the counter, but Cooke (and the package) recommends using it under a physician's guidance. Each bar costs $1.95. -- ML

Greenberg Appointed Associate Dean for Research

HARRY GREENBERG, MD, a gastroenterologist who is internationally known for his virology research, in January became the new senior associate dean for research at the School of Medicine.

Greenberg, 54, a professor of medicine and of microbiology and immunology, has been a member of the faculty since 1983. During that time, he has been entrusted with a variety of administrative jobs, including chief of the division of gastrointestinal medicine and associate chief of staff for research at the Palo Alto Veterans Affairs Health Care System. He will replace Edward Holmes, MD, who recently left Stanford to become dean of the school of medicine and vice chancellor of academic affairs at Duke University Medical Center.

Greenberg says he expects the next several years to be the "golden age of biomedical research," with the NIH budget on the rise and growing knowledge about the human genome. As the scientific community enters that golden era, "the key is for Stanford to continue to be a leader," he says.

Greenberg says the challenge will be to continue to recruit and support new faculty within the limitations of staffing, dollars and space. He notes that the new space at the nearly completed Center for Clinical Sciences Research (CCSR) has already been allocated, yet more room for research is still needed. One of his responsibilities will be to help define the school's research priorities and determine where and how to house the investigators.

He says he wants to encourage as much communication as possible between scientists in the lab and those in the clinic. "If there is any place where Stanford can improve, it is in taking its incredible expertise in the basic sciences and applying it to problems that affect human health," Greenberg says.

Greenberg's lab is based at the Palo Alto VA, where he will continue to spend some of his time. As part of his new position, he will remain the director of the VA's $30-million research program. He will relinquish his post as chief of Stanford's division of gastrointestinal medicine.

Greenberg also was recently appointed chair of the FDA's Vaccines and Related Biological Products Advisory Committee. The committee helps the FDA decide what vaccines and related drugs warrant approval. Greenberg will chair the committee for the next two years. -- RR

Wondering why some trout whirl and die

STANFORD IMMUNOLOGISTS are investigating a deadly parasite of fish to learn why it devastates only certain trout and salmon populations.

The parasite (Myxobolus cerebralis) invades young trout through the skin, then rapidly multiplies within the head and spinal cartilage. The ensuing pressure on nerves in the brainstem and spinal cord causes the fish to swim in erratic circles, lending the condition its descriptive name -- whirling disease. Debilitated fish have difficulty feeding and eventually starve or succumb to predators before they are old enough to reproduce.

According to the Whirling Disease Foundation, a non-profit organization based in Bozeman, Mont., the parasite is not transmissible to humans, but large populations of native trout in the Northeast and Pacific Northwest are being depleted, raising alarm among environmentalists and fly-fishing enthusiasts.

"The problem is extensive and it's getting worse," says Irving Weissman, MD, the Karel H. and Avice N. Beekhuis professor of cancer biology, professor of pathology and developmental biology and a member of the Whirling Disease Foundation's scientific advisory board. Weissman is also an avid fly-fisherman. "It has utterly devastated the fishing in the Madison River," he says, referring to a river in Montana. "The rainbow trout used to be several thousand per mile, and they are now down to less than fifty per mile."

The parasite, a European native, was introduced into North American waters in the late 1950s and has since spread to 22 states. But very little is known about the parasite or the disease that results from infection. Rainbow trout appear to fall prey to the disease most easily, although cutthroat trout and chinook salmon are also susceptible. Other trout and salmon species become infected, but are able to resist the disease.

When a diseased fish dies, thousands of parasite spores are released into the water. The spores are highly resilient and can survive for up to 30 years in an aquatic environment. In the water, the spores are ingested by the tubifex worm, the alternate host of the parasite. Inside the worm, the spores hatch into the parasitic form that can once again infect young trout. Fish can also become infected by eating other diseased fish.

To learn more about the disease, the foundation has granted $75,000 each to Peter Parham, PhD, professor of structural biology and of microbiology and immunology, and his collaborator, Ronald Hedrick, professor of veterinary medicine and epidemiology at University of California, Davis' School of Veterinary Medicine.

Researchers in Parham's lab hope to figure out why close relatives of the rainbow trout, such as coho salmon and brown trout, become infected with the parasite but rarely show any signs of clinical disease. They believe that genes in the fishes' immune systems may be the key. Hedrick's lab at UC Davis will collect the samples for the joint project, and conduct a pathology study to examine the interactions between the parasite and the host cell.

"What we can do at Stanford is look at the genetics to see if there's a resistant allele," says Benny Shum, a research assistant in Parham's lab and lead investigator of the whirling disease project. "We want to understand the diversity of these fish and see if some of them have genetic resistance to the disease."

Parham and Shum hope to identify genes or genetic combinations that are associated with inhibition or elimination of the parasite in disease-resistant fish. The increased knowledge about the genetic diversity that exists in fish stocks will benefit breeding programs, which can utilize this critical information if overwhelming parasitic infestation necessitates re-introducing fish into barren waters. Shum acknowledges that repopulation of lakes and rivers is a controversial issue. "But if we get to a stage where we have to repopulate, then we'd want to know the best fish to re-stock with," he says.

Weissman believes that a simple breeding program could be instituted if a resistance factor was found. Wild trout could be bred with trout that have resistant genes and be reared in a parasite-free environment. The resistant fish could then be released back into their native regions. "This approach is our one best hope," he says. -- KW

Vitamin D Shows Promise as Prostate Cancer Treatment

FOR HALF OF THE MEN WITH PROSTATE CANCER, surgery or radiation fails to eradicate the malignant cells, which continue their mad multiplication. As a stopgap treatment, doctors often resort to androgen ablation -- essentially chemical castration -- to rob the tumor cells of the male hormones they need to grow. Now a Stanford pilot study suggests that a derivative of vitamin D may stifle the growth of prostate cancer cells, providing a gentler alternative to androgen ablation.

The first sign of recurrent cancer is usually a rising score on the prostate specific antigen (PSA) test, which measures the blood level of a protein made by prostate cells. At this stage, patients often have no symptoms and no evidence of metastasis, says Coleman Gross, MD, an endocrinologist and clinical instructor in the Department of Medicine and lead author on the study. But the PSA test shows that cancer cells are proliferating unseen, like cockroaches beneath the sink.

The next treatment step is usually androgen ablation. However, for two reasons doctors usually allow PSA levels to climb to a certain level before applying this therapy. Not only does it cause undesirable side effects -- impotence, osteoporosis and hot flashes -- but it typically works for just two to five years, after which the cancer acquires the ability to grow without male hormones.

Gross and three Stanford colleagues began looking for another way to suppress the growth of prostate cancer cells and stretch the time before androgen ablation becomes necessary. They decided to test the effectiveness of a vitamin D derivative, which other research suggested might protect against prostate cancer. For instance, the skin makes vitamin D after exposure to sunlight, and prostate cancer is less prevalent in sunnier climates, such as the southern states. Moreover, some studies have found abnormally low levels of vitamin D in men with the disease.

In a preliminary study, the researchers gave doses of calcitriol, the active form of vitamin D, to seven men who had recurrent prostate cancer that had not metastasized. During the treatment, which lasted up to two years, PSA levels rose more slowly for six of the seven patients. However, PSA levels did not fall in six of the seven men, meaning that the cancer cells had merely slowed their rates of growth; they were not disappearing. The research group published their findings last year in the June 1998 Journal of Urology.

Because of these encouraging results, Gross and colleagues decided to participate in a larger, multicenter study, using a synthetic version, or analog, of vitamin D called EB1089. Research has shifted to EB1089 because unlike vitamin D, or calcitriol, the analog doesn't boost the quantity of calcium in patients' urine -- thus sparing the patients from an increased risk of developing kidney stones. The Stanford part of the study, which will ultimately include about 20 patients, began early this year and will run for approximately two years. -- ML

Resource center for cancer clinical trials: Open for business

STANFORD'S CANCER Clinical Trials Office, launched this fall as part of Stanford's Clinical Cancer Center, is designed to make understanding, setting up, conducting and participating in cancer trials easier for Stanford's busy researchers, newly trained scientists and even patients.

One impetus for setting up the office was the increasing pressure on faculty to see a larger number of patients -- which results in less time to complete clinical research, says the office's director Branimir Sikic, MD, professor of medicine and director of the NIH-funded General Clinical Research Center at Stanford.

"We hope to build an infrastructure that will provide help with such issues as protocol design, research personnel and human subjects [Institutional Review Board] procedures. These and other services, such as database and Web site development, should support physicians who want to conduct research but are often strapped for time," Sikic says. The new office will also help coordinate research nursing and data management.

A key task for Sikic's office is to help develop a cancer research network of affiliated community physicians, to be called Community Partners in Cancer Research. Collaboration will extend to hospitals and other institutions providing cancer services in the community, he adds.

Services planned for the network include forums, newsletters and continuing medical education courses. The trials office has already launched its series of monthly forums. Each session includes a progress report on an ongoing trial, discussion of a proposed protocol and updates on the overall cancer research program at Stanford, Sikic says. -- SM

Experimental drug halts chronic organ rejection

ORGAN TRANSPLANTS often fail because the body tries hard to oust the foreign tissue. Now, a study of monkeys shows that an experimental drug can halt an insidious form of organ rejection that until now has been impossible to treat.

The Stanford study measured the effects of the drug rapamycin on "chronic" rejection -- a progressive failure of the transplant that eventually strikes most patients who survive the first few months after surgery. Rapamycin is the first drug to show promise as a treatment for advanced chronic rejection, says Randall Morris, MD, a professor of cardiothoracic surgery and leader of the research team.

Surgeons worldwide perform some 50,000 transplant operations every year to replace failing hearts, kidneys, livers, lungs or other organs, Morris says. All of the more than 250,000 organ-transplant recipients living today are at lifelong risk of losing their transplants from chronic organ rejection.

Organ rejection stems from the body's uncompromising xenophobia. The immune system tries to attack anything it identifies as foreign, making no distinction between harmful microbes and a potentially lifesaving organ transplant. Over the last 30 years, prospects for organ recipients have grown much brighter with the discovery of cyclosporine and other immune-suppressant drugs that stifle "acute" rejection, the body's immediate assault on a transplant. Without these drugs, immune attacks would destroy the transplanted organ within a few weeks.

But doctors have been powerless to prevent or even treat the slower, chronic form of rejection. This destructive process can arise a year or more after surgery and has multiple causes.

Chronic rejection usually begins in the blood vessels within the transplant. Over time, scar tissue piles up inside these vessels, reducing or even choking off blood flow. If blockages become widespread, the organ starves from lack of oxygen and nutrients.

Rapamycin was a logical candidate for treating chronic rejection, Morris says, because it not only suppresses the immune system but also inhibits the multiplication of the smooth-muscle cells that form deposits of scar tissue within blood vessels. Other anti-rejection drugs typically inhibit only immune cells, he says.

To test rapamycin's effectiveness, the researchers created a surgical technique to examine chronic rejection in monkeys. Into each of 12 monkeys they grafted a segment of aorta taken from unrelated monkeys. Half of the monkeys received rapamycin, but the treatment did not start until 45 days after transplantation -- allowing plenty of time for rejection to proceed. The other monkeys received no treatment. They then tracked the course of rejection over 105 days.

To keep tabs on the graft, the researchers used a new medical device -- a flexible catheter as slender as a toothpick, tipped with an ultrasound transmitter. Periodically, they inserted the catheter into a leg artery and threaded it through the arterial system to the graft. The transmitter let the team capture ultrasound images of the interior of the grafted vessel and precisely measure the buildup of scar tissue.

By the 45th day, ultrasound images showed scarring in the transplants of all the monkeys.

In the untreated animals, scar tissue amassed throughout the rest of the experiment. But in the treated monkeys, images showed that the scarring had stopped growing by the experiment's end. Moreover, in several treated animals, scar tissue began to shrink -- diminishing by 30 percent in one monkey.

Several institutions have already conducted clinical trials of rapamycin for preventing acute rejection in kidney transplant patients, and the FDA is reviewing the results. If approved, the drug might be available next year, Morris says. -- ML