A QUICK LOOK at the latest developments from Stanford University Medical Center

New clues for cancer whodunits
Upping the statin quo
Oatmeal cookies beat low-fat chocolate chip
The new curriculum: Two years in
Stem cell institute update
A source of 'thinspiration'?

New cludes for cancer whodunits

A new technique that is more effective in identifying the mutations that cause cancer has cleared a long-standing genetic suspect in skin cancer and pointed the finger at another potential culprit. And researchers are hoping that the technique, developed under the direction of Paul Khavari, MD, PhD, and published in the June issue of Nature Genetics, can be applied to other forms of cancer.

David Plunkert

Khavari, the Carl J. Herzog Professor in Dermatology, and his colleagues grew human skin cells on the skin of mice where they could see the effects of mutations they induced.

“The surprise in this study was that what is perhaps the most famous mutation in this cancer didn’t cause melanoma,” Khavari says. That mutation — in a gene for the protein B-Raf — shows up in the majority of melanoma cases, prompting widespread belief that it plays a role in causing the disease. But when graduate student Yakov Chudnovsky and postdoctoral scholar Amy Adams, MD, PhD, made the B-Raf mutation in their melanoma model, the cells did not become cancerous.

Although these results came as a surprise, several cancer trials that target the B-Raf protein with chemotherapy haven’t been successful in treating melanoma. If people developing chemotherapy drugs had access to Khavari’s mouse model, they might have suspected that their trials would be in vain.

B-Raf turned out to be incapable of creating cancer, but another commonly mutated gene appeared to be a likely criminal. Mutations in the gene that makes a protein called PI3K did cause melanoma in the mice.

“These studies highlight which mutations are primary drivers of cancer and allow us to focus in on that pathway,” Chudnovsky says.

This work in melanoma could be a big step forward in studying one of the hardest cancers to treat. “Once it spreads, there are no therapies that are universally effective,” Khavari says.

The key to this study was developing a way to induce mutations in the human skin cells and transplant them onto the mice. In the past, researchers studied melanoma in a lab dish where cells don’t behave like normal cancers. And while mice can develop melanoma, it is not an ideal way to study human cancer.

The team hopes to test additional mutations and develop models for other forms of cancer. — AMY ADAMS

The research was funded by the Veterans Affairs Office of Research and Development and by the National Institutes of Arthritis and Musculoskeletal and Skin Diseases.

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Upping the statin quo

The cholesterol-lowering drugs known as statins are now the nation’s most prescribed class of drugs, with more than 126 million prescriptions filled in 2004. But new Stanford research shows that doctors are prescribing them in only half of their visits with patients who would benefit most from them: those who have high cholesterol levels in addition to a high or moderate risk of heart disease.

David Plunkert

“Although we did observe some inappropriate use of statins in low-risk patients, the predominant problem appears to be underuse in higher risk patients,” says lead author Jun Ma, MD, PhD, research associate at the Stanford Prevention Research Center. The findings were published in the May issue of the Public Library of Science-Medicine.

Statins reduce the level of cholesterol produced by the liver while boosting the liver’s ability to remove LDL cholesterol, the so-called “bad” cholesterol, from the blood. High LDL cholesterol levels increase the risk for heart disease.

For the study, Ma and her colleagues examined two national databases that tracked outpatient visits be-tween 1992 and 2002 and the types of medications that were either continued or prescribed. They then corre-lated the results with the number of patients who had been diagnosed with high cholesterol levels and whose risk for heart disease was categorized as either high (having heart disease, stroke or peripheral vascular disease in addition to diabetes), moderate (having two or more risk factors for heart disease, such as high blood pressure, obesity and cigarette smoking) or low (no more than one risk factor).

What they found was a wide therapeutic gap: fewer than half of the visits with patients in the moderate- and high-risk groups were associated with statin use in 2002. Among the high-risk patients, statin use rose from 14 percent of patient visits in 1992 to 50 percent in 2002. For those at moderate risk, statin use went from 9 percent of the visits in 1992 to 44 percent in 2002.

“The rate of use falls significantly short of the latest recommendations,” Ma says.

The researchers believe physicians should be more aggressive in trying statin therapy for moderate-risk patients and in offering counseling about diet and exercise improvements. — SUSAN IPAKTCHIAN

The study was funded by Merck Co. and by the Agency for Healthcare Research and Quality.

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Oatmeal cookies beat low-fat chocolate chip

Chalk up another win for Mom. A healthy diet calls for more than just steering clear of junk food. If you want to protect your heart, you have to eat your veggies.

David Plunkert

Christopher Gardner, PhD, assistant professor (research) of medicine at the Stanford Prevention Research Center, found that a low-fat diet rich in vegetables, fruits, whole grains and beans has twice the cholesterol-lowering power of a low-fat diet reliant on processed foods.

In other words, a meal of spinach salad, egg and oatmeal-carrot cookies is healthier for your heart than stir-fried lean beef and asparagus and low-fat chocolate chip cookies—even when both meals contain the same amount of saturated fat and cholesterol.

The finding, published in the May 3 issue of the Annals of Internal Medicine, comes from a comparison of two low-fat diets. The conventional diet focused solely on avoiding harmful saturated fat and cholesterol. The second diet included the same proportions of fat and cholesterol, plus lots of plant-based foods in accordance with American Heart Association guidelines. Both diets lowered total and low-density lipoprotein (LDL, or “bad”) cholesterol over the course of the four-week study. The conventional diet produced, on average, a 4.6 percent LDL decrease.

But the plant-based diet beat that hands-down: It achieved, on average, a 9.4 percent decrease in LDL. Researchers found no significant differences in changes in triglycerides or high-density lipoprotein (“good”) cholesterol.

 “The effect of diet on lowering cholesterol has been really minimized and undermined by a lot of clinicians and researchers saying, ‘Yes, it has an effect but it’s really trivial: It would be better to put you on drugs to control your cholesterol,’” Gardner says. “But we think part of the reason was that we weren’t really giving diet a fair shake.”

He hopes the research spurs greater appreciation for the AHA guidelines, which call for more whole grains and “colorful” foods, such as red bell peppers, carrots, broccoli and red cabbage, which are loaded with nutrients. — TONYA CLAYTON

The study was funded by the National Institutes of Health.

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The new curriculum: Two years in

Third-year medical student Celina Yong spent last summer in India. But she wasn’t there to eat curry and polish her yoga skills; she was too busy researching access to health care among the rural poor in the state of Uttar Pradesh. Yong’s project is a major part of her scholarly concentration — an area of personal academic interest required as part of Stanford’s new medical curriculum.

The idea behind the curriculum is to better integrate a broad medical education with an in-depth area of learning. Ideally, graduates of the curriculum — now entering its third year — will be more than just great clinicians; they will also be active investigators who help to shape 21st-century health care. School leaders say the new approach has been well-received by students and faculty.

“The students can tell it’s still a work in progress,” says associate dean for medical education Neil Gesundheit, MD, MPH. “But our curriculum is quite different from what other schools offer; in some ways, it has changed the profile of students who apply here.”

For example, applicants seem more excited about the opportunity to do research, he says.

For Yong, who was interested in international health-care issues as an undergraduate, the curriculum was a key factor in choosing Stanford. “It gives me the opportunity to pursue medical interests that don’t lend themselves to the classroom as well,” she explains.

Juan Carlos Montoy, who researched the economics of diabetes management last summer and fall, wasn’t particularly focused on research when he applied. But he has since had a change of heart. “I’m definitely planning to pursue research now,” he says.

Julie Parsonnet, MD, senior associate dean for medical education, says the scholarly concentrations help to foster passion for medicine, adding that “we hope not only to build leaders and scholars, but physicians who are committed to their work and to a life of learning.”

This fall, a new concentration in cardiovascular/pulmonary medicine is being added to the lineup, making a total of 12 options from which students will choose.

Among the 87 members of the class that entered in 2003, the most popular concentrations were com-munity health/public service (12 students) and immunology (10 students).

In the classroom, the curriculum features an organ-based learning system that integrates such areas as histology and physiology. Students also meet with patients earlier in their training. Parsonnet says students are enthusiastic about these changes, and many faculty members have found the students to be more serious about their coursework.

Gesundheit points to a telling statistic from a recent survey of third-quarter students: 76 percent say their coursework increased their enthusiasm for being a medical student. — MATTHEW EARLY WRIGHT

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Stem cell institute update

The institute encompassing Stanford’s stem cell research efforts has a brand new look — complete with a new name, new leadership and a new location.

The biggest change is the uncoupling of the Stanford Institute for Stem Cell Biology and Regenerative Medicine (formerly the Stanford Institute for Cancer/Stem Cell Biology and Medicine) and the Stanford Comprehensive Cancer Center. Both had been under the same umbrella with Irving Weissman, MD, the Virginia and DK Ludwig Professor for Clinical Investigation in Cancer Research, in the leadership role for the combined entity.

Although Weissman remains director of both the institute and the comprehensive cancer center, the two are now separate entities with new hires Michael Clarke, MD, as associate director of the institute and Beverly Mitchell, MD, as deputy director of the cancer center.

“Making these efforts discrete will help us to communicate more effectively with those communities who are less familiar with our initiatives and unique research agendas,” says Philip Pizzo, MD, dean of the School of Medicine.

The stem cell institute will continue to explore the connection between cancer biology and stem cells, which share the ability to self-renew.

Weissman and Clarke have both led efforts to identify the stem cells at the heart of cancers in the blood and breast. Other researchers are collaborating to identify cancer stem cells from a range of cancer types. Members of the stem cell institute will continue to study these cancer stem cells and, in conjunction with their colleagues at the cancer center, to apply their findings to treating human disease.

This fall, some faculty from the stem cell institute will move to newly renovated space a few miles from campus, along with faculty from the Neuroscience Institute. This move will take all embryonic stem cell research at Stanford to an isolated, non-federally funded location.

The building’s funding source is key, given that federal funds can be used only on a handful of embryonic stem cell lines created before August 2001. Researchers wanting to work with newer lines need space and equipment purchased with non-federal funds.

The long-term plan has the researchers moving back to campus when construction finishes on a new building sometime in the next five years. — AMY ADAMS

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A source of 'thinspiration'?

Red for “Ana,” purple for “Mia.” The beaded bracelets encircle tiny wrists world-wide. But they’re more than just a fashion accessory. These strands trumpet the name of the wearers’ best friend—the eating disorders anorexia or bulimia.

David Plunkert

Girls can pick out their favorites on many of the more popular pro-eating disorder Web sites. About 1 to 2 percent of people in this country are believed to have classic eating disorders like anorexia or bulimia, and an additional 5 percent have serious eating and weight disturbances.

In addition to selling merchandise, the sites provide “thinspiration” in the form of photographs, body weight goal charts, exercises and low-calorie recipes.

They also offer tips on hiding food-avoidance tactics.

Recent research from the School of Medicine and Lucile Packard Children’s Hospital suggests the sites are used by a significant number of adolescents with eating disorders. The study revealed that teens who visit the sites spend less time on schoolwork and more time in the hospital than those who do not use the sites.

“These Web sites are founded on the mistaken belief that eating disorders are not a disease, but a way of life,” says Rebecka Peebles, MD, an instructor in pediatric medicine and a member of the hospital’s Division of Adolescent Medicine. “They are well-designed and alluring, often with a gateway emphasizing the danger of the site, which can be attractive to teens.”

The researchers conducted an anonymous survey of 52 adolescents diagnosed with an eating disorder at the children’s hospital since 1997. They found that about half had visited Web sites related to eating disorders. Of that number, 40 percent had visited only sites promoting eating disorders and 34 percent strictly visited sites dedicated to recovery from the condition. About one-quarter frequented both types of sites.

More than 60 percent of adolescents visiting sites promoting eating disorders tried new weight-loss techniques or diet aids as a result of their visit.

The Web sites don’t uniformly tout the perceived advantages of eating disorders, however. Some even offer “in recovery” bracelets for those trying to climb back up that slippery slope to health.

“There is a profound ambivalence that embodies the pro-eating disorder sites,” says Peebles.

“There are discussions in chat rooms and on bulletin boards about how much the disorder pains sufferers and cautioning others against trying too hard to lose weight.”

A host of one Web site points out that “pro-ana” sites may provide a valuable function by keeping sufferers from feeling utterly isolated. “Without sites like this one, some people would have absolutely no one to talk to,” the host says.

The important thing to remember, says the study’s senior advisor, Iris Litt, MD, the Marron and Mary Elizabeth Kendrick Professor in Pediatrics, is that many patients are turning to the Internet for information and solidarity. “These Web sites offer peer group support,” says Litt, “which can be used for good or for evil.” — KRISTA CONGER

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