Volume 18 Number 1 Winter/Spring 2001

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

Robots play expanded role in delicate surgeries

TWO-YEAR-OLD ALEXANDER CUMMING'S HEART DEFECT WAS REPAIRED BY A ROBOT. BUT THE ROBOT, NAMED AESOP, WAS NOT ON ITS OWN. Under the control of Michael Black, MD, associate professor of cardiothoracic surgery, Aesop fixed the heart problem in three hours. When Alexander awoke, he required no respirator, his cheeks were pink and the only sign that he'd undergone heart surgery was a piece of tape the size of a Band-Aid on his chest -- all testimony to the coming age of medical robotics.

* The arm-shaped robot, which moves according to Black's voice commands, allows Black to direct heart surgeries using a minimally invasive technique that would otherwise be impossible. This technique allows heart surgery with far less trauma, recovery time and scarring than traditional methods of open-heart surgery.

"We're able to repair complex defects through a two-inch incision rather than the traditional sternotomy, which splits the breastbone from top to bottom," says Black, who serves as chief of cardiac surgery at Lucile Packard Children's Hospital. "As a result, the child recovers much faster and leaves the hospital sooner, usually in only two days." Traditional open-heart surgery requires a hospital stay of five to seven days and
results in a scar from neck to belly button.

Black began doing minimally invasive cardiac surgery when he was at Toronto's Hospital for Sick Children. There he treated relatively simple atrial-septal defects. Now he and a Stanford team address complicated repairs such as muscular apical-ventricular-septal defects, heart tumors, valvular lesions and obstructive lesions. To date, Black and the Stanford team have worked with Aesop to perform heart repairs on about 50 children.

* The surgery requires an exceptionally and uniquely talented surgeon. When operating Aesop, Black is outfitted with headgear that includes magnifying lenses and a microphone for communicating with the robot. Aesop responds to Black's voice only and follows commands such as, "Move up," "Move down" or "Stop." The movements are smooth and typically more precise than a human's. A fiber-optic camera, inserted through an incision in the patient's chest, transmits to a video monitor across the table from Black and projects images similar to those taken by conventional laparoscopic equipment. But because the camera is not hand-held (as standard laparoscopic equipment is), the images are exceptionally clear, not blurred or shaky.

At present more than 500 medical centers around the country are using Aesop, which was the first robot approved by the Food and Drug Administration for surgery. Black, though, is one of the few surgeons in the world using robotics regularly on children. When he began using the method on children, some doctors were critical in light of the excellent results most children's hospitals achieve with traditional methods.

Yet it's likely that Aesop is only the first step in robotics designed to be less invasive and more precise. The next-generation machine, called Zeus, is being developed by Santa Barbara-based Computer Motion Inc. (the creators of Aesop) and Mountain View's Intuitive Surgical Inc. Zeus, which Black plans to study for use in pediatric surgery, will operate on a patient without requiring a physician to be in the room. Theoretically, the surgeon could operate the robot from thousands of miles away using a computer and a joystick. -- CC

New treatment for re-narrowing of heart arteries after angioplasty

A NEW PROCEDURE BEING STUDIED

AT STANFORD MAY PROVIDE THE NEXT GENERATION

OF TREATMENT FOR CORONARY ARTERY

DISEASE. The Galileo Inhibit Study, as it's called, focuses on using

beta radiation therapy to treat patients with blocked arteries.

While such radiotherapy is commonly used for treating cancers, its use is at the cutting edge of cardiovascular medical research.

* Before the mid-1980s, anyone suffering severe blockage of the arteries of the heart faced the prospect of open-heart surgery. Then came the invention of angioplasty, a minimally invasive procedure in which a blocked artery is opened by inserting a small balloon in the blood vessel. In 1994, a procedure called "stenting" came into use, whereby a stent -- a kind of metal scaffolding -- is mounted on the balloon used in angioplasty and then left in the blood vessel after the balloon is removed.

The current study treats patients who suffer re-narrowing of these treated areas, what is termed "in-stent restenosis"(re-blockage of the arteries within the stent). While stenting has reduced artery re-blockage after angioplasty from about 50 percent to 20 percent (results vary), once a stent re-narrows, the chance of future restenosis is upward of 60 percent.

* The Galileo system is intended to drastically reduce this final rate of recurrence. "The re-narrowing of these treated areas is caused by an accumulation of tissue from injury to the blood vessel," explains Alan Yeung, MD, director of the Cardiac Catheterization and Interventional Laboratories at Stanford. "This is a similar phenomenon to keloid formation. Several studies have shown that radiation is helpful in preventing this tissue from re-growing."

* Under the Galileo system, beta radiation is delivered to these areas of re-blockage by using a small wire coated with a source of radiation. The wire is inserted into a balloon and placed in the bloodstream of a patient for two to five minutes. Because beta radiation -- as opposed to gamma radiation -- has a very specific, well-defined penetration range, its delivery is highly controlled. No lead or concrete barriers are necessary, and staff can remain in the room when a patient is treated. "Preliminary findings suggest a very low rate of re-restenosis," says Yeung. "It's a very promising technique -- no other method is available that treats restenosis effectively."

* Currently, about 100 patients are involved in the trial, which began in September 2000. A phase I study, involving 108 patients who suffered first-time and recurring artery blockage, found that beta radiation therapy resulted in re-blockage rates of only 8 percent, compared with 39 percent for patients who received no radiotherapy. Stanford is one of three centers in the United States using the new system, which is manufactured by Guidant Corporation in Santa Clara, Calif. -- CC

School of Medicine preserves its history in e-book

THROUGH A SEVEN-YEAR LABOR OF LOVE, EMERITUS PROFESSOR AND HONORARY CURATOR AT LANE LIBRARY JOHN L. WILSON, MD, HAS WRITTEN A DETAILED HISTORY OF THE MEDICAL SCHOOL, WHICH LANE LIBRARY HAS PUBLISHED AS AN E-BOOK ON ITS WEB SITE (HTTP://ELANE.STANFORD.EDU). THE BOOK IS CALLED Stanford University School of Medicine and Predecessor Schools: An Historical Perspective. Wilson began the book after retiring from the medical school in 1989. In those long-ago days before the World Wide Web, he envisioned a print book. But as the 1,400-page book neared completion, it became clear the book would be most useful in electronic form, in which readers had the ability to do quick searching, look at many original documents and photos, and follow hypertext links to other subjects and references. Acting director of Lane Library Valerie Su says Wilson's book is a tremendous resource. The book is very detailed, Su says, and it's easy to use. "It's really remarkable what Dr. Wilson has accomplished."

Wilson's book covers the early years of the medical school -- the years most at risk of being lost to history -- but the press of time kept him from documenting more recent events, especially those since 1959 when the medical school moved from San Francisco to Palo Alto.

Su says the library is looking for a volunteer interested in documenting this more recent history in a companion e-book. Lane Library is also interested in publishing additional e-books, both those existing on Stanford's servers only as well as reprints of books published elsewhere. --CV

RU-486 may dramatically relieve psychotic depression

A PRELIMINARY TRIAL SUGGESTS THAT THE CONTROVERSIAL DRUG RU-486, A RECENTLY APPROVED ABORTIFACIENT AND EMERGENCY CONTRACEPTIVE, MAY PROVIDE SUDDEN RELIEF FOR PSYCHOTIC DEPRESSION -- A DISEASE NORMALLY VERY DIFFICULT TO TREAT.

"Some psychotically depressed patients are dramatically better within a few days," says Alan Schatzberg, MD, chair of psychiatry and behavioral sciences. "They stop hearing voices and having pessimistic kinds of delusions, like they're dying or the world is ending. We've seen the response within a four-day study. This is fairly dramatic."

* Traditionally, patients with psychotic depression receive one of two treatments: combined antidepressant and antipsychotic medication, or electroconvulsive therapy (ECT). Even when effective, both treatments are relatively slow and can leave symptoms that last for months.

"With mifepristone (RU-486) there's a very quick intervention. The patients often feel better and then we can put them on conventional antidepressants without the antipsychotics or ECT," Schatzberg says. "What's interesting is that the results are not
effervescent. The patients feel better and it lasts. Nobody's had to come back, nobody's had to undergo ECT."

* The social implications of the treatment are profound, Schatzberg says, both because mifepristone might eliminate the need for shock treatments and because it comes from a drug with other uses that some people don't like.

Originally mifepristone was developed as a steroid treatment for Cushing's disease, to block the adrenal hormone cortisol. But since progesterone receptors and cortisol receptors are structurally related, mifepristone also blocks progesterone, an effect that makes it useful as an abortifacient and, in smaller doses, as an emergency contraceptive.

* Research over the last 17 years has revealed that cortisol, a hormone released during times of significant stress, is extremely elevated in psychotically depressed patients. It seems their sustained levels of cortisol create a chronic stress reaction. This in turn may cause psychotic depression, including memory problems, sleep disturbances and hallucinations.

In a preliminary trial, five psychotically depressed patients were treated with mifepristone and four showed marked improvement within about four days. Further studies are now under way and in need of volunteers. Volunteers who feel they may qualify as depressed individuals and are interested in participating should contact the Depression Research Clinic at (650) 725-4620 for an initial over-the-phone assessment. -- CC

New Center for Pulmonary Vascular Disease

STANFORD UNIVERSITY MEDICAL CENTER, THROUGH

THE LUCILE PACKARD FOUNDATION FOR

CHILDREN'S HEALTH, RECEIVED $31.8 MILLION

FROM AN ANONYMOUS DONOR THIS FALL TO ESTABLISH

A CENTER TO TREAT PATIENTS WITH PULMONARY

VASCULAR DISEASE AND SUPPORT RESEARCH

DEDICATED TO FINDING CURES.The Vera Moulton Wall Center for Pulmonary Vascular Disease at Stanford will provide comprehensive diagnostic and therapeutic services for adults and children with all forms of pulmonary vascular disease, focusing on pulmonary hypertension. The center also will support and expand research collaboration between the schools of medicine and engineering.

The center will be directed by Jeffrey A. Feinstein, MD, MPH, an assistant professor in pediatric cardiology and director of pediatric and congenital cardiac catherization at Lucile Packard Children's Hospital. Ramona L. Doyle, MD, an assistant professor in pulmonary and critical care medicine and associate director of the lung/heart-lung transplantation program, will co-direct. -- ED.

Colorful method of tracking gene expression

ONE OF THE MOST EXCITING MOLECULAR TOOLS AVAILABLE TO RESEARCHERS STUDYING THE TRANSFORMATION OF GENES INTO PROTEINS HAS BEEN THE GREEN FLUORESCENT PROTEIN, OR GFP. Tacking the nucleotide sequence of GFP onto a gene allows researchers to monitor that gene's expression, noting when it is first turned on and where the subsequent green-tagged protein goes within the cell or embryo.

But because GFP marks the finished product -- and doesn't change over time -- there is no way of knowing if the cell is still churning out the protein or if the signal is tracking the last members of a dying population.

This distinction can be important in cells where conditions change rapidly, such as those in a developing embryo. But a new protein that changes from green to red as it ages can help
researchers monitor the starts and stops of gene expression. The protein, developed at Stanford, provides an easy and reliable way to mark and analyze the "history" of gene expression, the researchers say.

"Lots of people are fascinated by this discovery because now you can essentially follow both parts of the regulatory process -- gene activation and deactivation -- by monitoring these colors," says Alexey Terskikh, PhD, a postdoctoral fellow in the laboratory of Irving Weissman, MD.

* The protein, known as E5, appears as a kaleidoscope of colors, allowing researchers to see not only when a gene is activated but also whether it is expressed continuously or as a discrete pulse. Newly synthesized E5 is bright green. In contrast, E5 that's been around for several hours is bright red. Constant synthesis gives rise to a population of green and red molecules, which appear yellow or orange to the human eye.

* The discovery of E5 was a surprise, Terskikh says. He was trying to improve on another tracking protein, drFP583, which glows red after several hours. He began by randomly mutating the protein to create versions that would turn red more quickly or would express a more narrow range of color. He found the desired
mutations but also noticed some strange mutants that glowed bright green one day and bright red the next.

"I thought maybe I made a mistake. So I repeated the experiment several times and found that I must be persistently making the same the mistake." Eventually he was convinced that E5 was actually changing color over time.

* Terskikh realized that if E5 displayed the same unique properties in real systems, it could be useful to researchers. Together with collaborators at Stanford and the Russian Academy of
Science in Moscow, Terskikh tested E5's activity in the worm Caenorhabditis elegans and the frog Xenopus laevis. The group's results, published in the Nov. 24, 2000, issue of Science magazine, showed that E5 can serve as a reliable molecular timer. -- KC

Stanford Hospital CEO announces retirement

MALINDA MITCHELL, PRESIDENT AND CHIEF EXECUTIVE OFFICER OF STANFORD HOSPITAL AND CLINICS, IS RETIRING AFTER NEARLY 26 YEARS OF SERVICE AT THE HOSPITAL.

Mitchell, 57, will step down from her post at the end of March. She will continue for some period of time to aid in the leadership transition while a search for a new CEO is conducted, says Eugene Bauer, MD, vice president for the medical center and dean of the School of Medicine.

"Malinda Mitchell has been a stalwart cornerstone of the hospital management for more than a decade," Bauer says. "She always brought three values to bear on any of the myriad tough problems that we have faced: What is best for patients? How can we support the academic mission? And is this good management?

"It has been a privilege to work with her," he adds.

Mitchell, who has undergraduate and graduate degrees in nursing and business, came to Stanford in 1975 as a clinical nursing coordinator in urologic surgery.

Over the next decade, she rose through the ranks to become one of the hospital's associate directors of nursing. During that period, she helped steer the hospital through its $175-million modernization project, which was completed in 1984.

She then took time off to obtain a master's degree in business through the Sloan Program at Stanford's Graduate School of Business, an intensive program for high-level managers who don't have a formal business degree. She returned to hospital administration in 1985, when she was appointed director of nursing.

By 1989, she had stepped in to assume the post of chief operating officer. As COO, she took on the task of directing the Operations Improvement program, a yearly budget improvement and cost-reduction effort that continues to this day.

Mitchell became interim president and chief executive officer in 1997, serving as the hospital's top administrator during the two-year merger with UC-San Francisco. When the merger ended in the spring of 2000, she assumed the job of president and chief executive officer of Stanford Hospital and Clinics.

The search for Mitchell's permanent successor is in progress, Bauer says. -- RR

Shooting a moving target

STANFORD RADIATION ONCOLOGISTS HAVE DESIGNED A COMPUTER PLAN THEY HOPE WILL OVERCOME PROBLEMS ARISING WHEN CLINICIANS TREAT BREAST AND LUNG CANCERS WITH INTENSITY-MODULATED RADIATION THERAPY -- A TREATMENT THAT PERMITS PRECISE CONTROL OF THE BEAM.

Though the treatment's precision usually allows oncologists to kill cancer cells and spare the surrounding, normal tissue, difficulties arise when treating cancers in the chest.

* The ability to train the IMRT beams on a specific area, which is so advantageous for attempts to destroy cancers in the lower trunk and head, creates a problem for treating chest-cavity tissues, which move as a person breathes. Now, Lei Xing, PhD, assistant professor of radiation oncology, has found a way to use computer optimization to compensate for this movement.

* A standard IMRT radiation treatment map assumes no movement of the tumor target. Xing and his colleagues produced a computer program that incorporates respiratory motion into the treatment design. Using image data and an optical tracking system that follows fixed points on the patient's skin, they determined how the breast and critical organs such as the heart and lungs move with each breath. When they compared the "static-design" map with the "movement-design" map, they found that a treatment plan based on the movement-design map produced a superior result.

* When the researchers applied the static-design map to a computerized breast that moves in a way that simulates a person breathing, they found the heart and lungs received an excessive dose of radiation. In addition, the amount of radiation in the targeted tumor varied unfavorably. Rather than achieving a uniform dose inside the target tissue, the researchers predicted that as the tumor moves with the rise and fall of the chest, some areas accumulate an excessive radiation dose that could prohibit future healing of the breast tissue, while others potentially receive too little radiation to kill tumor cells.

"If you can incorporate the breathing cycle into your treatment planning, you can then use IMRT to deliver an optimal treatment to the breast over the whole breathing cycle," says Arthur Boyer, PhD, director of the radiation physics division. "If you don't take into account the patient's breathing you might not deliver the dose you want to deliver."

* Xing says some medical centers are treating breast cancer with IMRT without compensating for breathing-induced movement. "I think that's wrong," says Xing. He and Boyer favor a more cautious approach. "We want to send the message that the breathing movement should be taken into account when planning the treatment. The conventional treatment is optimized only when the patient is static and breathing motion is ignored, and that's not real."

Xing plans to continue testing the new technique on the computer, but believes it will not be long before breast cancer and lung cancer patients at Stanford can begin being treated with IMRT. -- KW