University Times

A sister got more than her brother's kidney; she also got millions of cells from his immune system in a procedure that transplant surgeons at Pitt's Thomas E. Starzl Transplantation Institute, working with the University of Pittsburgh Cancer Institute (UPCI), hope will allow her eventual freedom from all anti-rejection drugs.

The technique, called peripheral blood stem cell transplantation, is standard for patients with certain types of cancers, but in what is believed to be a first, it was tried in a non-cancer patient receiving a kidney from a living donor as a means to induce drug-free tolerance of the transplanted organ.

On Jan. 11, a 54-year-old woman received a kidney donated by her 47-year-old brother. Three days later, in a simple bedside procedure taking less than 20 minutes, the woman also received an infusion of her brother's immune system cells taken from blood he had donated during an outpatient session last month. Both donor and recipient were discharged five days after the transplant.

The recipient's surgeon, Velma Scantlebury, associate professor of surgery at the Starzl Institute, said: "By all indications, the recipient's transplanted kidney is functioning well, and she has had no complications from the stem cell infusion. But it is too soon to know if the stem cell infusion will be effective. It will be several months or more before we'll determine whether it is safe to begin weaning her off immunosuppressive drugs."

"Unlike liver transplant patients, very few kidney recipients have been able to be safely weaned off immunosuppression. We think this is because the kidney contains less of the types of cells that are immunoprotective. It is presumed that the blood stem cell transplant will introduce enough of these good immune system cells to protect the organ from rejection," explained Ron Shapiro, professor of surgery with the Starzl Institute and the donor's surgeon.

Of the more than 13,000 kidney transplants that took place in the United States last year, more than 5,000 were transplants from living donors. Even patients who receive transplants from living donors must take a life-long regimen of immunosuppressant drugs to protect their organs from being rejected. Such drugs can cause serious complications, such as tumor growth, and make patients more susceptible to infections.

Transplant tolerance, which refers to the state by which a patient's immune system has fully accepted a transplanted organ, is a key area of study at Pitt. For nearly a decade, surgeons have been evaluating the long-term benefits of giving organ transplant recipients unmodified donor bone marrow infusions as a means to enhance chimerism, the co-existence of donor and recipient cells. About 300 patients have received donor bone marrow with their transplants, including nine living donor kidney transplant recipients.

As with the earlier transplants with bone marrow, the aim of the new treatment is to boost the level of chimerism, with the idea that tolerance is more likely to follow and successful weaning can occur. (None of the bone marrow patients has been completely weaned, but most are on reduced doses of anti-rejection drugs.) The transplant team believes the new treatment has advantages for both the donor and the recipient. The donor procedure is performed in an outpatient setting as opposed to in the operating room, and a greater quantity of specific cells can be obtained for infusion into the recipient.

"The content of lymphocytes in peripheral blood progenitor cells is 100 times more than in bone marrow, so we expect to be able to induce an enhanced state of chimerism, and eventually achieve tolerance of the transplanted organ," said Andrew Yeager, professor of medicine and pediatrics at Pitt's School of Medicine and director of UPCI's Stem Cell Transplant Center.

"With tolerance, we'd be able to taper the drugs or even wean the patient off the drugs completely. This would be a significant feat because most kidney transplant patients eventually develop chronic rejection, necessitating for some a return to dialysis or retransplantation," added Shapiro.

Stem cell transplantation has never been used in conjunction with living donor kidney transplantation. At the University of Miami, surgeons have tried the procedure in a handful of patients undergoing living donor liver transplants.

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Robotic gamma knife increases accuracy, speed of stereotactic brain surgery

The recently introduced gamma knife with robotic automatic patient positioning system (APS) permits greater accuracy in radiation-dose planning during brain surgery, provides faster treatment and more flexibility in dose delivery, according to a study published in the February issue of Neurosurgery.

The gamma knife procedure, commonly referred to as bloodless brain surgery, uses irradiation to treat arteriovenous malformations, acoustic neuromas, meningiomas, brain metastases, glial neoplasms, malignant skull base tumors, trigeminal neuralgia and epilepsy.

The new model gamma knife, first used at UPMC Health System last year, permits precise robotic controlled movement of the patient's head and stereotactic frame during the procedure. This study reports on the treatment of the first 134 patients using the new APS technology.

"We found the accuracy of the robotic system allows us to use greater numbers of smaller and narrower beams of radiation. This results in steeper fall-offs of the radiation outside the target area, resulting in a more conformal dose plan and a potentially better outcome for the patient," said Douglas S. Kondziolka, professor of neurological surgery and radiation oncology in the Pitt School of Medicine's department of neurological surgery and principal investigator in the study. Kondziolka is co-director with L. Dade Lunsford, the Lars Leksell professor and chairperson, department of neurological surgery, of UPMC's Center for Image-Guided Neurosurgery.

The study also found that because of the APS system, multiple uses of different sizes of collimator helmets used to focus the radiation were not needed, saving time and making the procedure more comfortable for patients.

The gamma knife delivers a single high dose of irradiation at targets of just several millimeters up to 3 centimeters in diameter. Because the beam focuses precisely on the offending tissues, effects on surrounding brain tissue are minimized.

Surgery using the gamma knife is safer than many existing procedures because patients need not undergo risky, open-skull procedures and adult patients do not require general anesthesia. It causes few side effects, and patients usually leave the hospital within 24 hours.

In 1987, UPMC was the first in the United States to treat patients with the first generation of gamma knife. Since then, the Department of Neurological Surgery has performed gamma knife procedures on almost 5,000 patients, the largest clinical experience in the United States.

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No link found between fertility drugs, ovarian cancer

Fertility drugs do not put women at a higher than average risk of ovarian cancer, according to the largest analysis to date on the topic, conducted by Graduate School of Public Health (GSPH) researchers and published in the Feb. 1 issue of the American Journal of Epidemiology.

"For more than a decade, controversy has surrounded the relationships among infertility, fertility drug use and the risk of ovarian cancer," said Roberta Ness, associate professor of epidemiology at GSPH and principal investigator on the study. "This analysis helps put to rest the questions that have been troubling physicians and the women who endure arduous fertility treatments."

While no association was found between ovarian cancer and fertility drugs, the study does point out a link between ovarian cancer and certain specific causes of infertility — namely, endometriosis and "unknown" reasons for infertility. The study suggests that some women who receive fertility treatments develop ovarian cancer because of underlying conditions that cause infertility, not because of the treatments themselves.

Investigators collected interview data on infertility and fertility drug use from eight case-control studies conducted between 1989 and 1999 in the United States, Denmark, Canada and Australia, including 5,207 women with ovarian cancer, and 7,705 women without ovarian cancer. In the study, infertility was signaled by prolonged unsuccessful episodes of trying to conceive, and by seeking medical help in conceiving.

Results showed that women who spent more than five years trying to conceive were at a 2.7-fold higher risk for ovarian cancer than those who tried for less than one year. Women who had used fertility drugs were not more likely to develop ovarian cancer than those who had never used fertility drugs. The risk of ovarian cancer dropped with each pregnancy.

Also, the infertile women who were most likely to develop ovarian cancer were those whose infertility resulted from endometriosis or from unknown causes.

Endometriosis is a condition in which cells from the uterine lining, or endometrium, migrate to various sites throughout the pelvis and attach to other organs, causing inflammation and pain, as well as infertility. In the recently published paper, Ness suggests that the local inflammation that is characteristic of endometriosis may play a role in ovarian cancer. Conversely, researchers are as yet unsure how to characterize unknown causes of infertility.

Researchers found that ovarian cancer was not associated with the following causes of infertility: ovulation or menstrual problems, ovarian cysts, blocked tubes, uterine development problems or cervical mucous and/or inflamed cervix.

Women who took fertility drugs but never became pregnant were more likely to have non-invasive tumors, according to the study, but the researchers suggest that more tumors were found among these women because they were under intense medical scrutiny while undergoing fertility treatment.

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Volunteers trained to treat cardiac arrest victims

Researchers in the Pitt medical school's Department of Emergency Medicine have trained more than 600 people on how to recognize and treat victims of sudden cardiac arrest to find out if the use of automated external defibrillators (AEDs) by non-medical personnel is more effective than only providing cardiopulmonary resuscitation (CPR).

The study, known as the public access defibrillation (PAD) trial, is being conducted by 24 centers throughout the United States and Canada. The ultimate goal is to implement effective emergency response systems at public locations with or without AEDs until emergency medical service personnel arrive.

Information gathered from the study will enable researchers to address a number of questions on the use of AEDs — where and how they should be deployed, how many should be deployed, whether the public can use them effectively and what the overall cost to the public would be.

An AED is a small portable device that analyzes heart rhythms and advises the operator, through computerized voice instructions, when to push a button to deliver a potentially lifesaving shock to the victim.

"Our hope is to strengthen the chain of survival by empowering lay people to provide emergency care before paramedics arrive," said Vince Mosesso, assistant professor of emergency medicine and principal investigator of the study.

Recent studies conducted by Mosesso proved that valuable time can be saved when emergency first responders, such as police, are trained and equipped with AEDs.

According to federal law and University policy, those who participate in a clinical research study must provide informed consent. Because of the nature of this trial, it is impossible to obtain consent at the time of cardiac arrest. For this reason, the researchers are notifying the public that the study is being conducted under federal guidelines and supervised locally by the University's Institutional Review Board, an administrative body that oversees medical research involving human subjects, when direct informed consent is not possible.

Researchers will make every attempt to provide notification to enrolled subjects or next of kin, and obtain informed consent for additional medical information from those who survive cardiac arrest. Researchers note that there is often a concern with legal liability associated with providing assistance in an emergency medical situation. However, Pennsylvania has "Good Samaritan" laws to protect those who assist in an emergency medical situation.

The National Heart, Lung and Blood Institute, the American Heart Association and manufacturers of AEDs are funding the study. The Pennsylvania-Delaware Affiliate of the American Heart Association also provided funding for the Pittsburgh site.The University of Washington, Seattle is the coordinating center for the PAD trial.

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Mechanism may cause mild cognitive impairment

A Pitt study has uncovered a completely different mechanism behind mild cognitive impairment (MCI), an increasingly common memory problem that is thought to be a precursor to Alzheimer's disease.

The results are surprising even to the researchers conducting the study and may explain why current medications don't improve memory function effectively. Further, the findings may redirect research into many of the newer treatments designed to prevent memory problems.

The study, published in the Jan. 31 Annals of Neurology, found that in older people with MCI, the brain produces more choline acetyltransferase (ChAT), an enzyme that is important in memory and cognitive functions. Researchers believe this is the brain's attempt to maintain normal function as the neurons that form communication lines to the brain's memory center die.

Strengthening their finding are autopsy results showing more than 60 percent of people who had MCI within a year of their death already had evidence of neurodegeneration that is seen in the early stages of Alzheimer's.

The results are almost the opposite of what most researchers believed — that a decrease in ChAT levels causes MCI — the theory behind today's most popular Alzheimer's treatments, which include drugs meant to boost levels of the enzyme's product, the neurotransmitter acetylcholine (ACh).

"Because we thought deficits in ChAT were responsible for memory problems in patients with MCI, the most common treatment we use is a class of drugs called cholinesterase inhibitors that help the brain produce more," said Steven T. DeKosky, professor of neurology, psychiatry, neurobiology and human genetics at the School of Medicine and principal investigator of the study.

"These results suggest that the brain increases production of ChAT on its own in people with MCI and that in addition to their use in early Alzheimer's, these drugs may be effective if used in patients who have a deficit in ChAT — those with advanced Alzheimer's.

"These findings suggest we should spend more time researching ways to slow down or stop the early stages of neurodegeneration," DeKosky added.

DeKosky and colleagues from Pitt and Rush Presbyterian-St. Luke's Medical Center in Chicago studied the brains of nuns, priests and brothers participating in the Religious Orders Study, which is based at the Rush Alzheimer's Disease Center. The participants all had been diagnosed as being either normal, having mild cognitive impairment or having Alzheimer's disease within a year of death.

Alzheimer's researchers had long believed memory and cognitive problems associated with MCI were caused when levels of ChAT in the cortical and hippocampal areas of the brain fell. ChAT is necessary to form the chemical ACh, which serves as a messenger carrying information between neurons to the hippocampus, where new memories are formed and stored. In this study, the first to report levels of ChAT in the hippocampus of humans with very mild Alzheimer's and MCI, they found ChAT levels actually were increased in people with MCI, but returned to normal levels in people with early-stage Alzheimer's. Only people with end-stage Alzheimer's had ChAT levels below normal.

Autopsies revealed that memory problems in people with MCI most likely are caused by neurodegenerative processes that occur very early in the process that leads to Alzheimer's, even before clinical signs are present. Brains of people with MCI were experiencing dysfunction and death of neurons in the entorhinal cortex, causing interference with the ability of the hippocampus to get information from the rest of the brain about what it is supposed to remember.

"If you compare the human brain to a computer, the hippocampus can be thought of as the brain's random access memory (RAM) chip," explained DeKosky. "The death of neurons from the entorhinal cortex to the hippocampus would be akin to breaking the connection between the computer's RAM and the rest of the motherboard."

According to DeKosky, the increase in ChAT in MCI demonstrates the brain's ability to compensate in one area for deficits in another to try to maintain normal function. As the disease progresses, the brain eventually loses that battle and levels return to normal, then decrease as the disease moves into its final stages.