University Times

Pitt faculty present results at Transplant 2001 meeting

Clinical and basic science research findings of more than 65 studies were presented by Pitt School of Medicine researchers at Transplant 2001, the joint scientific meeting of the American Society of Transplant Surgeons and the American Society of Transplantation.

Highlights of the findings, presented May 13-16 in Chicago, included the following:

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Lab studies indicate possible treatment for tumors in transplant patients

Post-transplant proliferative disorder (PTLD) is a complication associated with the Epstein Barr Virus (EBV), a virus that about 90 percent of the world population eventually will be exposed to. But many children and young adults have not yet been exposed to the virus, and because they must take drugs to control rejection, they are especially susceptible to the virus and the consequence of PTLD.

If an EBV-negative transplant patient is exposed to the virus or receives an organ that is positive for EBV, B cells in the patient's lymphoid tissue are likely to grow wildly to form cancerous tumors.

Results of laboratory studies reported by Diana M. Metes, research assistant professor of surgery at the Thomas E. Starzl Transplantation Institute, could point to novel immunological strategies to prevent or treat PTLD in transplant patients whose immune systems have not been educated to fight EBV.

Using blood samples from healthy individuals, she studied how certain immune system cells reacted when they were exposed to PTLD-like tumor cells. If the individual had previous exposure to EBV, specific types of immune system T cells — those that fight infections — tended to be much more active. Interestingly, when the PTLD-like cells were plunked into an environment with no EBV immune system recognition, the T cells reacted only in the presence of certain cytokines, proteins that can stimulate cell activity.

Introducing these T cells primed to recognize EBV into patients at risk for PTLD could allow their immune systems to effectively fight the virus if they were to receive an EBV-positive organ or were unknowingly ever exposed to the virus.

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Small intestines exposed to radiation less likely to be rejected

The majority of small intestine transplant recipients experience at least one episode of rejection within the first month of transplantation. But in a group of patients whose donor organs were exposed to radiation just prior to transplantation, the incidence was practically zero.

Rejection was observed in only one patient out of 13 in the study, reported Kareem Abu-Elmagd, associate professor of surgery and director of the Intestinal Rehabilitation and Transplant Center at Pitt's Starzl Transplantation Institute.

The strategy involves exposing the donor intestine to a single low dose of irradiation, transplanting the organ and then delivering donor bone marrow infusions. The radiation aims to kill mature donor immune system cells that the small bowel is saturated with so that the donor organ is less likely to serve as a target for the recipient's immune system.

The donor bone marrow infusion enhances a condition called chimerism, whereby certain types of donor and recipient cells learn to coexist peacefully. Chimerism is believed to influence the long-term survival of the transplanted organ. Three of five patients in a control group each had at least one serious episode of rejection.

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Researchers identify subtype of cell that promotes graft acceptance

In one of the few studies of its kind, researchers from the Starzl Transplantation Institute have found that a subtype of dendritic cell plays a key role in preventing organ rejection and may be associated with transplant tolerance, the long-term survival of a transplanted organ without the need for immunosuppressant drugs.

The findings are significant because dendritic cells, a rare type of white blood cell that is present in all tissues, have been thought only to be involved in prompting the rejection process. They do this by identifying and presenting antigens, or foreign substances, to other immune system cells that are programmed to destroy the antigen.

But some dendritic cells apparently regulate the immune response, determining that a frontline attack by T cells can be unwarranted.

Peta J. O'Connell, a visiting research instructor working with Angus W. Thomson, reported that a pre-transplant infusion of lymphoid dendritic cell subtypes derived from tissue such as the spleen allowed for prolonged survival in a mouse heart transplant model, even without the use of drugs to control rejection.

In contrast, myeloid dendritic cells accelerated the rejection response. O'Connell believes that the lymphoid-derived dendritic cells somehow disarm immune system T cells from doing their part to attack the donor organ by either causing their death or limiting their proliferation. The researchers plan to see if these "good" dendritic cells are present in liver and kidney transplant recipients who are off all immunosuppression as part of a larger effort under the direction of Thomson and Adriana Zeevi to identify laboratory profiles and tests consistent with tolerance.

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Gene therapy technique tested in animals prevents common type of donor organ injury

Cold ischemia — when the donor organ is without a blood supply — accounts for a significant portion of transplanted organ injury. This injury is compounded when oxygenated blood is reintroduced into the organ during surgery. Both situations somehow cause cells in the organ to self-destruct, therefore compromising the function of the graft.

A molecule that resides on the cell membrane is believed to play a key role in this process. Under certain conditions its activation induces a pathway to death by calling in a cascade of enzymes that break down the cell's nucleus.

Reporting on animal studies with promising clinical implications, researchers at the Starzl Transplantation Institute observed activation of this molecule in kidneys deprived of oxygen. But when they delivered a substance especially manipulated to target the molecule's genetic structure, the gene therapy technique successfully disarmed its ability to signal the cell death process, and significant ischemic injury was prevented.

According to Linlin Ma, a research fellow working with John Fung, the technique shows promise as a way of preventing ischemic injury in donor organs.

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Genetic profiles of hepatocellular cancers can predict recurrence after liver transplantation

Patients classified as having stage IV liver cancers do not qualify for liver transplantation, but based on an analysis of 69 patients transplanted for hepatocellular carcinoma at Pitt since 1981, some patients who are denied transplantation today because they meet criteria for advanced disease might actually be good candidates for transplantation and enjoy tumor-free long-term survival.

Andy Bonham, assistant professor of surgery, reported that six of the patients they followed — four of whom were transplanted 12 years ago — who would have been denied transplantation under today's guidelines, were found to have genetic characteristics that would predict a more benign course than the classic staging would suggest.

All are alive and well with no recurrence of their cancers despite the fact that at the time of transplantation they had very large tumors or multiple tumors in both lobes of the liver. Using tests to analyze the presence and mutations of tumor genes, Bonham reported that these patients' tumors were actually distinct early stage, non-aggressive ones.

The technique was able to identify these six patients out of 39 classified as stage IV. Overall, their analysis of the 69 patients found that patients with more genetic mutations in their tumors were more likely to have recurrence and short-term survival. Fewer mutations, even in situations with several tumors, corresponded with less of a chance of recurrence and longer survival. Seventeen of the 69 patients are still alive. Performing such tests on patients as they are being evaluated for transplantation could help guide treatment strategies, reported Bonham.

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Drug shows promise for children who develop post-transplant tumors

Pediatric transplant patients are especially at risk for developing a serious complication called post-transplant lymphoprolif-erative disorder (PTLD), whereby certain cells of the patient's immune system proliferate to form tumors that resemble a type of cancer called lymphoma.

Standard treatment involves temporarily reducing or eliminating the doses of drugs that are taken to suppress the immune system and prevent organ rejection. Some children fail to respond to this therapy, and their tumors can prove fatal. Many of these children face deadly consequences if the balancing act between protecting the organ from rejection and treating the cancerous tumors is done without precision.

Steven Webber, associate professor of pediatrics and medical director of the heart and lung transplant program at Children's Hospital, reported preliminary results of an eight-center study indicating that a drug called rituximab was effective for the majority of children who were not responsive to conventional treatment for PTLD. Tumors disappeared in 14 of 16 children in the study — recipients of heart, lung, liver, kidney or small bowel transplants. The drug targets a specific molecule on B cells, the cells that grow wildly and develop into tumors.

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Researchers 1st to view viral DNA 'ballet'

The complex process in which hundreds of protein molecules assemble around a single DNA molecule into a virus is like an intricately choreographed ballet, say Pitt researchers who announced in the April 27 issue of Science that they are the first to witness one of the main sequences of this microscopic dance in high resolution.

Roger Hendrix and Robert Duda, members of the Pittsburgh Bacteriophage Institute and Pitt's biological sciences department, are studying how viruses are assembled. They are collaborating with colleagues from the National Institutes of Health, the Institut de Biologie Structurale and the Scripps Research Institute.

Researchers studied the bacterial virus, HK97, and its precursor particle, or procapsid, using cryoelectron microscopy and X-ray crystallography, and were able for the first time to see at high resolution some of the proteins' movements.

"Coordinated like dancers in a ballet, the proteins initially assemble into a loosely organized structure, then progressively slip, slide, wiggle and change their shapes to produce a tightly intertwined and remarkably tough structure," Hendrix said.

Viruses have been likened to tiny spaceships that carry virus genes from the cell where they were created to the next cell the virus infects. The proteins that surround the DNA of the virus have two jobs: They must protect the DNA during transit, and they must deliver the DNA intact through the defenses of the cell in the act of infection.

"Once we understand in detail how viruses get assembled from their parts, we can start to think about how we might use that knowledge to sabotage the life cycles," Duda said.

"This should open the door for a lot of biologists," said Hendrix. "Even though we're looking at the behavior of only one particular protein of one particular bacterial virus, what we learn should be applicable to understanding lots of other proteins that carry out important reactions in the cell."

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Neurosurgeons studying substitute for spinal fusion bone graft

Pitt neurosurgeons are studying a bone graft substitute to determine if it can promote bone growth following spinal fusion surgery for lower back pain caused by degenerative disc disease.

The randomized, multi-center research study will enroll 370 patients nationally with about 40 patients being enrolled at UPMC Presbyterian Hospital.

The material is called Healos Bone Graft Substitute. Healos is a mineralized collagen matrix manufactured by Orquest, Inc., of Mountain View, Calif., with Minneapolis-based Sulzer Spine-Tech as distributor and sponsor of the clinical study.

"This study will determine the safety and efficacy of this new osteoconductive material," said William Welch, associate professor of neurological surgery and primary investigator of the study at UPMC.

Between each of the 24 vertebrae of the human spine is a vertebral disc, comprised of cartilage-like material that separates the vertebrae and allows flexibility of movement. Injury, aging or repeated stress can produce degenerative disc disease — drying out or collapse of the disc — which can lead to excessive motion in the spine, inflammation of the nerves in and around the spine, nerve dysfunction and severe, debilitating pain in the back, arms and legs.

Spinal fusion is an accepted surgical method of treatment for lower back pain. Over the past five years, manufacturers have developed FDA-approved titanium alloy cage-like products, which have been shown to alleviate lower back pain by promoting fusion between the vertebrae.

"These devices are placed between the lumbar vertebral bodies after the discs have been surgically removed. The cages are essentially hollow screws with holes drilled into the walls, which are then filled with bone taken from the iliac crest of the patient's hip. Over a period of months to years, bone grows across the vertebrae and through the cages to form a solid fusion," Welch said. "Healos, if found to be safe and effective, would potentially eliminate the need to take bone from the patient's own hip for use during spinal surgery, and may accelerate the bone fusion process. The process of removing a patient's own bone from their hip can be very painful during the post-operative healing process. Avoiding this pain is one of the goals of this study."

During surgery, a needle is placed into the iliac crest and a small amount of bone marrow is withdrawn. The Healos sponges are coated with the marrow before the sponges are inserted into the cages. The Healos/marrow combination is then used instead of autograft bone, according to Welch.

Back pain is the leading cause of workers' compensation expense, the second-leading reason for physician office visits and the third-leading reason for surgical procedures. Disc degeneration affects some 12 million people in the United States. More than 5 million Americans are disabled due to chronic back pain.

Geriatrics wins research award Pitt's division of geriatric medicine has won the clinical research award from the international Society for Urodynam-ics and Female Urology (SUFU), one of the world's leading societies in the field of voiding dysfunction and incontinence. The award was presented for a study of urinary incontinence in people over the age of 60.

The division of geriatric medicine at Pitt is one of the largest and is considered to be one of the best academic geriatric divisions in the United States. It was recently named a national Center for Geriatric Excellence by the Hartford Foundation.

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Docetaxel combination shows survival advantage as treatment for advanced lung cancer

A chemotherapy regimen of docetaxel (Taxotere) with cisplatin yields a significantly better overall survival rate than the combination of vinorelbine (Navelbine) and cisplatin in patients with advanced non-small cell lung cancer (NSCLC) who have not undergone prior chemotherapy, according to phase III trial data reported at the annual meeting of the American Society of Clinical Oncology.

The study, presented by Chandra P. Belani, professor of medicine and co-director of the University of Pittsburgh Cancer Institute's Lung Cancer Program, showed that patients who were treated with docetaxel and cisplatin survived significantly longer than those who received combination therapy with vinorelbine and cisplatin, a standard regimen used to treat advanced NSCLC.

The median survival for the docetaxel/cisplatin cohort was 10.9 months versus 10 months for the vinorelbine/cisplatin cohort. The one-and two-year survival rates were 46 percent and 20 percent versus 42 percent and 14 percent, respectively.

"While platinum-based chemotherapy is often viewed as a first-line therapy for patients with advanced non-small cell lung cancer, there is no established treatment standard for this population," Belani said. "The improved survival associated with the docetaxel/cisplatin combination means that a superior treatment may be available for this vast group of patients who are not candidates for surgical resection."

Lung cancer is the leading cause of cancer-related deaths worldwide and is primarily due to cigarette smoking.

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Professor awarded Heinz Endowments grant

The Heinz Endowments have awarded associate professor Stephen J. Bagnato, director of early childhood partnerships at Children's Hospital, a $1 million, three-year grant to continue his research of the efficacy and outcomes of high-quality early childhood education programs.

Bagnato's research team, called Scaling Progress in Early Childhood Settings (SPECS), uses an authentic assessment model to observe the natural learning of pre-schoolers in their everyday settings and to give feedback to teachers and parents so they can improve care. SPECS conducts longitudinal evaluations of child, family, program, health, nutrition, early literacy, community and school transition benchmarks in a broad effort to upgrade quality and scope of early care and education and early school success locally and across Pennsylvania.

SPECS follows children involved in Pittsburgh's Early Childhood Initiative (ECI) into third grade and works with principals, teachers and parents to document each child's success in acquiring developmental, pre-academic, social and behavioral competencies.

The new grant will enable SPECS to continue researching the comprehensive ECI programs in Braddock and Wilkinsburg that currently are operated by Pitt's Office of Child Development. SPECS also will continue to evaluate the early care and education programs in Sto-Rox, Homewood and East Liberty. With new Heinz funding, SPECS will expand to include diverse programs in Erie, York and Lancaster.

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New prostate cancer drug shows promise

Researchers at Pitt and Johns Hopkins report promising results in tests of a new prostate cancer drug known as ABT-627, made by Abbott Laboratories of Abbott Park, Ill.

In a phase II multi-national clinical trial, the drug delayed progression of advanced prostate cancer with few side effects in men no longer responding to hormone therapy.

Results of the study were announced at the American Society of Clinical Oncology (ASCO) annual meeting this week.

"For patients who have failed hormone therapy, and whose prostate cancer is progressing and may have spread to other parts of the body, the options for treatment are limited right now," said Michael Carducci, assistant professor of oncology at the Johns Hopkins Oncology Center and director of the study. "This low-toxicity drug may delay the need for more aggressive, but non-curative treatments like chemotherapy or radiation in these patients."

In one group of 244 patients who received either oral ABT-627 or a placebo, results show that progression of disease was delayed 69 days more in those on ABT-627 than in those on placebo. Those taking the drug took twice as long for their Prostate Specific Antigen (PSA) level to rise by more than 50 percent, an indicator of disease progression. Relatively few patients experienced side effects.

Related studies of 419 patients, led by Joel Nelson, professor and chair of urology at Pitt's School of Medicine, conclude that ABT-627 also stabilizes spread of prostate cancer (metastasis) to the bone. Often a painful effect of late-stage prostate cancer, bone metastasis signifies a poor prognosis in prostate cancer patients. In the study, patients who got a placebo experienced increases in biochemical markers indicating bone metastasis, whereas levels of those markers remained stable in patients receiving ABT-627.

ABT-627 blocks endothelin, a protein best known as a potent blood vessel constrictor. Prostate cancer cells secrete excess amounts of endothelin which may act as a growth enhancer and promote spread of cancer to the bone.

"Prostate cancer is a chronic disease requiring chronic therapy," Nelson said. "An oral, once-a-day medication, like the one we studied, is ideal."

Prostate cancer is diagnosed in approximately 180,400 men every year; close to 32,000 die annually. Most prostate cancers are found in the early stages of the disease and are highly curable. Studies suggest that the average life expectancy of men with hormone-resistant, progressive and metastatic prostate cancer is 12 months.

The study was supported by Abbott Pharmaceuticals. Car-ducci and Nelson are paid consultants to Abbott. The terms of this arrangement are being managed by the Johns Hopkins University and Pitt's School of Medicine in accordance with conflict of interest policies.

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Surgeons use ZEUS robotic system during surgery

Pitt surgeons are among the first in the United States to use the ZEUS Robotic Surgical System during endoscopic surgery for people who have chronic gastroesophageal reflux disease (GERD).

ZEUS enhances surgery using three robotic arms controlled by the surgeon, who sits at a nearby control console. As the surgeon works the controls, hand movements are replicated by robotic arms at the operative site in real time.

GERD is a disorder in which stomach acids reflux or surge upward, from the stomach into the esophagus. The edoscopic surgery, called Nissen fundopli-cation, involves wrapping the stomach around the esophagus to create a new valve that prevents the acid from refluxing into the stomach.

Surgery was performed May 11 at UPMC Presbyterian on a female as part of a multi-center research study to evaluate the safety and effectiveness of ZEUS in minimally invasive anti-reflux surgery. The research study also will compare short-term outcomes of patients who undergo standard laparoscopic Nissen fundoplication to those who undergo ZEUS-assisted surgery.

The randomized study will enroll 125 patients at five centers in the United States. About 25 patients will be enrolled in the study at Pitt. Half of the patients will undergo conventional minimally invasive surgery without ZEUS assist.

"ZEUS represents one of the first applications of robotic technology to the operating room. These early applications and trials will allow surgeons to work together with industry to continue to apply new robotic technology to enhance patient care," said James D. Luketich, section head of thoracic surgery, co-director of the University of Pittsburgh Cancer Institute's Lung Cancer Center, co-director of the Mark Ravitch/Leon C. Hirsch Center for Minimally Invasive Surgery and principal investigator of the study.

In a ZEUS-assisted minimally invasive Nissen fundopli-cation surgery, the surgeon creates five small incisions, called ports, in the upper abdomen. One ports is used to insert an endoscope that enables the surgeon to view the operating area. Other surgical instruments are held and moved by the ZEUS system through the remaining ports.

The surgeon views the operative site on a high-resolution monitor and operates handles that resemble conventional surgical instruments. The surgeon's hand movements are scaled, and hand tremor is filtered by the computer and translated via the robotic arms into precise micro movements at the operative site. The surgeon controls the movements of the endoscope through voice commands.

Robotic-assisted surgery has similar benefits to other minimally invasive procedures, including small incisions, roughly the diameter of a pencil, reduced trauma, shorter hospital stays and convalescent periods, improved surgeon precision and dexterity, improved visualization in 2-D or 3-D fields and minimized surgeon fatigue with an ergonomic operating environment.

The study is sponsored by Computer Motion, Inc., manufacturer of the ZEUS system.

In August 2000, surgeons at Pitt unveiled a prototype of the 21st century operating room which integrated Hermes, a robotic speech recognition system, and AESOP, a robotic endoscopic positioning system.

These systems give surgeons greater control over the operating room environment by extending their reach beyond the sterile field of the operating table, adding an extra "hand" to assist during surgery and making surgery less fatiguing for the surgeon and operating room staff.