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May 3, 2001


Interferon alpha-2b proven first effective drug treatment for malignant melanoma

A University of Pittsburgh Cancer Institute (UPCI) researcher announced last week the results of a national study confirming the effectiveness of the first and only effective therapy for high-risk malignant melanoma patients.

The study found that interferon alpha-2b (INTRON A) dramatically increases relapse-free and overall survival rates in such patients, said John M. Kirkwood, professor and vice chairperson of research, Health Sciences, at Pitt and director of the UPCI Melanoma Center.

Without this drug therapy, which is given after surgery, patients have a 1.5 times greater chance of relapse and death, researchers found.

"This report confirms our earlier evidence that interferon alpha-2b should be the standard adjuvant therapy for high-risk melanoma patients," Kirkwood said. "If physicians aggressively treat melanoma patients with this regimen, the epidemic number of deaths from this type of cancer will be reduced."

Malignant melanoma is the deadliest form of skin cancer; 47,000 cases were diagnosed last year, doubling the number found 20 years ago. Malignant melanoma is the No. 1 cancer-related cause of death in Americans aged 25-30.

Melanoma patients considered to be at high-risk are those with primary tumors greater than 4 mm in depth or whose melanoma has spread to the lymph nodes.

Study results were published April 27 in the Journal of Clinical Oncology.


Artificial lung reported to be on the horizon

A Pitt researcher who has developed a device that functions like a temporary set of lungs told a group of heart and lung transplant surgeons April 26 that such technology could have a tremendous impact for the nearly 750,000 patients with emphysema, chest trauma or acute respiratory distress, about 150,000 of whom die each year.

A potential application also exists for military personnel and civilians who become victims of chemical warfare or terrorist attack involving toxic gases, reported Brack Hattler, a Pitt professor of surgery.

In a keynote lecture at the 21st annual meeting of the International Society for Heart and Lung Transplantation, Hattler said laboratory and animal studies suggest the device could do an adequate job of exchanging carbon dioxide and oxygen in patients with compromised lungs, allowing the lungs to rest and heal.

"It's an alternative means of breathing," Hattler said.

A clinical trial of the device, called the Hattler Respiratory Catheter, is expected to begin in Europe in about a year. It will be only the second time an implantable artificial lung has been tested in humans. About 10 years ago, clinical testing of another device was halted because the device's design did not allow for sufficient gas exchange. In general, progress to develop an artificial lung lags years behind that of the artificial kidney, liver and heart.

"The artificial lung especially has lingered behind progress with artificial hearts and ventricular assist devices, not because the need for lungs has not been recognized, but because we have not had a full understanding of the engineering problems and the unique material requirements until recent years," explained Hattler, who has devoted the last 14 years to developing an artificial lung.

Together with bioengineer William J. Federspiel of Pitt's surgery department, Hattler has created an intravenous respiratory assist device that is easily inserted through a vein in the leg and positioned into the vena cava, the major vein returning blood to the heart. It consists of hollow fiber membranes that introduce oxygen into and remove carbon dioxide from the body. Key to its design, and a distinction from the device that failed, is a central balloon within the fibers that can inflate and deflate at a rate of 300 beats per minute to move the fibers and mix the blood. This allows for more efficient oxygenation of blood and removal of carbon dioxide. Respiration takes place even though the lungs are severely injured and functioning poorly.

The surface area of two lungs is about the size of a tennis court. The Hattler Catheter has a surface area equivalent to an 8 x 11inch sheet of paper and can perform about 50 percent of the gas exchange requirements of an adult. Blood is exposed to a tiny amount of foreign biomaterial — less than a half a square meter — minimizing the likelihood that there would be an infection or clotting caused by the interaction between blood and a synthetic surface, Hattler reported.

Because the Hattler Catheter is intended to temporarily take over the function of the lungs, it could meet a need for patients with acute respiratory failure, such as those with emphysema or those who have suffered trauma to the lungs. Currently, the standard of care is the use of extracorporeal membrane oxygenators, which are bulky and expensive units that can cause life-threatening complications and death in more than half of those who are treated with them.

The device is not envisioned for prolonged support, say as a bridge to transplant or as a total replacement of the lungs. However, findings from the clinical trial will lead to a greater understanding of what is required for the development of more long-term devices, Hattler said, enabling a jump-start for artificial lung researchers who are working to develop devices to provide long-term support for patients awaiting lung transplantation. About 25 percent of these patients die on the waiting list, largely because no means of support currently exists. Such devices, which are about two to three years from human testing, would need to be surgically implanted.

Support for Hattler's research has been provided through grants from the U.S. Department of Defense. Work has been conducted through Pitt's Center for Artificial Organ Development.


Faculty receive NIMH Career Development Awards

Three faculty members in the psychiatry department's Translational Neuroscience Program recently received five-year Career Development Awards from the National Institute of Mental Health (NIMH).

Joseph N. Pierri, assistant professor, received an award to study the role of the thalamus in the pathophysiology of schizophrenia. Assistant professor Leonid S. Krimer received an award to investigate the influence of dopamine, a neurotransmitter implicated in several psychiatric disorders, on the function of the cerebral cortex. Professor David A. Lewis received an award to study the normal functional architecture of the prefrontal cortex, a brain region involved in the pathophysiology of a number of psychiatric disorders, and to determine how prefrontal cortical circuitry is altered in individuals with schizophrenia.

The studies are designed to facilitate translation of knowledge regarding the biology of the brain to achieve a better understanding of the causes of schizophrenia and other disorders and to improve treatment of these illnesses.

Mortality rates for type 1 diabetes drop dramatically in county Mortality rates for people with type 1 diabetes are declining for the first time in Allegheny County since researchers at Pitt's Graduate School of Public Health began tracking these rates 20 years ago. Investigators believe this drop may be occurring nationwide. They reported on their findings in the May issue of Diabetes Care, a journal of the American Diabetes Association.

"For Allegheny County children diagnosed with type 1 diabetes in the late 1970s, the chance of dying after 20 years has dropped by more than 50 percent," said senior investigator Trevor Orchard, professor of epidemiology, medicine and pediatrics. "These dramatic changes reflect the improvements in diabetes management that began in the early 1980s, once patients were able to monitor their blood sugars better and physicians could monitor the effects of treatment changes using the hemoglobin A1c test — a long-term blood sugar test. We suspect these changes are likely to be seen generally, beyond Allegheny County."

Type 1 diabetes usually begins before the age of 30 and affects some 750,000 Americans. People with this disease have lost the ability to produce the hormone insulin, which controls blood sugar, so they require daily insulin injections. For more than 20 years, Orchard and his colleagues have been following 1,075 type 1 diabetes patients in Allegheny County who were diagnosed between 1965 and 1979. Until recently, these patients experienced a consistently high mortality rate. Their most recent analysis, however, shows a first-time, significant drop in mortality rate among those diagnosed later in the 14-year period.

Of the 1,075 patients identified at the study's start in 1980, 75 deaths were observed in the 20 years after diagnosis, with significantly more deaths occurring among patients diagnosed in 1965-1969 (33 patients, or 8.4 percent) than among those diagnosed in 1975-1979 (15 patients, or 3.5 percent).

The mortality of African-Americans was significantly higher than that of Caucasians, with 50 percent of African Americans in the study having died within 20 years of diagnosis.

"While mortality was higher among African Americans with type 1 diabetes than it was among Caucasians with type 1 diabetes, the difference was similar to racial differences in mortality rates among the general population," said Janice Dorman, associate professor of epidemiology and pediatrics, and study co-investigator. "This indicates that factors unrelated to the diabetes are responsible for the higher death rates."

"While the results of this study are encouraging, we still have a long way to go in increasing the long-term survival of people with type 1 diabetes," said Orchard.

"Mortality rates for individuals with this disease are still more than twice what they are for people without diabetes."

A previous Pitt study found that mortality rates for type 1 diabetics in Allegheny County are significantly higher than those in Finland, a country that has one of the highest type 1 diabetic mortality rates.


UPCI begins polyp study

Researchers at the University of Pittsburgh Cancer Institute (UPCI) are participating in an international multi-center trial to determine if Vioxx, a drug approved for pain relief and arthritis, can safely and effectively prevent the recurrence of precancerous growths in the colon. There is currently no treatment to prevent the recurrence of these growths, called adenomatous polyps, which are the precursors to colon cancer.

Next to lung cancer, colorectal cancer is the second leading cause of cancer-related deaths in the United States. It affects both men and women to a significant degree. Each year, colorectal cancer is diagnosed in more than 140,000 patients in the United States with an annual mortality of 56,000 individuals.

Prevention of colorectal cancer is currently focused on identifying individuals with precursor growths and removing them during colonoscopy, a procedure where a scope is put into the large bowel to inspect the lining for cancer and pre-cancerous changes, thereby preventing subsequent development of cancer. Patients who develop polyps are more likely to get them again and need to undergo routine surveillance.

"Since adenomatous polyps play a significant role in the progression to colorectal cancer, it is critical to eliminate them in the early stages before cancer develops, or to prevent them from forming," said Robert E. Schoen, associate professor of medicine and epidemiology, director of the Colorectal and G.I. Cancer Prevention and Control Research at UPCI and principal investigator of the study.

Vioxx, which is manufactured by Merck & Co., Inc., has been approved by the U.S. Food and Drug Administration for the treatment of symptoms related to osteoarthritis, the management of acute pain and the treatment of menstrual cramps. Recent studies suggest that drugs like Vioxx may be effective in preventing the recurrence of colon polyps as well.

About 60 participants in Pittsburgh will take part in the study, which is a three-year, randomized trial. More than 2,400 patients will be enrolled at 70 sites in the U.S., Canada and Europe.

Despite improvements of surgical technique and the development of adjuvant chemotherapy, cure rates for advanced colorectal disease have remained low. Endoscopic removal of polyps is the standard of care. Research has focused on developing a safe chemopreventive treatment that will effectively reduce recurrent polyp growths. "Ultimately, this research could lead to a therapy which would prevent colorectal cancer from developing," said Schoen.


Researchers confirm Prozac is effective in sustaining eating disorder remission

Fluoxetine hydrochloride (Prozac) is effective in helping people with anorexia nervosa maintain healthy body weight, according to a study by Pitt researchers published in the April issue of Biological Psychiatry.

The research is the first to suggest that an antidepressant may be useful in helping recovering anorexics sustain normal weight post-hospitalization. It also provides additional evidence that eating disorders are true biochemical brain illnesses, along the lines of depression and other mood disorders.

According to the research, fluoxetine, one of a class of drugs called selective serotonin reuptake inhibitors, stabilizes the brain's supply of serotonin, a neurotransmitter associated with mood and appetite, by preventing its reuptake, or re-absorption, by the brain. This helps to correct the changes in brain function responsible for many of anorexia's symptoms, which include depression, anxiety and obsessions and compulsions.

In the study, Walter H. Kaye, professor of psychiatry at Pitt's School of Medicine, and his colleagues followed for one year 35 anorexia outpatients who were discharged from the hospital after they recovered a significant amount of their body weight. Fluoxetine was prescribed for 16 of the patients while the remainder took a placebo. Among the patients on fluoxetine, 10 of 16 did not relapse and maintained a healthy body weight, while only three out of 19 on placebo were successful.

"We are very excited by the results," Kaye said. "Until now, there have been no effective drug treatments for anorexia."

Kaye cautioned that for fluoxetine to be effective, patients must first get to a healthy body weight. "If they are malnourished, their serotonin system may be unresponsive to medication," Kaye explained. "Serotonin comes from tryptophan, an amino acid which can only be obtained in the diet. Often, the only way to help them return to a healthy body weight is through structured inpatient treatment. Once patients have a healthy body weight, a medication that helps them maintain it outside of the hospital and prevent relapse may ultimately save lives."

Anorexia nervosa is a chronic and dangerous disorder that if left untreated, is ultimately fatal. It affects mostly young women and often starts in the early teen years. Eating disorders often run in families and may have a genetic component.

The Price Foundation of Geneva, Switzerland, is funding new research by Kaye to uncover the genes responsible and to help develop new medical treatments for eating disorders.


Psychological, educational services reduce children's involvement with fire

Pitt research suggests that structured treatments designed specifically to intervene with children who set fires are more effective in the long-term than having a firefighter visit the child's home, a commonly used intervention for child fire setters.

Cognitive behavioral therapy (CBT) and fire safety education (FSE) were found to significantly curtail firesetting and matchplay behaviors up to a year after intervention. More fires were set by children who received a home visit by a firefighter (HVF) during this one-year follow-up period.

Results of the study were published in the March 2001 issue of the Journal of Child Psychology and Psychiatry.

"Our results show that children who set fires are less likely to exhibit either firesetting or matchplay by 12-month follow-up if they receive CBT or FSE, rather than HVF," said David J. Kolko, associate professor of child psychiatry, psychology and pediatrics at Pitt's School of Medicine. "Our research shows that using these two alternative approaches can reduce the number of repeat occurrences of these behaviors."

Kolko cautioned that because children set fires for different reasons, including curiosity and behavior problems, researchers need to determine how best to apply each intervention — for example, CBT may work better for kids with behavioral problems and FSE may work better for children who are just curious about fire. Those interventions would then need to be refined to achieve the best results.

For the study, Kolko assessed a total of 70 children who had set a recent fire. Of the 54 children who entered the study, 38 were assigned to receive either CBT or FSE and 16 received HVF. At the conclusion of the intervention period, all three interventions were associated with a marked decrease in fire-related activities.

"In light of this study, it is our hope that CBT and FSE can become a more integral part of the standard services available for child firesetters," said Kolko. "These results also give us a base upon which to expand our research to find out what types of alterations can be made to CBT and FSE to make those interventions more effective."

Statistics from the National Fire Prevention Association indicate that children playing with fire were responsible for more than 98,000 fires in the United States that caused 408 civilian deaths, 3,130 injuries and more than $300 million in direct property damages in a year (1994). Research conducted by Kolko over 15 years shows that, in some cases, more than half of all child firesetters will repeat the activity over a two-year period.

Some form of home visit from a fighter, according to Kolko, is a common method of helping child firesetters and was never meant to be a long-term service. It usually involves a firefighter going to the home of a child who has set a fire, reviewing with the child and parents some ways to avoid using fire, and handing out some educational materials. Even though this brief home visit may not have been as effective as the other two more intensive interventions, it was associated with a significant reduction in the number of fires that were set by those children and may be a cost-effective alternative service.

Cognitive-behavioral therapy for child firesetters involves the application of psychological strategies to enhance the child's self-control, assertion and problem-solving and parents' use of effective discipline and communication, whereas fire safety education involves training in several fire safety principles and prevention activities.

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