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Children's Hospital Researchers Contribute to Clinical Advances
 Patients and families benefit not only from the care they receive at UW Children's Hospital, but also from the latest research conducted by its scientists. The rapid translation of research findings for use by UW clinicians ensures that sick children receive the most advanced treatments available.
"All staff members have easy access to the expertise of colleagues in other specialties," says Aaron Friedman, MD, medical director of UW Children's Hospital. "On any given day, doctors here may be discussing the latest advances in treating common sinus infections or reviewing research about brain tumors."
Faculty from the UW Medical School's Department of Pediatrics are currently involved in approximately 70 basic and clinical research projects. What follows are just a few areas in which faculty members and other scientists at UW Children's Hospital have made their mark on the national scene.
Childhood Cancer
The survival rate for leukemia and other childhood cancers has improved more dramatically over the past three decades than for any other form of the disease. Today, nearly four out of five children with this cancer ultimately will be cured.
The Pediatric Hematology/Oncology Division at UW Children's Hospital, headed by Paul Sondel, MD (PG), PhD, has played no small role in this remarkable improvement. Much of the progress occurred through collaborative work with the national Children's Oncology Group (COG). The UW team has continued to provide leadership for past and present clinical trials, and Sondel has served as immunotherapy leader for the group.
"Our institution was one of the initial members of the COG," Sondel says. "With almost half of all childhood cancer patients in the United States participating in COG research protocols, great strides have been made toward more effective cancer treatments and higher cure rates."
One such protocol seeks to determine whether children with high-risk neuroblastoma, a malignancy largely found in infants and toddlers that is especially difficult to treat, are less likely to experience a recurrence of their disease following treatment with a form of immunotherapy pioneered by Sondel's research lab. In this nationwide trial, following the completion of chemotherapy, some children will receive immunotherapy consisting of anti-tumor monoclonal antibody together with two growth factors (IL2 and GM-CSF) that help white blood cells use the antibody to kill cancer cells. Ongoing research in Sondel's lab, supported by the National Cancer Institute, is investigating ways that linking the IL2 directly to the antibody can improve the anti-tumor effectiveness of this strategy.
Another study, expected to be the largest childhood cancer clinical trial in history, is led by UW Children's Hospital's Yousif Matloub, MD, clinical director of pediatric hematology and oncology. This trial, which is testing improved schedules for the administration of effective drug combinations, aims to enhance the treatment and cure rates for children with acute lymphoblastic leukemia, while decreasing the side effects of the treatment.
"We have three major goals," Sondel says. "We want to improve the cure rate, especially for children with malignant brain tumors and other cancers where the survival rate is not as high. We want to prevent some of the side effects associated with cancer treatments. And third, we are calling for leadership at the national level to help former childhood cancer patients mainstream back into a normal life at school or work."
Cystic Fibrosis
The debate was intense back in the early 1980s. Do early diagnosis and treatment of cystic fibrosis (CF) really benefit patients with this disease--and do the benefits outweigh the risks of stigmatizing children who might have CF?
Researchers at UW Children's Hospital, led by Philip Farrell, MD, PhD, and Michael Rock, MD, tackled that question in 1985 when they launched a clinical study involving every newborn in Wisconsin. Cystic fibrosis, the most common potentially fatal genetic disease among Caucasians, produces pancreatic deficiency, chronic respiratory problems and salt loss that can lead to severe dehydration.
In April 1985, the Wisconsin CF Neonatal Screening Group (including researchers from UW Medical School, the Medical College of Wisconsin and the State Laboratory of Hygiene) began the nation's only randomized, controlled clinical trial of newborn screening for CF. All infants born in the state were tested for CF, and half were randomly assigned to early diagnosis and treatment; the other half received standard diagnosis and treatment. Patient enrollment in the study ended in June 1994, but the wealth of information from the research has proved a treasure trove for those concerned about children with CF.
Among the studies already published from the CF data, the most recent, in the Journal of the American Medical Association, revealed both risks and potential benefits of early treatment of CF. In that study, researchers found a pronounced "center effect"; that is, infants treated in clinics where they mixed with older CF patients had a much higher risk of lung infection with a common but dangerous germ than those treated in separate clinics dedicated only to infants and young children with CF. The researchers say that means infection risk could be reduced if more children were seen in such specialized clinics.
Juvenile Diabetes
While caring for diabetic children for over 30 years, Michael J. MacDonald, MD, of UW Children's Hospital, also has been among the nation's premier researchers of this disease, which is diagnosed in one in 300 children each year.
MacDonald studies the genetics of type 1 diabetes and the biochemistry of the pancreatic insulin cell. He began his diabetes research while still a medical student at Washington University in St. Louis, showing that the frequency of type 1 diabetes is lower and type 2 diabetes is higher in African-American children.
Since coming to Madison in 1974, MacDonald and his team have been studying the biochemistry of the insulin cell. The work, supported by the National Institutes of Health and the Robert Wood Johnson Family Trust, attempts to elucidate the ways in which metabolic fuels, such as glucose and amino acids, stimulate insulin release.
"With metabolic, enzymologic and molecular biologic approaches, we have discovered several signaling pathways in the insulin cell," MacDonald says. "This information is of potential benefit for preserving insulin cells for transplantation and bioengineering artificial insulin cells for the treatment of type 1 diabetes."
MacDonald's work also has been helpful in understanding the biochemical failure of the insulin cell in type 2 diabetes. With the support of the Oscar Rennebohm Foundation, MacDonald launched UW Children's Diabetes Center in 1990. The Rennebohm Foundation sponsors the other major interest of his laboratory--studying the inheritance of childhood diabetes. Many families attending the diabetes clinic at UW Children's Hospital have volunteered for this study.
In 1980, MacDonald was one of the first to recognize the benefits of the insulin pump in the treatment of diabetes in children. Since then, the UW pediatric diabetes clinic has helped several hundred children with diabetes improve their lives with "the pump."
Asthma in Children
Why do some allergic children develop chronic asthma and others do not? Over the last decade, the number of children diagnosed with asthma has increased an astonishing 170 percent--and no one seems able to explain why. Robert Lemanske, MD '75, a nationally recognized asthma researcher who treats asthmatic patients at UW Children's Hospital, eagerly seeks the answers.
One of Lemanske's high-profile research studies, known as COAST (Childhood Origins of Asthma), is based on his theory that children develop asthma because of a combination of bad genetic luck and a common childhood virus.
Some children, Lemanske says, inherit an imbalance of immune system hormones called cytokines and, as a result, become allergic to environmental triggers like house dust or pet dander. Because not all allergic children develop asthma, Lemanske believes that something has to direct the allergic response into the lower airway.
"We believe that that 'something' is actually the respiratory syncytial virus (RSV)," states Lemanske. "The time at which children catch this virus, which nearly every child gets by age two, may explain why some kids develop asthma and others do not."
With the generous help of some 300 families who have participated in the COAST study, Lemanske's efforts could prove to be a major breakthrough.
"If the COAST project shows our theory to be correct," Lemanske says, "it would help physicians identify children at risk of developing asthma and allow them to intervene aggressively at the first signs of the disease. By doing so, we can forestall lung damage later in life."
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 Paul Sondel, MD, PhD
 Yousif Matloub, MD
 Philip Farrell, MD, PhD
 Michael Rock, MD
 Michael J. McDonald, MD
 Robert Lemanske, MD
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