Project Closes Gap Between Evidence and Practice, Wins Quality Transformation Award

Dr. Samir Shah 

Dr. Samir Shah and a team of 60 undertook a successful project to put evidence-based goals into practice around use of antibiotics.

In March, the Society of Hospital Medicine presented its Excellence in Teamwork in Quality Improvement Award to a team of 60 healthcare professionals at Cincinnati Children’s.

Their project was to close the gap between protocol-based evidence and applying that evidence to clinical care.

“We focused on infections, which are the most common reason for children being hospitalized,” explains Samir Shah, MD, Director, Division of Hospital Medicine. “There can be large gaps between best practice, as demonstrated in published research or guidelines, and actual care. We decided to close that gap at our medical center, and we developed implementation strategies easily replicated at other institutions.”

The team tackled issues with the greatest impact on patient safety and clinical outcomes. Specific projects included decreasing reliance on intravenous antibiotics and using oral antibiotics at hospital discharge instead; decreasing use of X-rays of the bladder for infants and children with their first urinary tract infection; increasing use of lactobacillus to treat acute gastroenteritis; improving antibiotic prescribing in community-acquired pneumonia; and shortening the duration of antibiotic use in treating skin and soft tissue infections.

The multidisciplinary team included staff from Hospital Medicine, General and Community Pediatrics; Emergency Medicine; Division of Pharmacy; Infection Diseases; Anderson Center for Health System Transformation; Information Services; Human Resources; Patient Services and Decision Support.

Hostetter Named Director of Research Foundation

Dr. Margaret “Peggy” Hostetter 

Dr. Margaret “Peggy” Hostetter is the first woman to head the Cincinnati Children’s Research Foundation.

Margaret “Peggy” Hostetter, MD, has been selected to serve as Director of the Cincinnati Children’s Research Foundation, B.K. Rachford Professor and Chair of the Department of Pediatrics, University of Cincinnati College of Medicine, and Chief Medical Officer of Cincinnati Children’s.

Hostetter assumes her new role on July 1. She succeeds Arnold Strauss, MD, who has served in these positions since 2007.

“Cincinnati Children’s is a remarkable institution with leadership, faculty, and staff whose commitment to the improvement of children’s health is extraordinary,” Hostetter says. “I am honored to serve in this very special role.”

Hostetter came to Cincinnati Children’s in 2010 as the Albert B. Sabin Professor and Director of the Division of Infectious Diseases. She is funded by the National Institutes of Health for leading the Pediatric Scientist Development Program and by the Bill and Melinda Gates Foundation for her studies of Candida albicans, the yeast that causes vaginal colonization in pregnant women as well as potentially fatal bloodstream infections in premature infants and immunocompromised individuals. Hostetter and her laboratory hold six patents for discoveries in these areas.

Hostetter earned her MD from Baylor College of Medicine and completed her residency and fellowship in pediatric infectious diseases at Boston Children’s Hospital. After leading the Division of Pediatric Infectious Diseases at the University of Minnesota, she served as Jean McLean Wallace Professor of Pediatrics and Chair of the Department of Pediatrics at Yale University until joining Cincinnati Children’s.

Among her many honors are the American Academy of Pediatrics Award for Excellence in Research and the Maxwell Finland Lectureship of the Infectious Diseases Society of America. In 1993, Hostetter was the second woman elected to the presidency of the Society for Pediatric Research, 30 years after the election of her mentor, Mary Ellen Avery.  She is a member of that organization as well as of the American Pediatric Society, the American Society for Clinical Investigation, the Association of American Physicians, and the Institute of Medicine of the National Academy of Sciences.

Adding to her list of accomplishments, Hostetter was recently voted President-Elect of the American Pediatric Society and will assume the presidency in May 2015.

“Peggy is an outstanding leader in pediatrics, dedicated to the development of physician-scientists and to discoveries that will change our care of children throughout the world,” says Strauss.

 Twins Provide Clues for Battling Leukemia

Dr. Gang Huang 

Research co-authored by Dr. Gang Huang found the gene mutations responsible for a virulent form of acute myeloid leukemia.

Scientists have found a promising new target for treating a deadly malignancy, thanks to identical twins.

A recent study co-authored by a cancer researcher at Cincinnati Children’s involved twin 3-year-old girls, one of whom was healthy while the other developed multi-lineage leukemia (MLL), an aggressive form of acute myeloid leukemia. By comparing the girls’ blood cells, the scientists identified in the twin with MLL a cascade of cancer-fueling gene mutations and DNA misalignments that traced back to two mutations in the gene SETD2.

The research team from China and the United States reported their findings online Feb. 9 in Nature Genetics.

“These mutations contribute to the initiation and progression of leukemia by promoting the self-renewal potential of leukemia stem cells,” says Gang Huang, PhD, the Cincinnati Children’s researcher who was corresponding author of the study.

The SETD2 gene normally suppresses tumor growth, but mutations disrupt this process and fuel the development of MLL. The SETD2 mutations also activated two other genes (mTOR and JAK-STAT) known to contribute to cancer and leukemia.

Researchers found SETD2 mutations in 6.2 percent of the blood samples from 241 people with various forms of leukemia.  The scientists tested mTOR-inhibiting medications on the pre-leukemic cells generated by the SETD2 gene mutations, which resulted in a marked decrease in cell growth.

Huang says these tests demonstrate that there are multiple opportunities to improve MLL treatment. The researchers plan to continue their work by looking for drugs that can target the MLL fusion-SETD2-H3K36me3 pathway. They also continue to look for additional pathways activated by SETD2 mutations.

The twin sisters’ genomes were compared at the laboratory of co-corresponding author Qian-fei Wang, PhD, Beijing Institute of Genomics. Several other institutions in China and a research center in Chicago also collaborated on the study.

Receipts Could Pose Harm to Cashiers

Dr. Shelley Ehrlich 

A study led by Dr. Shelley Ehrlich was the first to show that the harmful chemical BPA can penetrate the skin.

Extensive handling of thermal receipts from cash registers significantly increases exposure to the chemical bisphenol A (BPA). BPA is used as a coating on the receipt paper.

The study, published in the Journal of the American Medical Association, is believed to be the first to show that BPA penetrates skin. The chemical has been implicated in health problems associated with ingesting food or drinks from cans or plastic bottles that contain it.

“We observed an increase in urinary BPA concentrations after continuously handling receipts for two hours without gloves,” says Shelley Ehrlich, MD, an obstetrician/gynecologist and epidemiologist at Cincinnati Children’s and the study’s lead author. When the simulation was repeated using gloves, there was no significant increase in urinary levels of the chemical.

The study involved 24 volunteers at the Harvard School of Public Health who printed and handled receipts continuously for two hours without gloves. The researchers detected BPA in 83 percent of the students prior to handling the receipts and in 100 percent of the students after handling the receipts. 

Urinary concentrations of BPA were more than three times higher after handling the receipts. Twelve participants who provided sequential urine samples over a 24-hour period had more than a five-fold increase in BPA urinary concentrations compared to baseline. There was no significant increase in urinary BPA when participants wore gloves.

This study shows that cashiers in supermarkets and gas stations, bank tellers, and librarians could be at higher risk by absorbing BPA through their skin when handling receipts. 

“While our study findings showed that continuous thermal receipt handling without the use of gloves significantly increased urinary concentrations of BPA, a larger study is needed to confirm our findings and evaluate the clinical implications of this type of exposure,” Ehrlich says.

Shock Value

Simple blood test works in adults and children to quickly predict severity of septic shock.

Dr. Hector Wong 

The biomarkers for risk of death in adults were nearly the same as those in children, says Dr. Hector Wong.

A doctor at Cincinnati Children’s has developed a test that quickly and accurately predicts the risk of death for patients suffering from septic shock — a severe systemic infection that rapidly damages vital organs. It is one of the leading causes of death in hospitalized adults and children.

The simple blood test measures five biomarkers, or proteins, in the blood. Results are combined with other information about the patient to estimate the probability of surviving the illness.

The test should enable doctors to decide more quickly whether a severely sick person needs aggressive life-saving treatment, says Hector Wong, MD, Director of the Division of Critical Care Medicine. The study was led by Wong and Christopher Lindsell, PhD, of the University of Cincinnati College of Medicine.

Finding ways to treat septic shock has been tricky. Clinical trials of treatments to stop the infection are complicated by patients too sick to be saved by the therapies or not sick enough to warrant them.

“Substantial resources are invested in trying to find new treatments for septic shock, but the vast majority of them fail in clinical trials because mortality risk varies widely in septic shock patients,” explains Wong.

Results of the test’s effectiveness were reported in April in Critical Care Medicine. The researchers developed a similar test for children, the results of which were published in PLOS ONE earlier this year. The new study involved 882 adults in intensive care units in the United States, Finland and Canada. One important similarity in their findings was that three of the biomarkers identifying risk for adults were the same as those in children, providing potential targets for treatment.

Study funding came from the National Institutes of Health and the Center for Technology Commercialization at Cincinnati Children’s.

 Gene Therapy for Hurler Syndrome Shows Promising Results

Dr. Dao Pan 

An experimental gene therapy given to mice completely corrected the fatal genetic disorder known as Hurler’s syndrome, says Dr. Dao Pan. Now, will it work in humans?

Scientists from Cincinnati Children’s and the National Institute of Neurological Disorders and Stroke (NINDS) have developed an experimental gene therapy that could possibly cure Hurler syndrome, an unusual and often fatal genetic disorder.

Children with Hurler syndrome lack the critical lysosomal enzyme alpha-L-iduronidase (IDUA) and cannot break down sugar molecules called glycosaminoglycans.  The molecules build up in the body and cause extensive damage. In the study, the researchers successfully used engineered blood platelets and bone marrow cells to deliver gene therapy to mice bred to exhibit the disease. The gene therapy enabled the cells to produce IDUA, resulting in a complete metabolic correction of the disease.

The results were published online in February, in the Proceedings of the National Academy of Sciences. “Our findings demonstrate a unique and somewhat surprising delivery pathway for lysosomal enzymes,” says Dao Pan, PhD, corresponding author and researcher in the Division of Experimental Hematology and Cancer Biology. “We show proof of concept that platelets and megakaryocytes are capable of generating and storing fully functional lysosomal enzymes, which can lead to their targeted and efficient delivery to vital tissues where they are needed.”

Pan and colleagues — including Roscoe Brady, MD, a researcher at NINDS — engineered human megakaryocytic cells capable of overexpressing IDUA.  Once infused, the cells produced large amounts of functional IDUA and could cross-correct other cells. More study is needed to determine if the treatment would be safe and effective for human patients.

 Cincinnati Children’s Named First U.S. INSPIRE Site

Dr. John Clancy 

As an INSPIRE site, we can further expand our trials of advanced treatments, says Dr. John Clancy, who oversees our Office for Clinical and Translational Research.

Cincinnati Children’s is the first academic medical center in the United States to be named an INSPIRE (Investigator Networks, Site Partnerships and Infrastructure for Research Excellence) site by Pfizer.

Pfizer created the INSPIRE designation in 2013 to recognize medical facilities for their expertise and quality in conducting clinical trials. There are currently just over 100 INSPIRE sites in the world.

“Not only does this designation recognize our role as a leader in conducting treatment trials for children and adults,” says John P. Clancy, MD, Medical Director of the Office for Clinical and Translational Research, “but it will also allow us to expand our program to deliver even more advanced and potentially lifesaving treatments to our patients.” 

INSPIRE sites receive early consideration for research opportunities with Pfizer and non-financial assistance with audits and other quality measures. Hospitals chosen as INSPIRE sites must meet strict criteria in how they conduct clinical trials, including having medical expertise in key disease areas, highly trained staff and dedicated resources for clinical research. They must also meet specific trial recruitment goals and timelines.

Annually, Cincinnati Children’s has more than 2,250 investigator-initiated, industry- and federally-sponsored IRB-active protocols, including pediatric Phase I-IV and select adult (vaccine and cancer) Phase I-IV clinical studies.

Cincinnati Children’s is accredited to conduct clinical research by the Association for the Accreditation of Human Research Protection Programs and has been conducting pediatric research since 1931.

 Drug Stops Cancer, But Not As Thought

Dr. Biplab Dasgupta’s 

Dr. Biplab Dasgupta’s study of the diabetes drug metformin for cancer treatment showed the drug worked by inhibiting the mTOR molecule.

Researchers from Cincinnati Children’s Hospital Medical Center who led a study of the drug metformin for cancer treatment have found that it works, but not the way it was believed.

In a report published Jan. 13 in Proceedings of the National Academy of Sciences, the research team challenged the belief that the drug activates a molecular regulator of cell metabolism called AMPK to suppress tumor growth.

Extensive laboratory tests revealed that metformin does stop cancer, although not by activating AMPK. Instead, in tests involving glioma brain cancer cells, the authors found that metformin inhibits a different molecule called mammalian target of rapamycin (mTOR), which has been linked to many other cancers.

Originally developed to treat diabetes, metformin suppresses the actions of insulin and insulin-like growth factors — two molecules that support cancer growth, according to Biplab Dasgupta, PhD, principal investigator and a researcher in the Division of Hematology/Oncology at Cincinnati Children’s. “Our findings do not suggest that clinical trials using metformin should be stopped. Metformin appears to be a very useful drug, but the drug’s mechanism of cancer suppression is not clear,” he says.

Dasgupta suggests that while one important cellular effect of metformin in cancer cells is inhibition of mTOR independent of AMPK, activation of AMPK itself may actually fuel growth of certain cancers. Recent unpublished work from his lab indicates this.

“Our findings unveil a potential role for AMPK as a tumor growth supporter, not a suppressor, in the type of cancer that we study. This is why clinicians using metformin in clinical trials should use caution during data interpretation.”

Ultimately, improving targeted cancer therapies will require more accurate understanding of AMPK’s role and a better understanding of how a drug like metformin stops cancer, says Dasgupta.

The study involved scientists from Cincinnati Children’s; the University of Cincinnati College of Medicine; the Mayfield Clinic; the Mayo Clinic; Katholieke Universiteit and Antwerp University Hospital in Belgium; and the Inserm Institut Cochin and the Universite Paris Decartes in Paris.

Funding for the study came from CancerFreeKids, the Smith-Brinker Golf Foundation, a Cincinnati Children’s Trustee Scholar Grant and the National Institutes of Health.