News in Brief

Making Leukemia treatment stick

Better survival rates for kids with leukemia have been a great success story in the battle against cancer. But for some children, even highly advanced stem cell transplants are not enough to prevent the cancer from coming back.

Qishen Pang, PhD, a researcher at Cincinnati Children’s, is working to correct that problem. He is using a five year, $1.58 million grant from the National Cancer Institute to study a way to make stem cell transplantation more effective.

For nearly 20 years, Pang has studied Fanconi anemia (FA) as a model for understanding bone marrow failure and leukemia. In 2008, Pang and colleagues published a paper in the journal Blood reporting that FA patients show significantly reduced activity of an important compound called Cdc42. The grant will allow Pang to explore a novel concept: manipulating Cdc42 levels as a way to prepare a patient so that stem cell transplants can have maximum effect.

“Cdc42 is a critical regulator of the stem cell and bone marrow microenvironment,” Pang says. “Relapse occurs because treatment didn’t get to the stem cells. For transplants to be fully effective, we must first open up the stem cell niche to ‘chase out’ the cancer stem cells.”

Preparing patients for stem cell transplants already involves administering toxic radiation or chemotherapy to destroy cancer-ridden bone marrow. But this approach does not reach dormant cancer stem cells, Pang says.

If Cdc42 levels can be controlled, it could help lure cancer stem cells out of dormancy and make them more vulnerable to attack.

“Many cancer drugs only work when the cancer cells are actively dividing,” Pang says.

His study involves using mouse models to analyze a Cdc42 inhibitor called CASIN, which was developed at Cincinnati Children’s several years ago. If these pre-clinical studies show promise, future steps would include human clinical trials as well as research to determine if other cancers can be treated this way.

“Other solid-tumor cancers may also have abnormal Cdc42 activity. This may be a way to augment chemotherapy,” Pang says.

Study explores ways to boost the heart's healing power 

When a person’s heart starts to fail, the body attempts to compensate to keep the damaged organ pumping as long as possible.

A researcher at Cincinnati Children’s is using a four-year, $1.9 million federal grant to harness one of those compensatory strategies – a gene called TSP4 – as a possible approach to treating heart failure.

The work is funded by the National Heart, Lung and Blood Institute and led by Jeffery Molkentin, PhD, a researcher with our Heart Institute and investigator with the Howard Hughes Medical Institute.

Heart failure primarily affects older adults. But some children also develop heart failure, including many who had surgery as infants to correct hypoplastic left heart syndrome, Molkentin says. Moreover, “Heart failure patients have a poor prognosis. More than half die within five years,” he says.

Previous research shows that several genes become upregulated during heart failure. Most of those changes reflect the damage process, but not all.

“There is a whole family of thrombospondin genes. Collectively, this gene family has received lots of research attention. But TSP4 is a newer one,” Molkentin says. “It is mostly restricted to heart and skeletal muscle and appears to help those tissues deal with injury.”

Previous studies have shown that TSP4 mutations can predispose people to heart attacks. Mice bred to lack TSP4 die quickly after cardiac stress, while those bred for strong upregulation of TSP4 appear protected from cardiac damage.

Researchers believe TSP4 triggers an adaptive stress response in the cell’s endoplasmic reticulum (ER). This improves the cell’s ability to process unfolded proteins, which occur as a result of tissue damage and would otherwise cause further cell death.

Children's joins group studying asthma in urban environments

Cincinnati Children’s Hospital Medical Center has joined a national research effort to shed light on the growing problem of asthma in our inner cities.

The Inner City Asthma Consortium (ICAC) was formed in 2002 by the National Institute of Allergy and Infectious Diseases (NIAID) to reduce asthma severity, to prevent asthma among inner-city children, and to identify asthma-triggering factors that may be unique to life in urban environments. The consortium has grown to 11 sites, now including Cincinnati Children’s.

The medical center will receive about $3.5 million over four years to participate in large-scale clinical studies through ICAC.

“It’s a huge step for Cincinnati Children’s to be involved in a network like this. We have an opportunity to impact the way we manage asthma on a national scale,” says Gurjit Khurana Hershey, MD, PhD, director of the Division of Asthma Research and principal investigator for ICAC here. Carolyn Kercsmar, MD, director of the Asthma Center, Division of Pulmonary Medicine, is a co-investigator for the study.

Cincinnati Children’s serves about 7,000 children with asthma each year, including more than 3,000 emergency visits and 885 hospital admissions. Asthma affects about 150 million people worldwide, according to the World Health Organization (WHO). In the United States alone, asthma results in about 2 million emergency hospital visits and nearly 5,000 deaths a year.

The consortium is pursuing several lines of research, including comparing treatment regimens, searching for biomarkers to predict asthma severity and detailing environmental factors.

“Part of this is about doing extensive analysis of the microbiology of the home environment and how it may be different from someone who doesn’t live in the inner city,” Hershey says. “Some of these allergens are already known. But there may be other microbes in the inner city environment that we are not aware of.”

New dermatology director will expand treatment research

Our ability to care for and conduct research into the many skin problems that afflict children will get a boost this summer. Kara Shah, MD, PhD, will join Cincinnati Children’s on Aug. 1 as director of the Division of Dermatology.

Shah comes to us from the Children’s Hospital of Philadelphia, where she completed a fellowship in pediatric dermatology and ran specialized dermatology clinics. Her interests are in atopic dermatitis (eczema), genetic skin diseases (genodermatoses) and skin cancers.

"I'm hoping to develop our capacity to evaluate skin cancers in children, including melanoma and lymphoma of the skin," she says. "I want to expand our clinical research into these conditions so that we can treat them more effectively."

Shah adds that melanoma, while still rare in children, is becoming more common, and is still not well understood.

“The numbers are growing,” she says. “It’s probably partially related to sun exposure, particularly in older children and adolescents. And we’re seeing more kids who are cancer survivors and who have skin problems from
chemotherapy, or who are on chronic immunosuppression for other diseases. They also have an increased risk.”

One effort Shah is particularly enthusiastic about will be working with allergist Amal Assa’Ad, MD, to start a center focused on the treatment of eczema. Beyond that, she wants to make sure that dermatology services are readily available to other specialists throughout the hospital.

“I’d like to establish pediatric dermatology as a specialty that’s well integrated with all the care that’s offered here,” she says

Test for LAM disease now available

The first blood test for lymphangioleiomyomatosis (LAM), a rare and often undiagnosed lung disease, is now available for clinical use.

The test was developed at Cincinnati Children's Hospital Medical Center and the University of Cincinnati (UC) in conjunction with Circadian Technologies of Australia.

LAM causes shortness of breath and lung collapse. It affects mostly women, often striking during childbearing years. An estimated 250,000 women worldwide have undiagnosed LAM.

The clinical test, called serum VEGF-D (vascular endothelial growth factor-D), was recently validated by Cincinnati Children's as a tool for detecting LAM. Researchers at Cincinnati Children’s and UC determined that high levels of VEGF-D are indicative of LAM in women whose chest CT scans show cystic lung disease.

The findings were published in the Aug. 10, 2010, issue of Chest by a team led by Lisa Young, MD, director of the Pediatric Rare Lung Diseases Program at Cincinnati Children’s and Frank McCormack, MD, director of the Division of Pulmonary, Critical Care and Sleep Medicine at the University of Cincinnati.

"We are optimistic that serum VEGF-D will reduce the need for surgical lung biopsy and allow for intervention and trial recruitment earlier in the disease course," says McCormack, who also serves as scientific director of the LAM Foundation.

Young says a test that predicts the presence of LAM in women with tuberous sclerosis complex also could potentially reduce the need for repeat CT scans, limiting the lifetime radiation exposure of LAM patients.

Cincinnati Children’s and UC investigators reported on a potential treatment for LAM March 16 in the online New England Journal of Medicine. Sirolimus was shown to stabilize lung function and improve some measures of functional performance and quality of life.

Doctors in the United States can order the LAM test through the Translational Trials Development and Support Laboratory at Cincinnati Children's.

Hospitalist research director will focus on treatment effectiveness

With new treatments surfacing every day, how can doctors be certain of what will work best for every patient?

There are no easy answers, but help might lie in the new and growing science of comparative effectiveness research. The quest for more certainty in medical treatment has led to a focus on evidence-based practice and outcomes, led by a new breed of researchers like Samir Shah, MD, MSCE, who will join Cincinnati Children’s this August.

Shah will be research director of our Hospitalist Program and a member of the Division of Infectious Diseases. Previously at the Children’s Hospital of Philadelphia, he completed fellowship training in both pediatric infectious diseases and academic general pediatrics. He also earned a master’s degree in clinical epidemiology. His experience led him to focus on the more common childhood infections – and the treatment decisions that often challenge pediatricians.

“My combined training prompted my interest in the more common diseases that affect children who are otherwise healthy, such as pneumonia and meningitis,” Shah says. “My goal is to create knowledge that clinicians can use to change how they care for patients.”

Shah has published extensively on the subject of childhood infections. His latest study was published this spring in the Journal of Hospital Medicine. It focused on how kids with empyema, a complication of pneumonia, were treated in 40 hospitals across the country. And it showed how treatment of the same condition varied widely – both among and within hospitals.

Shah says this is just one of countless examples of how practice differs because doctors have no clear-cut evidence that one treatment works better than another. “In addition to conducting randomized trials of different treatments,” Shah says, “we need to consider hospital-level factors that might contribute to unwarranted variation in clinical practice and outcomes.”

Shah hopes to conduct effectiveness research that will help improve outcomes not only at Cincinnati Children’s, but far beyond our walls.

A member of the Pediatric Research in Inpatient Settings (PRIS) network, he will work collaboratively with fellow hospitalists in 80 centers throughout the United States and Canada to study key questions in inpatient pediatric care.

Biotech venture receives $11 million investment

AssureRx Health, Inc., a biotech company developing personalized medicine technology created at Cincinnati Children’s, has received a major infusion of venture capital.

A group of investors led by Claremont Creek Ventures and Sequoia Capital invested $11 million in AssureRx. Other investors include Cincinnati Children’s and CincyTech.

The company’s first commercial product is GeneSightRx®, technology that helps doctors prescribe the right drug at the right dose for patients with psychiatric conditions.

GeneSightRx uses algorithms that combine patient genetics, clinical pharmacology, evidence-based medicine and environmental factors to help doctors find the best dose for their patients. Initial research for the product was done by neurologist Tracy Glauser, MD, pharmacologist Alexander Vinks, PharmD, PhD, and researcher John Pestian, PhD, Division of Biomedical Informatics.

“This capital investment is an important step forward in translating our pharmacogenetic research into improved clinical practice,” says Glauser. “It’s just one example of the type of translational research occurring here that can impact thousands of kids around the world.”

Cincinnati Children’s licensed the GeneSightRx technology to AssureRx in 2006 and helped launch the company with seed money from its Tomorrow Fund. AssureRx is one of six biomedical start-ups Cincinnati Children’s has launched in the last five years.

This latest investment will pay off in a number of ways, says Niki Robinson, PhD, who oversees the Center for Technology Commercialization at Cincinnati Children’s.

“It validates the innovation and impact of our researchers. It provides the opportunity to improve outcomes for patients around the world. And it has the potential to generate revenue that can be reinvested in research,” Robinson says.

Examining Cilia's role in craniofacial disorders

Can malfunctions in a common cellular “antenna” explain some of the most unusual disruptions in human facial development?

Samantha Brugmann, PhD, a new researcher in the Divisions of Plastic Surgery and Developmental Biology at Cincinnati Children’s, has received a three year, $747,000 federal grant to find out.

Brugmann is studying how defects in primary cilia of bone cells affect craniofacial development. These tube-like protrusions from cell surfaces act as receptors for important molecular signals – which in this case instruct cells to proliferate.

Malfunctions in primary cilia may lead to rare conditions which affect mid-facial development including hypertelorism (abnormally wide gaps between the eyes) and diprosopus (an unusual duplication of central facial structures).

“Craniofacial disorders are particularly damaging to children,” Brugmann says. “Not only because of the extensive and repeated surgeries needed to correct them, but also because of the stigma that goes along with having a craniofacial disorder.”

Her current study is funded by the National Institute of Dental and Craniofacial Research. It involves using an avian model to explore how neural crest cells use cilia to process molecular signals.

“We are isolating neural crest cells at four key stages in the development process,” Brugmann says. “Are the cells migrating correctly? Are they proliferating to the right amount? Are they forming skeletal elements correctly?”

If defective primary cilia can be confirmed as a common root cause of craniofacial disorders with mid-facial expansion, such findings eventually could lead to gene screening tests. However, years of further work would be needed to translate such knowledge into preventive treatment.

Helping kids with ADHD improve reading skills

Along with difficulties staying calm, focused and organized at school, kids with ADHD – attention deficit hyperactivity disorder – seem to have trouble learning the same way as their peers.

So how do you help a child with ADHD who struggles with reading? Leanne Tamm, PhD, a clinical psychologist in the Division of Behavioral Medicine and Clinical Psychology and researcher in the Center for ADHD at Cincinnati Children’s, is looking for answers.

Tamm is principal investigator at Children’s on a study with the University of Texas Health Science Center at Houston. They will compare outcomes of children receiving ADHD intervention, reading intervention or a combination of both.

The study is in its first of a five-year, $2.7 million grant from the National Institute of Child Health & Human Development.

After being screened at school, 216 second through fifth-graders will receive a free ADHD evaluation and reading assessment, followed by 16 weeks of intervention. Children are randomly assigned to receive ADHD intervention only (which includes behavioral strategies for parents and medication for the kids), reading intervention only (which includes 64 sessions with a reading tutor) or both.

“The interesting question is how to approach treating these kids, figuring out where to intervene and what to do with them,” Tamm says.

Researchers will use the data on how kids do after the intervention program to try to guide future clinical treatment.

New Esophageal Center expands treatment for disorders

Daniel von Allmen, MD, eagerly awaits the visit of a 3-year-old patient. The child has already had his share of hospital visits; von Allmen hopes this one will be different. It is an opportunity to put into practice what the surgeon believes is an ideal approach to treating the child’s esophageal atresia.

When the child arrives, pediatric surgeon von Allmen will share the operating room with specialists in three other disciplines to determine the child’s treatment. Esophageal atresia is rare, occurring in about one in every 4,000 children. Something goes awry during fetal development and the esophagus develops abnormally. The consequences can be devastating.

The child has had multiple surgeries elsewhere, with little success. von Allmen believes that this time, they can find a solution that works – if all goes well, in a single visit.

It’s an approach that’s at the heart of the new Esophageal Center that von Allmen oversees. The center treats esophageal atresia as well as strictures, fistulas, caustic ingestions and most other esophageal disorders.

Its specialists include pediatric surgeons, otolaryngologists, gastroenterologists and pulmonologists. All are experienced in repairing esophageal disorders. Cincinnati Children’s has long been a referral center for these complicated cases, through its Aerodigestive and Sleep Center.

Based on experience so far, von Allmen expects that most of the children who come to the center will already have had at least one unsuccessful surgery.

“This is just an extremely complicated problem. We have a lot of experience with it, so we can bring a lot of resources to bear.”

He is confident that those resources will make a child’s visit a lot easier and far more worthwhile.

“The beauty of this program is that it brings the best minds and specialties together, in one place at one time,” he says. “We gather the child’s records, meet as a team, decide what the plan should be, and orchestrate things so that in one two- to three-day visit they can have everything done. When the family leaves, they have a plan for the child’s ongoing care.”

von Allmen also hopes to work closely with Cincinnati Children’s researchers to explore better treatments for these complex, life limiting disorders.