Bench to Bedside

May 2014

The 2014 Scientific Symposium: Capturing a Snapshot


With over 500 investigators (plus fellows, assistants, and a staff in the thousands) spread across a campus comprising more than 1.5 million square feet of space, The Children’s Hospital of Philadelphia Research Institute is a big, sprawling place. Research Institute investigations run the gamut of scientific inquiry, from those focused on injury research to genetic studies to clinical and surgical projects.

Now in its 11th year, the Research Institute Scientific Symposium aims to capture a snapshot of some of the groundbreaking work going on at the Institute every day. This year’s Symposium, held May 8 in the Colket Translational Research Building, featured presentations on the role of the circadian rhythm in lung function, the effects of brain tumors on survivors and their families, and genetic investigation of rare pediatric diseases.

In his opening remarks — which focused on genomics and politics — Chief Scientific Officer and Director of the Research Institute, Philip R. Johnson, MD, noted that when it comes to detailed biological and genetic information, “the more we know the less we know.” For example, a person’s genome can now be sequenced in just a few days for several thousand dollars. But deciphering and managing the abundance of information generated by next-generation sequencing methods remains a challenge, Dr. Johnson noted.

Touching on politics, Dr. Johnson referenced a commentary published in PNAS on the state of biomedical research in the United States, which points out a number of issues in the field — such pressure to publish and “hypercompetition” — could lead to a decline in science and scientific training. Moreover, unpredictable levels of federal support have led to uncertainty throughout the field. We need Congress to ensure a stable level of funding, Dr. Johnson said, because “basic science is where the real discoveries come from.”

“Fundamental, basic biological research is a very important part of what we do here at CHOP,” said one of the day’s presenters, Janis Burkhardt, PhD.

Sleep, Sheep, Green, & Everything in Between

The day began with a series of mentored presentations, with senior and junior researchers presenting jointly on a topic. Phyllis Dennery, MD, and Shaon Sengupta, MDDS, MPH, led off with a talk on the role of the circadian rhythm in the neonatal lung. A key question of their research, Dr. Dennery said, was whether clinical care could be optimized to match circadian rhythms. For example, she pointed out, heart attacks are more likely in the morning than at night.

This talk was followed by a presentation led by fetal surgery pioneer Alan Flake, MD. Along with Emily Partridge, MD, Dr. Flake has been working on a groundbreaking project to develop an extrauterine life support system that could help improve outcomes for severely premature babies. A combined engineering and medical challenge, Drs. Flake and Partridge have been working on a tank-based external uterus, going so far as to raise several (now healthy) premature lambs.

While there is much work to do, in addition to possibly breaking new clinical ground — and giving hope to parents of extremely low birth-weight premature infants — Drs. Flake and Partridge’s project is a powerful research tool, allowing “us to ask a lot of questions about the role of the placenta in fetal development.”

In addition to mentored presentations, the 2014 Scientific Symposium also featured a number of collaborative talks, given by investigators who worked together on projects, often across disciplines. An example is the presentation given by Jonathan Spergel, MD, PhD, and Elia Tait Wojno, PhD, on eosinophilic esophagitis (EoE). A pediatric allergist, Dr. Spergel worked closely with Dr. Tait Wojno, a microbiologist working in the lab of the University of Pennsylvania’s David Artis, PhD, to better understand the root causes of EoE, which is often painful and can cause weight loss, vomiting, heartburn, and swallowing difficulties.

The day’s highlights were its keynote speeches. The internal keynote speaker was Joseph W. St. Geme, III, MD, CHOP’s new physician-in-chief and chair of the Department of Pediatrics at the University of Pennsylvania, who researches host-pathogen interactions. In particular, Dr. St. Geme’s work has been focused on the bacterium Haemophilus influenzae, a normal member of the bacterial flora that is associated with invasive infections and localized respiratory tract disease. The Symposium’s external keynote speaker, meanwhile, was Eric Green, MD, PhD, director of the National Human Genome Research Institute. Dr. Green spoke about the history and future of genomic medicine.

“Currently, the revolution happening in medicine is genomics,” said CHOP’s Ian Krantz, MD, during his introduction of Dr. Green. Since the end of the Human Genome Project in 2001, “our knowledge of epigenomics has exponentially grown,” Dr. Green said. “We’ve learned a lot in 11 years, but we really have to be realistic and recognize that we’re probably going to study this for decades.” Our work, Dr. Green noted, is hardly done, as we’ll likely study genomics “for decades … for generations to come.”

“It is a remarkable time we’re living in,” Dr. Green opined.

To learn more about 2014 CHOP Research Scientific Symposium, see the Symposium website.

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CHOP Launches Violence Prevention Initiative


The Children’s Hospital of Philadelphia recently unveiled its Violence Prevention Initiative (VPI) in a press conference at the Karabots Pediatric Care Center in West Philadelphia. A set of CHOP programs designed to reduce the severity and impact of violence and aggression on children and families in Philadelphia communities and across the country, Mayor Michael Nutter, Councilwoman Jannie L. Blackwell, Department of Human Services Commissioner Anne Marie Ambrose, and the School District of Philadelphia’s Chief of Student Services Karyn Lynch delivered remarks in support of the VPI at the initiative’s launch.

“Every day we see the consequences of violence in our Emergency Department, in our operating rooms and on our patient units,” said Steven M. Altschuler, MD, CEO of The Children’s Hospital of Philadelphia. “Just since May 1st, 38 people — including six children — have been injured by gun violence in the City of Philadelphia. This number does not include non-gun-related violence, or the trauma imposed on witnesses, friends, family, and communities in which the threat of violence is a daily reality.”

“As an institution that exists to promote the health and well-being of children and as the nation’s leading pediatric hospital, it is our responsibility to find ways to prevent this epidemic from spreading. With the creation of VPI, we hope to find a way to stop the violence that is taking such a toll on children and families in our community,” Dr. Altschuler added.

VPI is led by a multidisciplinary team made up of some of the nation’s foremost experts in hospital-based violence intervention, evidence-based anti-bullying methods, and trauma-informed care. Through the strength of its long-time partnerships with community organizations, CHOP’s VPI builds on years of rigorous public health research to address and prevent ongoing concerns such as bullying in schools, intimate partner violence in the home and violent assaults in the community.

“More than 40 percent of young people in the U.S. are exposed to some form of violence — the intentional use of physical force or power, threatened or actual, against another person or group,” said Stephen Leff, PhD, a CHOP psychologist and co-director of VPI. “Youth can be exposed to violence in their homes, schools and communities with serious, lifelong consequences, including poor emotional and developmental health; long-term changes within the brain and stress reactions; school failure, drug abuse and delinquency; and the likelihood to perpetuate violence.”

The VPI programs concentrate CHOP’s medical training, mental health programs, provider training, research expertise, and knowledge of public health policies to interrupt violence while ensuring that limited resources are spent efficiently with the greatest chance for impact. Interventions occur at locations that are relevant to CHOP patients — within schools, primary care, and hospital sites.

The majority of children reached by VPI may never be CHOP patients, but instead witness violence in their schools or communities. VPI works within schools to provide evidence-based, whole-school approaches to bullying prevention for children in third through eighth grade. These programs address the multiple forms that aggression and bullying can take, including physical, social (such as gossiping and threatening to withdraw friendships), and cyber-bullying. This training gives them tools to handle and avoid more dire forms of violence as they grow older.

In addition, intimate partner violence (IPV) counselors support clinical staff in screening for and addressing IPV and teen dating violence in our patient population. This is a partnership with Lutheran Settlement House, with the goal of minimizing the adverse effects of childhood IPV exposure. Healthcare provider training and parenting education is also provided.

And children ages 8 through 18 who arrive in CHOP’s Emergency Department with injuries from an assault receive long-term intensive support from a violence prevention counselor in the hospital and after discharge to reduce re-injury or retaliation and to promote physical and emotional healing.

“VPI programs reach beyond the hospital and doctors office into schools, homes, neighborhoods, and recreation centers by empowering and training kids and adults to interrupt the cycle of violence,” said Joel Fein, MD, MPH, a CHOP Emergency Physician and co-director of VPI. “Through the practice of trauma-informed care, an approach that recognizes that traumatic experiences affect the way people respond to professional outreach and services, VPI aims to become a national model for hospital-led youth violence prevention.”

Further information about VPI and its specific programs can be found at

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Researchers Must Talk the Same Talk to Advance Science


What one researcher describes as asthma, another might call reactive airway disease. Unfortunately, such examples demonstrate the lack of a common pediatric research terminology, which can present barriers to data reuse, sharing, and integration. Leaders at The Children’s Hospital of Philadelphia recently published an article in Pediatrics that encourages the research community to start using the same language. In their paper, CHOP experts described the Pediatric Terminology Harmonization Initiative, which aims to provide uniform definitions and descriptions of clinical observations and data in pediatric research.

The National Institute of Child Health and Human Development is coordinating the effort in collaboration with the Enterprise Vocabulary Services of the National Cancer Institute, in order to fill a gap in the pediatric research infrastructure in the U.S.

“It is of critical importance to address this gap if we’re going to advance our scientific understanding of the causes of childhood disease,” said Christopher B. Forrest, MD, PhD, professor of pediatrics at CHOP. “Science advances through reproducibility. And when we all use different terms, we’re not able to reproduce research.”

Dr. Forrest compared the initiative to the Rosetta Stone, an ancient tablet with passages of identical meaning written in three languages that helped to decode the riddle of hieroglyphics.

“The Rosetta Stone was a big advance that allowed us to translate different languages,” Dr. Forrest said. “That’s what the terminology project does. It’s a common language that eventually will act as a Rosetta Stone for different research projects. It will allow communication across research studies.”

Traditionally, when a research team sets up a study, they have many questions in mind to tackle. But perhaps another study team across the country with the same study concept phrases their questions in an entirely different way. This could convolute attempts to pool the results.

Michael A. Padula, MD, MBI, medical director of informatics for the Division of Neonatology at CHOP, gave an example from three studies that the National Institutes of Health had funded about the off-label use of nitric oxide in premature infants. The New England Journal of Medicine published the three studies’ results: Two found it not to be beneficial, but the other found it was beneficial. The NIH convened a panel to interpret the results, but they were unable to make any conclusions because each study used slightly different definitions of bronchopulmonary dysplasia, which was the main outcome that the studies measured.

“They spent a great deal of money to fund these studies, but in the end they weren’t much farther along,” Dr. Padula said. “It was a missed opportunity. Had they been able to retrieve a granular level of data to allow them to harmonize the different definitions, then they would have been able to make a more definitive conclusion about the therapy.”

Embracing Common Terms Remains a Challenge

It can be a challenge for the research community to reach consensus on an accurate definition of a complex disease such as bronchopulmonary dysplasia or even on a common condition such as asthma. Some researchers may be reluctant to embrace a set vocabulary because they prefer certain customized terms. L. Charles Bailey, MD, PhD, an assistant professor in CHOP’s divisions of Oncology and Hematology, used the analogy of how people describe different shades of colors — red vs. rose, for instance.

“The research community must make a conceptual leap to say that we’re all going to agree to call this red in certain contexts, even though we can tell the shades apart, because it is more important for us to collaborate than it is for me to say exactly that my color is rose,” Dr. Bailey said.

Hence why the subject matter experts assembled through the Pediatric Terminology Harmonization Initiative are working to develop semantic interoperability. They are systematically going through each field of medical specialization to align like concepts, define them appropriately so that they relate to both research and clinical care, and then tether them to reference terminology sets that researchers can access easily.

Although the scope of the terminology project is substantial and time-consuming, CHOP’s experts explained why it is important to pursue it now. First, it is becoming increasing important to perform collaborative pediatric research to answer questions from broader perspectives. For example, PEDSnet is a national initiative of children’s hospitals and disease specific networks that are working together to reduce the barriers to rapid and better clinical research. PEDSnet will tap into the pediatric research terminology effort as it begins to create a common data model, said Dr. Forrest, who is the principal investigator of PEDSnet.

A common pediatric research terminology also will be an essential part of the National Children’s Health Study, led by Steven Hirschfeld, MD, PhD, who co-authored the Pediatrics article. The National Children’s Health study will be collecting huge amounts of data that must be aligned to allow translation of the evidence into clinical practice.

Second, the era of health care information exchange is creating a sea change because the care that clinicians provide is now linked to electronic health records (EHRs) that operate using specific languages and terminologies. However, most EHR systems currently do not describe pediatric conditions thoroughly or support pediatric research. Organizers of the pediatric terminology project want to get their foot into the door as EHRs are constructed so that they all map to the same standardized concepts when referring to pediatric patients.

“From the research side, this is a fabulous opportunity because all kinds of information are (is) being collected,” Dr. Bailey said.

One of the biggest barriers to widespread adoption of a common pediatric research terminology is raising awareness, Dr. Bailey noted. The NICHD website already has harmonized several terminology reference subsets for pediatric specialties that researchers can consult and begin to deliberately design studies to be consistent and interoperable.

“Start thinking about how the research you’re doing connects to the questions that your colleagues are trying to answer and how everyone could benefit from shared terminology,” Dr. Bailey said.

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Investigating a New Approach to Eosinophilic Esophagitis


Many of the major milestones in understanding eosinophilic esophagitis (EoE), a food allergy that affects the esophagus, began in research laboratories at The Children’s Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania. Investigators discovered the first gene related to the disease, and they identified an immunological pathway that makes EoE distinctive from other food allergies. Now, they are pursuing a novel approach to cure the chronic disorder, as no medications are approved currently to treat EoE.

“If it works, it can potentially revolutionize clinical care,” said Jonathan Spergel, MD, who is leading the proof-of-concept study called SMILEE.

Dr. Spergel is co-director of CHOP’s Center for Pediatric Eosinophilic Disorders, which treats 1,500 patients with EoE from all over the world. About 70 percent of the patients have milk-induced EoE. When Dr. Spergel first began studying EoE, little was known about the disease, but diagnoses of this disorder are increasing rapidly as awareness grows. “I have been fascinated to understand exactly who gets EoE, who’s at risk, and what’s the best way of treating it,” said Dr. Spergel, who is also chief of CHOP’s allergy section.

During an allergic reaction to a food associated with EoE, high quantities of eosinophils, a type of white blood cell, congregate in the esophagus. This muscular tube that carries food from the throat to the stomach gets swollen. Children with EoE experience varying symptoms including belly pain, trouble swallowing, uncontrollable reflux, and failure to thrive.

Physicians currently approach EoE treatment two ways. First, is avoidance of the food that causes the allergic reaction. Second, is prescription of topical steroids to coat the esophagus. Dr. Spergel pointed out that these options do not address the underlying disease; they only control the symptoms.

“Can we do something better? That’s the question this study is asking,” Dr. Spergel said. “We’re trying to induce tolerance using a novel method — epicutaneous immunotherapy (EPITTM).”

EPIT is a desensitization method developed and patented by DBV Technologies (DBV) and uses Viaskin® technology. The application of a Viaskin per day involves maintaining an allergen on the skin of an allergic person for repeated and prolonged periods. DBV will provide a grant to Children’s Hospital to support the clinical trial. DBV and Dr. Spergel designed the double-blind, placebo-controlled, randomized trial to assess the effectiveness and safety of using an investigational new drug intended for EPIT, Viaskin® Milk, an allergen extract of milk administered via a skin patch.

“What we think happens is when the milk is absorbed through the skin, it interacts with antigen-presenting cells, which then induce T regulatory cells, and these T regulatory cells then cause the body not to be allergic anymore,” Dr. Spergel said.

Dr. Spergel anticipates that the SMILEE study — also is supported by donations from grateful CHOP families — will include participants ages 4 to 17. If it turns out that EPIT works, Dr. Spergel said it would be a major turning point for EoE treatment.

“We would be able to completely change the way we treat the disease,” Dr. Spergel said. “All these patients who have been unable to drink milk now would be able to drink milk and improve their quality of life.”

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Blocking Paths to Resistance to T Cell Therapy


Tremendous interest in immunotherapy approaches to cancer treatment is building, as researchers look for new ways to train patients’ own immune system to recognize and attack their tumors.

Andrei Thomas-Tikhonenko, PhD, and Stephan A. Grupp, MD, PhD, investigators from CHOP’s Center for Childhood Cancer Research (CCCR), have begun a unique collaboration that will contribute to the understanding of how immunotherapy can improve the survival of children with B cell acute lymphoblastic leukemia (B-ALL) that resists standard therapy. As the team moves aggressively into this area of research, Dr. Thomas-Tikhonenko described their investigations as “very fresh, new, and exciting.”

B-ALL is a common form of leukemia in which B cells that are found in the immune system become cancerous. Most children with B-ALL are highly responsive to treatment, but 15 percent will have high-risk relapsed or refractory disease that is not curable with chemotherapy.

The biological importance of CD19, a protein that is broadly expressed on the surface of B-cell tumors, has been a research focus for many years in the lab of Dr. Thomas-Tikhonenko, a cancer cell biologist. Yet he never anticipated that his work would be of assistance to a high profile project that used CD19 as a prime target for an innovative cell therapy with some remarkable success for patients with B-ALL who were out of therapeutic options.

Dr. Grupp — who is an attending physician and the CCCR’s director of Translational Research  — and his colleagues from the University of Pennsylvania, demonstrated in a groundbreaking trial that they could genetically re-engineer immune cells taken from a patient’s own blood, called T cells, and return them to the body where they multiplied rapidly to seek and destroy cancer cells that expressed CD19. These chimeric antigen receptor-armed T cells (CTL019) — formerly known as CART19 — received widespread attention last year when an article in the The New England Journal of Medicine described how one of the first pediatric patients to receive the investigational treatment achieved a complete response and remained cancer-free.

Responding to Relapse

However, another patient who also had a complete response to the same treatment, suffered a relapse two months later when other leukemia cells appeared that did not harbor CD19, essentially making them invisible to CTL019. Drs. Thomas-Tikhonenko and Grupp are working together to determine the mechanism of relapse after successful CART19 therapies and to investigate the potential use of the drug dasatinib to stave off such relapses.

A Quest for Cures two-year grant from the Leukemia & Lymphoma Society will support their work. What the research team learns about resistance will help to inform how chimeric antigen receptors potentially can be designed better as personalized therapies for subsets of patients.

“It was part serendipity and part rational design that basic scientists like myself and physician-scientists like Dr. Grupp are in the same institution,” Dr. Thomas-Tikhonenko said. “We talk to each other and learn from each other. That could only happen in a place like CHOP where basic research is valued.”

Together, they will conduct comprehensive profiling of the B-ALL cells that are no longer making CD19. The investigators want to know how B-cell tumors grow without CD19. Do they have alternative mechanisms of survival, rather than CD19-based? Can production of CD19 be restarted so that the cancer cell is once again visible to the immune system?

“We are going to look at the major proteins that are activated upon CTL019 treatment and interrogate their expression patterns, to see if we can get any hints as to what would make B-ALL cells uniquely susceptible to another therapy,” Dr. Thomas-Tikhonenko said. “We need more targets.”

A central hypothesis that they are testing is that the emergence of pre-existing CD19-negative B-ALL cells can be prevented by combining CTL019 and dasatinib. Dasatinib is a drug in a class of medications that is efficient at stopping activity of another cancer-related protein called Lyn that CD19 turns on. Even when CD19 is gone, Lyn appears to remain as a second in command signaling the tumor cells to multiply. So far, preliminary research in mice performed by another CHOP collaborator, David M. Barrett, MD, shows that using CTL019 and dasatinib together is beneficial in some cases.

Another important research direction is to understand the mechanism of CD19 silencing. When tumor cells are put under pressure, whether it is chemotherapy, radiation, or immunotherapy, they often rearrange their genomes and get rid of genes that are not helpful to them. One possibility is that following CTL019 therapy the CD19 gene is forever lost. But is it also possible that it is retained in CD19-negative B-ALL cells, but simply fails to become active or function properly.

“This would be good news,” Dr. Thomas-Tikhonenko explained. “If we can find some defects in how the protein is made, then potentially we can correct the problem with drugs that restore protein production — and sensitivity to CTL019.” Elena Sotillo, PhD, a CHOP scientist, is currently pursuing this part of the Quest for the Cure study.

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Researcher Explores Vitamin Supplementation in Sickle Cell Disease


Especially for children, vitamins are essential to growth and development. Unfortunately, many pediatric diseases are associated with suboptimal levels of vitamins and vitamin deficiencies. One Children’s Hospital investigator, Kelly A. Dougherty, PhD, works to better understand the connection between childhood diseases and vitamin levels.

An assistant professor of pediatrics and exercise physiologist, Dr. Dougherty recently received a K23 award from the NIH that will support her investigation of vitamin A supplementation and sickle cell disease. Additionally, she recently published an article in the Journal of the Pediatric Infectious Diseases Society on vitamin D deficiency in children with HIV.

Vitamin A and SCD

The K23 award — which is designed to foster young investigators’ careers — will support Dr. Dougherty’s investigation of vitamin A deficiency in children with type SS sickle cell disease (SCD). In addition to being most famous for anemia and episodes of pain, SCD is also linked to suboptimal levels of vitamin A, which can lead to poor growth and hospitalizations. Vitamin A deficiency is associated with vision problems and a decreased ability to fight infections.

Dr. Dougherty’s new project builds on research led by CHOP’s Virginia Stallings, MD, published in The American Journal of Clinical Nutrition in 2012. That study, of which Dr. Dougherty was the first author and which included contributions from CHOP’s Kwaku Ohene-Frempong, MD, and Babette S. Zemel, PhD, sought to determine whether supplementation could optimize vitamin A status in children with type SS SCD. However, despite 12 months of study, the investigators found vitamin A supplementation at doses recommended for healthy children did not improve the patients’ serum retinol levels.

For her new investigation, Dr. Dougherty will study the safety and efficacy of much higher doses of vitamin A — 2500 and 5000 IU/day, versus the 2012 study’s ceiling of 2000 IU. The researchers — who also include  Dr. Stallings (who is Dr. Dougherty’s mentor), Kim Smith-Whitely, MD, Mortimer Poncz, MD, Justine Shults, PhD, Graham Quinn, MD, MSCE, and Mary B. Leonard, MD, MSCE — plan to test what effect these higher doses of vitamin A have on children with SCD compared to healthy subjects. A key component of the study, Dr. Dougherty said, is the stable isotope testing which will assess how much vitamin A is stored in patients’ livers.

The big question posed by the 2012 American Journal of Clinical Nutrition study is where the vitamin A went — in other words, did the patients eliminate it via urination or a bowel movement, or was it still in their bodies, or sequestered in the liver? — so with her new project Dr. Dougherty is looking to get a sense of the patients’ “total body vitamin A status,” she said.

From SCD to HIV

The Journal of the Pediatric Infectious Diseases Society (JPIDS) study, meanwhile, explores a different vitamin in a different patient population. Namely, vitamin D in children with HIV. While HIV-related research is a newer area for Dr. Dougherty, the HIV research makes sense as she is “interested in physical activity and nutrition issues in children with chronic diseases,” and “children with HIV have been shown to be deficient with vitamin D,” Dr. Dougherty said.

Published online in late March, Dr. Stallings was the principle investigator of the JPIDS investigation while Dr. Dougherty acted as its first author. With this dose-finding study, the researchers sought to determine the vitamin D dose needed to bring HIV patients with suboptimal levels of vitamin D up to normal levels. Suboptimal vitamin D “is common in HIV infected individuals and associated with increased risk of HIV disease severity and death,” the authors note. In general, vitamin D deficiency is associated with the possibility of developing rickets in children or osteoporosis in adults.

44 subjects age 8.3 to 24.7 years old — 57 percent of whom had behaviorally acquired HIV and 43 percent of whom had perinatally acquired HIV — were given either vitamin D supplements at 4,000 or 7,000 IU/day and assessed at 6 and 12 weeks. The researchers found a dose of 7,000 IU/day was “safe and effective in children and young adults with HIV.”

Overall, the goal of all of Dr. Dougherty’s work is to find ways to improve outcomes and quality of life for pediatric patients’ suffering from chronic disease, she said.

To learn more about AIDS/HIV, sickle cell disease research, clinical nutrition, and healthy diets, see The Children’s Hospital of Philadelphia website.

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Prophylactic Antibiotics Halve Repeat UTI Rate


The use of prophylactic antibiotics to prevent urinary tract infections (UTIs) associated with vesicoureteral reflux (VUR) has been controversial, and a multisite clinical trial in which The Children’s Hospital of Philadelphia participated in is adding to the debate. Results from the trial published in The New England Journal of Medicine were “pretty dramatic,” according to co-investigator Ron Keren, MD, MPH, vice president of quality and chief quality officer for CHOP.

About 5 percent of children will experience a UTI by the time they reach age 6, and approximately one-third of these patients have VUR. When a child with VUR urinates, some urine backs up in the ureters toward the kidneys and so the bladder does not empty completely. This increases the chance of a UTI occurring, and if it reaches the kidneys, it is often accompanied by a fever and is called pyelonephritis.

“The problem with pyelonephritis is that it sometimes results in kidney scarring, and there is a concern that this could lead to high blood pressure and renal failure when you get older,” Dr. Keren explained.

Clinicians currently use a long-term course of daily antibiotics or antireflux surgery to treat children with VUR. However, an international clinical study conducted in the 1980s that compared the two approaches showed no difference in the rates of recurrent UTIs or renal scarring. More recent trials that looked at antibiotics’ effectiveness had conflicting results and methodological weaknesses, so researchers launched the Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) trial to obtain more evidence to guide clinical practice.

The study included 607 children, mostly girls, between the ages of 2 and 6 who had VUR. They were recruited from 19 clinical sites across the U.S and followed for two years. Researchers analyzed the data to determine if children who received daily doses of trimethoprim-sulfamethoxazole had fewer recurrences of UTIs than children who received the placebo and if there were any differences in the occurrence of renal scarring.

“The rate of recurrent UTIs was cut in half for those in the antimicrobial prophylaxis group,” Dr. Keren said. “I was surprised that the prophylactic antibiotics worked as well as they did.”

The percentage of children getting UTIs continued to increase over time in the placebo group but not in the treatment group, Dr. Keren pointed out, which demonstrates the sustained effectiveness of antibiotic prophylaxis. Also, certain subgroups of children — those with bowel and bladder dysfunction and those who had febrile UTIs — seemed to benefit the most from the long-term antibiotics.

The occurrence of renal scarring did not differ significantly between the treatment and placebo groups. This finding likely will add fuel to an ongoing debate, Dr. Keren said. Some physicians will say it is not worth using daily antibiotics in children with VUR if they do not prevent kidney damage. Others will say it is important to continue to treat these children with antibiotics because a UTI recurrence could land them in the emergency room or hospital.

Another contentious issue among clinicians is the use of urinary tract imaging, known as a voiding cystourethrogram (VCUG), to screen for VUR. While VCUG can be a helpful diagnostic tool, it involves radiation exposure, is invasive and uncomfortable, and can be traumatic for young children. Current guidelines recommend that physicians take a watchful waiting approach until a second febrile UTI happens before suggesting that a child go through the procedure. Part of the rationale for the watchful waiting approach was the lack of strong evidence for the effectiveness of prophylaxis in children found to have VUR.

“Now that we know that prophylaxis works, this changes our calculus about the risks and benefits of getting a VCUG on every child who has a first UTI,” Dr. Keren said.

But even without prophylaxis, only one-quarter of children with VUR will experience a repeat UTI, so Dr. Keren emphasized that it is important to explain to families what the research shows and to help parents to make informed decisions about whether to proceed with VCUG imaging.

With so many ongoing discussions about the best ways to approach UTIs, the issue is ripe for further research. Dr. Keren is involved with another NIH supported study that follows a design similar to RIVUR, known as the Careful Urinary Tract Infection Evaluation (CUTIE) trial, but it is focusing on the rate of recurrent UTIs and kidney scarring in children who do not have VUR.

The RIVUR study was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases and the National Center for Advancing Translational Science. In addition to CHOP, the primary clinical trial sites included Children’s Hospital of Pittsburgh; Women and Children’s Hospital of Buffalo; Wayne State University School of Medicine, Detroit; and Johns Hopkins School of Medicine, Baltimore.

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Patient Engagement Study Set to Inform National Policy


Clinicians tapping on computers during patient visits has become routine in the era of electronic health records (EHRs). Now families are increasingly encouraged to spend some screen time on their own entering health-related preferences and goals.

“Incorporating these patient-generated reports systematically into the electronic data we collect can help healthcare providers to tailor treatment and respond to patients’ and families’ most important concerns,” said Alexander G.  Fiks, MD, MSCE, assistant professor of pediatrics and co-medical director of the Pediatric Research Consortium (PeRC) at CHOP.

Patients’ ability to submit health information and actively participate in their healthcare is a main focus of Meaningful Use Stage 3 (MU3) criteria. The federal government allocated $27 billion to fund a staged program to boost the meaningful use of EHRs. A phased approach to participation helps eligible providers move from creating information in Stage 1, to exchanging health information in Stage 2, to focusing on improved outcomes in Stage 3.

Yet a knowledge gap remains one of the best ways to accomplish MU3’s objectives, so the Agency for Healthcare Research and Quality funded 12 research projects to provide real-world evidence to inform MU3 policy development and implementation. Dr. Fiks is the principal investigator of one of those studies underway at The Children’s Hospital of Philadelphia. It aims to help policymakers understand the feasibility of using patient portals linked to EHRs to foster patient engagement in pediatrics.

“Data is lacking on which Meaningful Use goals can be reasonably achieved in pediatric primary care settings,” Dr. Fiks said. “We are on track to potentially shape what the expectations should be about using patient portals and these types of tools to collect patient reported outcome data as Stage 3 is rolled out.”

Patient portals are online healthcare applications that allow patients to communicate with their healthcare providers, such as by transferring information about upcoming appointments and test results. The study will use “MyAsthma,” a patient portal created and tested at CHOP that offers advanced functionality to increase shared decision making among parents and clinicians.

MyAsthma provides asthma education, collects patient-reported outcomes, evaluates medication use and side effects, and tracks parent’s preferences and goals. The portal transmits information entered by parents to the clinician’s office, which allows the medical team to address immediate problems and adjust treatment if needed. Dr. Fiks and colleagues recently described the portal’s development in the April issue of The Journal of Ambulatory Care Management.

Asthma an Ideal Model

Asthma is well-suited to the study of patient portals because it has a high prevalence, affecting more than 7 million children in the U.S., especially in socioeconomically disadvantaged communities. It requires symptoms to be tracked over time, and it poses a significant burden on patients’ and families’ quality of life. Patients with persistent asthma regularly use controller medications, so patient portals also may help in medication management for this population.

“On a monthly basis, families check in,” Dr. Fiks said, “so their healthcare isn’t just tied to office visits. There is ongoing monitoring of how kids with this condition are doing.”

A unique aspect of the study is its approach to primary care research across two networks. The American Academy of Pediatrics electronic subnetwork of Pediatric Research in Office Settings (ePROS) is collaborating with PeRC. This is enabling the researchers to evaluate two types of patient portals used across multiple EHR vendors in varied pediatric primary care settings with at least 20 percent Medicaid patients.

“Little is known about the effectiveness of meaningful use policy, and even less is known about how it applies to pediatrics,” Dr. Fiks said. “Most meaningful use research has primarily been structured within adult health care settings. Being able to inform how the process works within pediatric settings is important because the needs of children are different.”

Dr. Fiks anticipates a rapid turnaround time for study results. The majority of data from parent surveys will be collected by the end of summer, followed by individual interviews of parents and practitioners to describe any factors that facilitated or posed barriers to patient portal adoption.  He expects to identify strategies that will directly inform national healthcare priorities for MU3, which are scheduled to take effect in 2017.

“There’s a lot of satisfaction for me as a pediatrician in thinking about ways to transform primary care using technology so that we can more effectively help kids with chronic conditions who need the most attention,” Dr. Fiks said.

CHOP’s Center for Biomedical Informatics, Center for Pediatric Clinical Effectiveness, and PolicyLab also are contributing to the study.

“It is really a great collaboration among groups that brings together CHOP’s health service research expertise, policy expertise, and technological expertise,” Dr. Fiks said.

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Study Probes Diet-Related Seizure Freedom

Story9_Seizure Freedom

Most children with epilepsy lead active and fulfilling lives, with the help of modern therapies. Yet 20 to 30 percent of children with epilepsy do not respond to medications, which physicians call medication-resistant or intractable epilepsy.

Researchers at The Children’s Hospital of Philadelphia are continually looking into ways to lower the frequency of seizures that children with medication-resistant epilepsy experience on a sometimes daily basis. Alternative treatment options may include the ketogenic diet, vagal nerve stimulator, or epilepsy surgery.

The ketogenic diet, which is low in carbohydrates and high in fat, achieves seizure freedom in 15 to 20 percent of patients and greater than 90 percent seizure reduction in one-third of children with medication-resistant epilepsy; however, few studies have considered its long-term outcomes. Katherine S. Taub, MD, an epileptologist at CHOP and assistant professor of neurology at the Perelman School of Medicine, published a study in the journal Epilepsia that provides evidence to support the continued use of the ketogenic diet in patients with initial seizure freedom even after breakthrough seizures.

“For children who are seizing daily, it has a big impact on their lives,” Dr. Taub said. “Physicians should encourage patients to continue the diet as treatment even if they have seizure recurrence because they can still have a meaningful reduction in their total number of seizures.”

Epilepsy is a brain disorder that affects 1 percent of children in the U.S. Many types of epilepsy exist, each with its own seizure types and frequent neurological comorbidity. Children are diagnosed with epilepsy if they have had more than two unprovoked (no precipitating cause) seizures. Seizures occur when clusters of nerve cells, or neurons, in the brain have a burst of abnormal electrical signals that temporarily interrupts normal electrical brain function.

Researchers are unsure of exactly how the ketogenic diet inhibits epileptic seizures. The diet consists of 90 percent fats, 7 percent protein, and 3 percent carbohydrates, and it requires precise measuring and steadfast adherence.

In this retrospective cohort study, participants were patients at CHOP between 1991 and 2009 who had been unsuccessfully treated with four or more antiepileptic drugs prior to ketogenic diet initiation. The majority had daily seizures. Sixty-five participants achieved seizure freedom for a minimum of one month during ketogenic diet treatment. When Dr. Taub examined the probability of their sustained seizure freedom, the average time to seizure recurrence was three months or less, and the likelihood of remaining seizure-free at 18 months was 3 percent.

“A high number of patients on the diet did have breakthrough seizures, but none of our patients returned to their baseline seizure frequency,” Dr. Taub said.

Another significant finding that Dr. Taub discovered while comparing this data to previous studies is that a consistent definition of sustained seizure freedom is lacking in the medical literature. Such a consensus would facilitate future studies, such as a head-to-head study comparing the ketogenic diet versus other antiepileptic medications.

“If we’re going to be sharing comparative data between centers, then we should establish an agreed upon definition for seizure freedom, so we can evaluate institutions’ success of the diet,” Dr. Taub said.

The study’s co-authors included Sudha Kilaru Kessler, MD, an attending physician at CHOP, and Christina Bergqvist, MD, an attending physician and director of CHOP’s Ketogenic Diet Program, which is one of the largest of its kind in the country providing resources and training for families.

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Cell Therapy Expert Receives Three Honors


It has been a busy few weeks for The Children’s Hospital of Philadelphia’s Stephan Grupp, MD, PhD. Dr. Grupp, the director of Translational Research at the Center for Childhood Cancer Research, recently received three awards for his groundbreaking immune therapy work using genetically engineered, cancer-fighting T cells. Dr. Grupp received awards from the Clinical Research Forum, the European Society for Blood and Marrow Transplantation, and was honored alongside the University of Pennsylvania by the bioscience organization Pennsylvania Bio.

Dr. Grupp has received a great deal of attention for his investigation of using cell therapy (known as CART19 or CTL019 therapy) to treat an aggressive form of childhood leukemia, acute lymphoblastic leukemia (ALL). Last year his work — conducted in partnership with the University of Pennsylvania’s Carl June, MD — led to dramatic, extraordinary results published in The New England Journal of Medicine: two children with untreatable ALL achieved a complete response after being treated with immune therapy. Since receiving the treatment one of those patients remains healthy and cancer-free two years later.

The Clinical Research Forum (CRF) award, the 2014 Herbert Pardes Clinical Research Excellence Award, is one of ten recent awards handed out by the CRF to projects “that benefit the health and wellbeing of the general public.” Named for New York-Presbyterian Hospital’s Herb Pardes, MD, the 2014 Herbert Pardes Award is the CRF’s top prize, and was awarded at an April 10 reception in Washington, DC.

The European Society for Blood and Marrow Transplantation (EBMT), meanwhile, handed a team of researchers led by Dr. Grupp the 2014 van Bekkum Award, named for transplantation and bone marrow researcher Dirk van Bekkum, MD, PhD. The EBMT’s van Bekkum award is given to the best abstract presented at the Society’s annual meeting, held March 30 to April 2 in Milan, Italy.

In addition to Dr. Grupp, Penn’s Dr. June and David Porter, MD, as well as CHOP’s David Teachey, MD and Shannon Maude MD, PhD, among others, were co-authors on the abstract, “T cells engineered with a CAR targeting CD19 (CTL019 cells) produce significant in vivo proliferation, complete responses and long-term persistence without GVHD in children and adults with relapsed/refractory ALL.”

The data presented at the Clinical Research Forum and EBMT updated the data published in the New England Journal of Medicine. “Our group has now treated 25 kids and 5 adults with relapsed/refractory ALL,” said Dr. Grupp. “We have seen unexpectedly high rates of complete remission: 90 percent in this group of patients, many of who had no other treatment options. These results are leading to a phase 2 trial at six pediatric hospitals, with CHOP as the lead site.”

Rounding out the list of plaudits, at the recent 2014 Pennsylvania Bio Annual Dinner & Awards Celebration, CHOP and Penn — led by Drs. Grupp and June, respectively — were jointly honored for their cell therapy work with PA Bio’s Patient Impact Award.

“It’s an honor to have our cell therapy research recognized by such prestigious organizations,” said Dr. Grupp. “This is potentially revolutionary work, but its success to date — and going forward — would not have been possible without multidisciplinary, truly collaborative input from investigators across CHOP and Penn. I cannot thank my colleagues enough.”

Recent papers which Dr. Grupp has either led or contributed to include a study of managing the cytokine release syndrome associated with T cell therapy, a study of chimeric antigen receptors, and managing toxicity for patients receiving T cell therapies.

To learn more about cancer research at The Children’s Hospital of Philadelphia, see the Center for Childhood Cancer Research website or the Hospital’s Cancer Center.

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Biodegradable Nanoparticles May Hold Therapeutic Use


Nanoparticles have been heralded as a potentially “disruptive technology” in biomedicine, and as a changing platform that could replace conventional technologies, both as drug delivery vehicles and diagnostic tools to help discover and treat disease.

First, however, researchers must demonstrate the properly timed disintegration of these extremely small structures, a process essential for their performance and their ability to be safely cleared out of a patient’s body after their job is done. A new study presents a unique method to directly measure nanoparticle degradation in real time within biological environments.

“Nanoparticles are made with very diverse designs and properties, but all of them need to be eventually eliminated from the body after they complete their task,” said cardiology researcher Michael Chorny, PhD, of The Children’s Hospital of Philadelphia (CHOP). “We offer a new method to analyze and characterize nanoparticle disassembly, as a necessary step in translating nanoparticles into clinical use.”

Dr. Chorny and colleagues described this novel methodology recently in the Proceedings of the National Academy of Sciences.

The CHOP team has long investigated biodegradable nanoparticles for medical use. With diameters ranging from a few tens to a few hundreds of nanometers, these particles are 10 to 1000 times smaller than red blood cells. One major challenge continuously monitoring the fate of nanoparticles in model biological settings and in living cells without disrupting cell functions.

“Accurately measuring nanoparticle disassembly in real time directly in media of interest, such as the interior of a living cell or other types of complex biological milieu, is challenging. Our goal here was to develop such a noninvasive method providing unbiased results,” said Dr. Chorny.

The study team used a physical phenomenon called Förster resonance energy transfer, or FRET, as a sort of molecular ruler to measure the distance between the components of their particles. Researchers labelled their formulations with fluorescent probes exhibiting the radiationless transfer of energy, i.e., FRET, when located within the same particle.

This process results in a special pattern of fluorescence, a “fingerprint” of physically intact particles, which gradually disappears as particle disassembly proceeds. This change in the nanoparticle fluorescent properties can be monitored without separating the particles from their environment, allowing for undistorted, continuous measurements of their integrity.

The rate of disassembly is highly relevant to potential applications. For instance, some nanoparticles might carry a drug intended for quick action, while others should keep the drug protected and released in a controlled fashion over time. Creating formulation properties for these tasks may require carefully adjusting the time frame of the nanoparticle disassembly. This is where this technique can become a valuable tool, greatly facilitating the optimization process.

In the current study, the scientists analyzed how nanoparticles disintegrated both in liquid and semi-liquid media, and in vascular cells simulating the fate of particles used to deliver therapy to injured blood vessels. “We found that disassembly is likely to occur more rapidly early in the vessel healing process and slow down later. This may have implications for the design of nanoparticles intended for targeted drug, gene or cell therapy of vascular disease,” said Dr. Chorny.

While immediately relevant to restenosis therapy and magnetically guided delivery, the current research also has much broader potential applications, said Dr. Chorny. “Nanoparticles could be formulated with contrast agents for diagnostic imaging, or could deliver anticancer drugs to a tumor,” he said. “Our measuring tool can help researchers to develop and optimize their nanomedicine formulations for a range of medical uses.”

More information about the study is available on the Research website

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Study Identifies Sleep Apnea Risk Factors


While obstructive sleep apnea syndrome (OSAS) is a relatively common condition, affecting about 2 to 4 percent of young children, the scientific community is just opening its eyes to pediatric sleep disorders. Little is known, for example, about the characteristics that increase OSAS severity in children.

OSAS occurs when a child stops breathing during sleep, usually because there is a blockage from enlarged tonsils or adenoids. Many of the pauses, called apneas and hypopneas, cause a brief arousal that increases muscle tone, opens the airway, and allows the child to resume breathing. These repeated disruptions result in restless sleep. Recurrent nightly episodes of obstructive apnea are associated with adverse behavioral, cognitive, quality of life, and health outcomes in children.

Researchers from the Sleep Center at The Children’s Hospital of Philadelphia were involved with a large, multicenter study called the Childhood Adenotonsillectomy Study for Children With OSAS (CHAT), and recently they used the study’s baseline data to perform a cross-sectional screening to analyze which factors predict OSAS severity. They examined data from 421 children ages 5 to 9 years who had undergone sleep testing, known as polysomnography, and evaluated the relationship between their levels of OSAS to sex, race, body mass index, environmental tobacco smoke (ETS), prematurity, socioeconomic variables, and comorbidities.

“If presumably you know some of the risk factors, you might be able to address some of those risk factors and preempt the sleep apnea or at least diagnosis it earlier,” said Carole L. Marcus, MBBCh, director of CHOP’s Sleep Center, who was first author for the CHAT study and also participated in the auxiliary study that appeared in SLEEP in February.

The auxiliary study found that African American race predicted OSAS severity, which supports previous research. This is especially interesting, Dr. Marcus said, because the CHAT study results showed that African American children had less improvement postoperatively, both in terms of polysomnographic changes and behavioral changes. Much debate exists about why African American race would be associated with higher OSAS severity and poorer outcomes after surgery, but some research suggests genetic, craniofacial, and environmental components play a role.

“They have worse disease, but they don’t respond as well to the therapy and possibly have more complications from the treatment,” Dr. Marcus said. “That definitely deserves further research. We also found in another related study that looked at continuous positive airway pressure, which is an alternative therapy for kids who don’t improve following surgical therapy, that they had poor adherence to CPAP. So they’re definitely a more difficult group to treat.”

Study participants’ exposure to secondhand smoke was another significant risk factor for increased OSAS severity that researchers identified.  ETS has previously been connected to snoring in children, so this novel finding advances pediatric sleep research by demonstrating its effect on OSAS.

African American race and exposure to ETS were each associated with an approximately 20 percent increase in apnea-hypopnea index. More research is needed, Dr. Marcus said, to define these specific factors and suggest better OSAS screening strategies that focus on African American children and children exposed to ETS.

In the meantime, pediatricians can use this study’s findings to promote awareness of OSAS by asking parents about snoring at their children’s regular healthcare maintenance visits, Dr. Marcus said. It also provides an ideal opportunity to encourage families with smokers to quit and protect their children from secondhand smoke.

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Rare Disease Project Has Made “Major Progress”


Imagine facing a devastating medical problem, but when you searched for a diagnosis, even the experts had no answers because your condition was so rare. In the U.S., a disease is considered rare if it affects fewer than 200,000 people. Many rare diseases have genetic origins, and almost 70 percent of Americans affected by a rare disease are children, according to the National Organization for Rare Disorders (NORD).

NORD hosted Rare Disease Day USA Feb. 28, when the U.S. joined more than 80 nations around the world to focus attention on rare diseases as an important global public health challenge. Rare Disease Day also presented the opportunity to recognize the important gains made through international cooperation in clinical and scientific research.

Since 2012, The Children’s Hospital of Philadelphia and BGI, the world’s largest genomics organization, have been collaborating on the 1,000 Rare Diseases Project to accelerate the discovery of genetic variants underlying rare diseases. By using next-generation sequencing (NGS) technologies, researchers from CHOP and BGI are one-third of the way toward their goal of sequencing 1,000 rare diseases.

“We have made major progress,” said Hakon Hakonarson, MD, PhD, director of the Center for Applied Genomics at CHOP who directs the project. “A number of our discoveries have exciting potential because there are existing drug therapies that could be repositioned or repurposed for some of these rare diseases we have now resolved. That will be a big impact.”

One of the project’s first success stories involved a family that had been coming to CHOP for almost 20 years. The parents wanted to track down the disease that caused their son and daughter to have progressive muscular weakness and also weakening of the heart muscle (cardiomyopathy) beginning at age 8.

Through whole-genome sequencing, the research team located RBCK1, a disease-predisposing gene for a novel and extremely rare single-gene disorder that had never been identified before. Genetic mutation shortens the protein that RBCK1 encodes, and then the modified protein accumulates in muscle fibers. Researchers confirmed that truncating mutations in RBCK1 were the culprit when they found the same exact gene to be mutated in a second family that had a comparable disease profile. Genome Medicine published their findings in 2013.

“It was very rewarding,” Dr. Hakonarson said. “The families have been fundraising for us so that we can gain a better understanding of the mechanism by which the gene mutation causes this devastating disease.”

Additional Mutations Identified

Another study published in the American Journal of Human Genetics determined that mutations in PDGFRB cause autosomal-dominant infantile myofibromatosis (AD IM). The disorder arises in infancy and childhood and is characterized by proliferative fibrous tumors affecting the skin, muscle, bone, and internal organs. Researchers performed whole-exome sequencing in members of nine unrelated families diagnosed with AD IM to identify the genetic origin of the disorder. In addition to pinpointing PDGFRB, they highlighted NOTCH3 as another disease-causing gene for infantile myofibromatosis.

“Both of these genes have been targeted by drugs that pharmaceutical companies have developed for totally different diseases,” Dr. Hakonarson said. “We have the opportunity to make a big shortcut here to develop new therapies to treat this disease.”

Other studies published by the investigators have shown:

Overall, the researchers have collectively identified between 40 and 50 new diseases so far, and they continue to make discoveries that elucidate rare diseases and resolve weighty questions for families.

“When we find these new mutations, the clinicians who treat these families have been able to validate these mutations by rigorous clinical testing and inform families that this is the disease-causing gene, and they have been immensely appreciative,” Dr. Hakonarson said. “They can go to other geneticists and clinicians and share these results. Now that they know what causes the disease, they can have other family members tested, and prenatal testing becomes an option for future pregnancies.”

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CRSO Works to Make Investigators’ Lives Easier


In a move designed to facilitate investigations across the organization, The Children’s Hospital of Philadelphia Research Institute recently created a new office that consolidates clinical trial support, IND/IDE assistance, and general research support in one office. CHOP Research’s Clinical Research Support Office (CRSO) provides leadership, guidance, and support services to researchers conducting both investigator-initiated and industry-sponsored research projects.

Leading the CRSO is Mathew Hodgson, who joined Children’s Hospital in February. Before he came to CHOP, Hodgson most recently directed the Dartmouth Clinical Trials Office at the Dartmouth-Hitchcock Medical Center, and has more than a decade of healthcare experience. Prior to working at Dartmouth, Hodgson held a number of clinical research leadership roles at Cincinnati Children’s Hospital Medical Center.

The position at CHOP attracted Hodgson because “it had some of the pieces I already have in my bucket — like contracting, IND/IDE support — but also the opportunity for clinical engagement,” as well as “the reputation of CHOP and its pediatric mission,” he said.

Currently, the CRSO is comprised of approximately 40 clinical research professionals, including research coordinators, nurses, project managers, regulatory associates, marketing and recruitment specialists, and administrative support professionals. The CRSO’s services include clinical research support, an IND/IDE and support function, recruitment support, and research navigation assistance. The CRSO is also working to add a clinical trial contract office, Hodgson said. Alongside Hodgson, longtime CHOP and Penn clinical research expert Jennifer Goldfarb acts as the associate director of the CRSO.

The CRSO supports a wide array of clinical research projects. In fiscal 2013, for example, the offices that are now under the CRSO umbrella coordinated 534 study visits, and supported 39 investigators and studies across 16 departments and divisions, or 6 percent of active clinical research projects at CHOP.

The CRSO supports “all aspects of clinical research,” and not just clinical trials, Hodgson pointed out. “We support non-industry studies as well as industry-funded studies and clinical research projects,” he said. And in cases when the CRSO may not have a resource in-house — such as highly specialized study-design personnel — they can either recruit to fill that role or partner with other departments, Hodgson said.

Another feature the CRSO is in the process of implementing is its “research navigator” service. Rather than being associated with one person, the navigator is an email and phone service the CRSO will use to route inquiries “to the right office,” Hodgson said.

“I think this is central to what the mission is of the CRSO: the CRSO is the place to come when you need a service to support clinical research, and then we will either support it or direct you to the appropriate people,” Hodgson said.

To learn more about the CRSO, see the Office’s website.

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Oncologist Honored for Neuroblastoma Research


The Advances in Neuroblastoma Research Association (ANRA) recently presented its highest honor to pediatric oncologist Garrett M. Brodeur, MD, of the Cancer Center at The Children’s Hospital of Philadelphia (CHOP). Dr. Brodeur received the ANRA Lifetime Achievement Award at the association’s international meeting. The award singles out a researcher who has achieved worldwide scientific prominence in investigating neuroblastoma over the course of an exceptional career.

The most common solid tumor of childhood, neuroblastoma attacks the peripheral nervous system, typically appearing as a tumor in a child’s abdomen or chest. Neuroblastoma varies greatly in severity, ranging from forms that spontaneously disappear to high-risk subtypes that are difficult to cure. Because of this variability, researchers have sought ways to predict the course of disease to better select the most appropriate treatment for each patient.

Over his career, Dr. Brodeur has focused on identifying the genes, proteins, and biological pathways that give rise to neuroblastoma and drive its clinical behavior. He has also built on this knowledge to help develop more effective and less toxic treatments for children.

In the 1980s, Dr. Brodeur showed some neuroblastoma cells developed multiple copies of the MYCN gene, which identified a high-risk subtype of neuroblastoma, necessitating more aggressive treatment. This discovery ushered in the current era of genomic analysis of tumors, both in adult and pediatric oncology. Profiling specific molecular alterations in a specific patient’s tumor helps guide oncologists toward the most appropriate treatment.

Dr. Brodeur and his fellow colleagues also discovered important neuroblastoma-related genetic changes. He collaborated with other CHOP researchers who identified the ALK gene as the gene responsible for most cases of hereditary neuroblastoma.

Another major focus of his research regards the role of TRK receptor tyrosine kinases, which control the clinical behavior of neuroblastomas. His work led to a clinical trial with a novel drug that selectively blocks these signals. He is now working on the second generation of such drugs, as well as on nanoparticle delivery systems to treat patients with less abrasive treatments.

Dr. Brodeur has been a member of the CHOP medical staff since 1993 and holds the Audrey E. Evans Endowed Chair in Pediatric Oncology at the Hospital. He is also a professor of Pediatrics in the Perelman School of Medicine at the University of Pennsylvania, where he is an associate director of the Abramson Cancer Center. Last year, Dr. Brodeur received the prestigious Pediatric Oncology Award from the American Society of Clinical Oncology.

To read more about Dr. Brodeur’s award, see the full press release.

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Produced by The Children’s Hospital of Philadelphia Research Institute.

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