Accelerating Breakthroughs

Frontier Programs Create New Paths for Research Discovery and Clinical Care

Frontier Programs Create New Paths for Research Discovery and Clinical Care

Frontiersmen historically are a rare breed of adventurers willing to brave the unknown in order to discover new paths. The physician-researchers who are leading new Frontier Programs at Children’s Hospital of Philadelphia embody this pioneering spirit as they forge ahead to help children achieve optimal health and better lives.

The Frontier Programs initiative at CHOP designates funding to large internal programs that connect translational research and clinical care in extraordinary ways. This spring, 19 programs applied, and after a rigorous review process, the oversight panel selected two outstanding programs: the Thoracic Insufficiency Syndrome (TIS) Program and the Inflammatory Bowel Disease (IBD) Program.

Breathing Easier: Thoracic Insufficiency Syndrome Program

TIS encompasses a group of at least 28 rare and potentially fatal disorders in which spinal and chest wall deformities early in life compromise children’s lung growth and ability to breathe. Robert Campbell, MD, director of the Center for Thoracic Insufficiency Syndrome (CTIS) at CHOP and an attending surgeon, invented the first FDA-approved Vertical Expandable Prosthetic Titanium Rib (VEPTR device) that enables surgical reconstructive procedures to enlarge these children’s rib cages and help to correct scoliosis to increase their chances of lung growth.

As VEPTR has become the standard of care for treating TIS, CTIS has treated more patients and more acute cases from all over the world and increased surgical volume for patients with TIS by an average of 15 percent every year since 2012 at CHOP. The need for more TIS research has grown along with the Center.

Being named a Frontier Program will allow Dr. Campbell and a multidisciplinary team of specialists to perform sophisticated imaging, construct new metrics for clinical outcomes, better understand the biomechanics of TIS, and establish reliable evidence to support new surgical strategies and develop new medical devices.

“The Frontier funding supports programs that are clinically robust and have the potential for rapid advancement,” Dr. Campbell said. “It’s like getting a turbo charger. It’s hard to win the race if you don’t have one.”

CTIS hit the starting line with about 20 research projects that are underway. For four years, Dr. Campbell and his colleagues have collaborated with Jayaram Udupa, PhD, a professor of Radiologic Science from the University of Pennsylvania Department of Radiology Medical Image Processing Group, to develop dynamic lung magnetic resonance imaging (dMRI) image analysis as a way to measure thoracic performance — which is how well the thorax, spine, and rib cage work in combination — before and after surgical intervention for TIS. The research team will refine and scientifically validate this new assessment technique in correlation with pulmonary function.

In order to get a complete view of the anatomy in these unusual diseases that the CTIS treats, the research team also collaborates with Sriram Balasubramanian, PhD, an associate professor in the School of Biomedical Engineering, Science and Health Systems at Drexel University, to perform detailed software analysis of computed tomography (CT) scans of patients, which shows bone better than MRIs.

Together, these approaches will be the basis for the CTIS’ advanced imaging research program. One of the investigators’ first projects is called the Virtual Growing Child, which will help to establish normative data for comparative analysis. Quantifying the degree of dysfunction in the rib cage and diaphragm will provide a new metric to define thoracic performance in TIS.

CTIS also is launching a basic science lab that will establish an animal model of TIS. Casey Olson, PhD, a medical bioengineer who recently joined the CTIS team, will be leading this research to better understand at an anatomic level how expanding these children’s chests promotes lung growth. This biological platform will help them to develop new devices and surgical methods that closely mimic thoracic function to treat TIS.

As this body of research forms the scientific basis for TIS surgical interventions, Dr. Campbell also is excited to pursue studies that focus on patients’ and families’ quality of life outcomes. Measuring these surgeries’ success goes beyond if the MRI and CT images look better, he pointed out. Many children who receive VEPTR devices are no longer dependent on oxygen support or mechanical ventilators. When these children can breathe easier, so can their parents, in many ways.

Dr. Campbell shared the example of a mother who had been sleeping every night at her son’s bedside so that she could suction him if he became congested or had mucus plugs in his lungs. As the surgery slowly allowed her son’s lungs to expand and move, he became more comfortable and could sleep through the night — and so could mom in her own bed.

“After treatment, these children feel better, are happier,” Dr. Campbell said. “They gain weight. They don’t go to the emergency room or intensive care unit as much, and they recover faster from illnesses. We don’t measure those type of things yet, but the Frontier funding will make it possible. We’re very appreciative of this. There are so many innovations at CHOP just waiting to happen.”

Making it Personal: Inflammatory Bowel Disease Program

Frontier funding will expand pediatric IBD care and research at CHOP, as an inventive multidisciplinary team takes a new approach that combines genomics and microbiome analysis to fulfill an unmet need for improved diagnostic modalities and therapeutics. IBD is a chronic autoimmune disease that includes Crohn disease and ulcerative colitis, and it has been rapidly increasing in incidence — especially among young children — mostly likely due to a complex combination of genetic and environmental factors.

The Center for Pediatric Inflammatory Bowel Disease at CHOP is the largest of its kind in the country, providing care for more than 1,400 children and adolescents. Under the combined leadership of Robert Baldassano, MD, and Andrew Grossman, MD, co-directors of the Center for Pediatric IBD; and Judith Kelsen, MD, a pediatric gastroenterologist and researcher; the Frontier program will increase the Center’s size and scope to provide the most advanced comprehensive care to pediatric patients with IBD from the U.S. and internationally. At the same time, their scientific observations will generate novel insights into pediatric IBD, which often is harder to treat than older-onset IBD, and can have dramatic consequences including poor growth, malnutrition, and the need for intravenous feeding and surgeries.

“The bottom line is we’re trying to improve the care of children who are suffering with this disease all over the world,” Dr. Baldassano said. “We believe that the model we are creating will be used at other institutions five or 10 years from now.”

At the heart of this model is CHOP’s ability to provide personalized medicine for children with IBD. Patients treated by the Center for Pediatric IBD undergo next-generation sequencing to identify the genetic defects that may underlie their disease. This not only aids diagnosis, but it also suggests which medications have the best chance of being effective. Another benefit is that it provides CHOP the opportunity to develop new gene-based therapies.

For example, previous research by Dr. Baldassano and his colleagues at the Center for Applied Genomics at CHOP discovered that many children with pediatric IBD and other autoimmune diseases have loss of function mutations in a specific immune regulatory protein that dampens inflammation caused by a pro-inflammatory protein called LIGHT. As part of a CHOP collaboration with industry partners that was announced in June, Dr. Baldassano will help to test a potential therapy that would be a first-in-class anti-LIGHT monoclonal antibody that binds excessive LIGHT to help control inflammation in pediatric patients with IBD.

The Center for Pediatric IBD also aims to move science forward by analyzing patients’ microbiome, which is the community of microbes that live on and within your body (the bulk of these organisms live in the gut) and contribute to numerous biological functions. Growing evidence supports the idea that the microbiome helps drive inflammatory bowel disease in people who are genetically predisposed.

In order to better understand the intestinal environment associated with IBD and characterize the disease more comprehensively, the Center for Pediatric IBD collects stool samples from IBD patients and uses next generation sequencing techniques available through the PennCHOP Microbiome Program, which Dr. Baldassano also codirects, to sequence hundreds of microorganisms’ genomes. The researchers will establish microbiota signatures of subsets of pediatric IBD, and then they will correlate these key communities of bacteria with patients’ genetic variants to help select the most appropriate therapeutic options.

“We believe the future of treating IBD will require us to combine the microbial information with the genetic information to figure out how the immune system is being manipulated by both,” Dr. Kelsen said. “Ultimately, we want to really understand the individual person’s disease to provide optimal therapy.”

The Center for Pediatric IBD team’s national leadership in clinical, translational, and basic research in IBD is exemplified by its expertise in treating very-early onset IBD (VEO-IBD), which is IBD that presents before age 5. Children with VEO-IBD are a unique part of the IBD patient population because they frequently present with more severe symptoms and greater extent of GI tract involvement than older children and adults with IBD. In addition, these patients tend to respond poorly to conventional IBD therapies used for older patients.

Research led by Dr. Kelsen identified some of the underlying genetic causes of VEO-IBD that may allow for targeted therapy in these children. These gene variants appear to influence the immune system and may result in defective or inappropriate immune responses that contribute to the development of VEO-IBD. For many of the patients who Dr. Kelsen sees in the VEO-IBD clinic that she runs with Kathleen Sullivan, MD, PhD, chief of the division of Allergy and Immunology, they are now using therapies that are directed to diseases of the immune system, instead of prescribing traditional IBD drugs.

Dr. Kelsen shared the inspiring story of a young infant with a form of IBD who spent four months in CHOP’s ICU being cared for by specialists from gastroenterology, immunology, and rheumatology who were committed to figuring out why she was so gravely ill. They discovered that she had a gene defect that caused an overwhelming inflammatory response. The team received compassionate use permission from the U.S. Food and Drug Administration to try an investigational drug that blocked that inflammatory process from happening. They recently described the patient’s case in the Journal of Allergy and Clinical Immunology.

“She went from an infant who was incredibly sick and couldn’t tolerate even an ounce of formula by mouth to a little girl who is now eating pizza and growing,” Dr. Kelsen said.

Dr. Kelsen and her colleagues expect to have many more success stories to tell, as the Center for Pediatric IBD at CHOP utilizes this multidisciplinary translational research approach to provide personalized therapy to more children worldwide. Already, they receive biospecimens from IBD patients nationally and internationally to perform sophisticated sequencing, analysis, and interpretation.

“We are incredibly excited,” Dr. Kelsen said. “This is an opportunity to provide better care and better science so that hopefully we can change the natural history of the disease.”

Valuable Lessons Learned From Research in Schools

Valuable Lessons Learned From Research in Schools

Why are top-notch scientists at Children’s Hospital of Philadelphia going back to school? They are conducting enlightening research projects — from implementing behavioral health interventions to analyzing what’s on school cafeterias’ menus — to ensure that students are prepared to learn and excel. Let’s take a look at some of the research in education that rose to the head of the class this year. (Now pay attention … there may be a quiz later!)

Empowering “Mean” Girls to Use Positive Social Influence

One of these thought-provoking projects is a small-group in-school educational program that teaches positive social skills, called Friend to Friend (F2F). F2F has been in development and testing for more than 15 years by Stephen Leff, PhD, co-director of the Violence Prevention Initiative (VPI) at CHOP and professor of Clinical Psychology in Pediatrics and Psychiatry in the Perelman School of Medicine at the University of Pennsylvania, in collaboration with CHOP experts, students, parents, teachers, and other school stakeholders.

The program’s curricula and innovative teaching methods include videos, cartoons, and role-plays targeted to urban, ethnic minority girls. These educational tools are designed to help girls in third to fifth grade find friendlier alternatives to relational aggression, the set of behaviors colloquially known as “mean girl” behaviors that are often a component of bullying.

One year after a randomized controlled trial of F2F, participating relationally aggressive girls had sustained improvements in social behaviors, Dr. Leff and colleagues reported in the journal Psychology of Violence. Another CHOP study reported in the journal Behavior Modification showed benefits for the entire classroom environment. The program’s inclusion of a co-teaching role for girls to share their new friendship-focused skills with their classmates may have turned the greater social influence that many such “mean girls” often hold into a force for good. Through VPI, future directions for the program are focused on scaling F2F to reach more classrooms in more schools.

Program Helps Parents Find the Good in Bad Child Behavior

Joanne Wood, MD, MSHP, is an attending physician and faculty member in PolicyLab at CHOP, and she also is a mom who knows how stressful parenting can be when children are misbehaving. Dr. Wood and colleagues Philip Scribano, DO, MSCE and Steven Berkowitz, MD, in PolicyLab realized that, in some cases, negative and reactive parenting can lead to increased child behavior problems and downstream undesired effects on school readiness, academic outcomes, and behavioral health disorders.

“And really we want to keep kids from getting there,” said Dr. Wood, who is also an assistant professor of Pediatrics at Penn.

She found a promising tool to do so in a small-group parenting intervention called CARE, which she helped implement and evaluate during PolicyLab’s work with the city of Philadelphia helping caregivers in the foster care system. Through a combination of lectures with discussions, role plays, and other interactive elements, caregivers became familiar with positive parenting and stress-management skills for themselves and for their children.

Providing a six-week version of this program, called PriCARE, to parents of preschool-age children at CHOP’s primary care facility in South Philadelphia was effective at improving ratings of child behavior and improving parent attitudes. Dr. Wood and her colleagues reported these results in the journal Academic Pediatrics. They hope that with further study the program will prove to prevent children’s later problems in school or with mental health.

New Project Aims to Reduce Inner City Students’ Anxiety

When children from low-income, urban backgrounds start their school days, often their minds are already filled with weighty issues that can lead to anxiety disorders and aggressive and antisocial behavior. Unfortunately, counselors in inner city schools usually are scarce, overextended, and lack adequate training to provide effective behavioral health services.

Bringing mental health services to underserved schools and students has been the research focus of Ricardo Eiraldi, PhD, a psychologist in the department of Child and Adolescent Psychiatry and Behavioral Sciences and program director of the Behavioral Health in Urban Schools program at CHOP, for two decades. His latest project is to use a “train the trainer” approach to train mental health agency supervisors and therapists to provide cognitive-based therapy in schools and reduce behavior problems.

Dr. Eiraldi and his study team received a new grant this year from the National Institute of Mental Health to find effective approaches to build internal capacity within under-resourced schools in order to provide mental health services to children who present excessive anxiety. Thirty-six schools in Philadelphia will participate, and the researchers expect to enroll 90 therapists, a minimum of 18 clinical supervisors, and 360 students in grades four through eight. By the conclusion of the five-year grant, the study team aims to report on the children’s outcomes, implementation outcomes, and cost-effectiveness. The study protocol was published in the journal Implementation Science.

“Low income, ethnic, minority children are much less likely to receive high quality mental health services compared to those in the middle class who are not ethnic minorities, so schools can play a very major role in addressing mental health issues in children,” said Dr. Eiraldi, who also is an associate professor of Clinical Psychology in Pediatrics and Psychiatry at Penn.

In another study currently in its fourth year in six schools in Philadelphia, Dr. Eiraldi and colleagues are testing two levels of support provided to school personnel for the implementation of School-Wide Positive Behavioral Interventions and Supports (SWPBIS), a service delivery framework used to improve school climate and children’s mental health. This project is described in detail in Implementation Science. In an article published in Behavior Modification, Dr. Eiraldi and his study team reported that a pilot study of SWPBIS showed children with a diagnosis of depression, anxiety, or behavior problems who received the small group–based services over 14 once-a-week sessions had a decrease in their diagnostic severity level.

Cafeteria Lunches Come With a Side of State Laws, But Are They Effective?

State and local lawmakers over the last few years have introduced healthy changes in the places where kids spend most of their day, most of the year: schools. Such laws take a range of approaches, such as requiring in-school nutrition education, restricting the sale of junk food in cafeterias and school vending machines, or requiring specific credentials for school food service directors. But there is limited data about the effectiveness of these policies.

A CHOP study published in Preventive Medicine examined nine types of such laws and identified two that were associated with decreased obesity, although the data couldn’t determine cause and effect. Deepak Palakshappa, MD, MSHP, an attending physician at CHOP, instructor in General Pediatrics at Penn, and faculty member in PolicyLab and the Center for Pediatric Clinical Effectiveness, and his colleagues’ main analysis looked at possible associations between the strength of state nutrition laws in 2010 and the weight of children age 10 to 17 in those states in 2011, controlling for state-level differences in children’s weight in prior years and for reported differences between children’s nutrition and physical activity that could affect their weight status outside of school.

Strong laws limiting the sales of unhealthy or junk foods in cafeterias, vending machines, and school stores (known as competitive food and beverage laws) had a significant association with lower obesity in the 10-year-old, elementary-aged children. And strong laws limiting food and beverage advertising in schools were associated with lower obesity in all ages of youth studied. The other seven categories of laws showed no significant associations.

Making a Better Connection for Children With Attention-Deficit Hyperactivity Disorder

Remember that experiment when you and your best friend made a telephone using just cups and some string? But when the string went slack, your conversation was lost. In much the same way, a poor connection exists between the two separate systems — healthcare and schools — that are involved with the treatment of children who have attention-deficit hyperactivity disorder (ADHD). Alexander G. Fiks, MD, MSCE; Thomas J. Power, PhD; Robert W. Grundmeier, MD; Jeremy Michel, MD; and colleagues at the Center for Pediatric Clinical Effectiveness, PolicyLab, and the Department of Biomedical and Health Informatics at CHOP have developed an electronic portal called ADHD Care Assistant to help better coordinate communication between pediatricians and teachers, bringing their treatment plans into alignment with families’ goals.

“ADHD Care Assistant closes this barrier where there might be intermittent doctor-family communication sometimes, and it brings the teacher centrally into the conversation,” Dr. Fiks said.

The electronic portal helps to gather information from parents and teachers of children with ADHD on their symptoms, treatment, and medication side effects. They complete online check-in surveys using ADHD rating scales, and the results are shared with the children’s primary care physicians via the hospital’s electronic health record (EHR).

Findings from a feasibility study conducted across 19 primary care providers in CHOP’s network showed that 67 percent of providers activated the ADHD Care Assistant system for at least one patient, and 32 percent activated it for five or more cases. The results appeared in Advances in School Mental Health Promotion. In that article, the authors also discussed the challenges of developing the portal, such as meeting the needs of multiple school districts with different resources and policies about electronic information sharing.

“Our ongoing work is related to building relationships between the health system and the schools that enable there to be trust and understanding of what’s going to be accomplished on both ends so that information can move to the benefit of kids without encountering substantial barriers,” Dr. Fiks said.

A new clinical trial called Communication to Improve Shared-Decision Making in ADHD (ADHD-Link) led by James Guevara, MD, MPH, an attending physician at CHOP, an associate professor of Pediatrics and Epidemiology at Penn, and a founding member of PolicyLab, will explore whether using the online portal plus a care manager can help to improve care coordination. The care manager will contact families every three months during the study to discuss their child’s ADHD care and help to communicate their goals and preferences to the child’s physicians and teachers, identify new concerns, and problem-solve. Approximately 300 participants will be enrolled, and they will be randomly assigned to use either the EHR portal alone or the portal plus a care manager. The Patient-Centered Outcomes Research Institute is providing funds for the study.

“Good health isn’t housed only in the health system,” said Dr. Fiks, who also is an ADHD-Link co-investigator. “It requires collaboration across school systems and engagement of a community.”

Seeing the Unseen to Change the Picture for Lymphatic Disorders

Seeing the Unseen to Change the Picture for Lymphatic Disorders

A baby born with fluid-filled body cavities and unusual swelling is a rare sight in neonatology, but experienced neonatologists know these chylous disorders can be dire. With few medical interventions available for these largely mysterious and often devastating conditions of the lymphatic system, these infants face a poor prognosis if the symptoms do not resolve on their own.

“Caring for neonates with lymphatic disorders can be very challenging given the limited understanding we have on these diseases,” said Dalal Taha, DO, an attending neonatologist at Children’s Hospital of Philadelphia and assistant professor of Clinical Pediatrics at the Perelman School of Medicine at the University of Pennsylvania. “We are beginning to see that change, now that we have the capability to perform advanced imaging.”

Interventional radiologist Maxim Itkin, MD, and pediatric cardiologist Yoav Dori, MD, PhD, are the pioneers behind new imaging techniques and minimally invasive interventions for lymphatic disorders. Their efforts have kick-started the rapid emergence of lymphatics as a new specialty in medicine and led to the establishment of the Center for Lymphatic Imaging and Interventions Program at CHOP and the Hospital of the University of Pennsylvania (HUP), directed by Dr. Itkin. They are showing that the lymphatic system plays an understudied role in many diseases, providing new ideas for minimally invasive treatments, and offering insights into fields from pulmonology to immunology. Neonatology is only one of these many specialties where the pair is beginning to make inroads with help from so-called “lymphomaniacs,” like Dr. Taha, who see the potential in their new approaches.

“Max and I have gone from department to department giving lectures and showing images, and we’re still doing this constantly,” said Dr. Dori, director of Pediatric Lymphatic Imaging and Interventions and Lymphatic Research at CHOP and assistant professor of Pediatrics at the Perelman School of Medicine. “We’re trying to educate and get everybody up to speed about what we’re dealing with, what are these disease processes, and how to treat them.”

Imaging Drives Everything

The lymphatic system is a set of vessels throughout the body that collects fluids from soft tissues and organs, especially the liver and intestine. It carries those fluids to the thoracic duct, the largest lymphatic vessel, from which the fluid is transported back into the veins. But due to the vessels’ small size and unpredictable anatomy, older standard lymphatic imaging methods, which involve injecting imaging dye through a patient’s foot, are both difficult and time-consuming, while producing low-resolution and incomplete imaging of the flow of lymph through the body.

Drs. Itkin and Dori’s new methods to image the lymphatic system have revolutionized the potential for treatments in the way imaging innovations transformed treatments in many of the body’s other systems 50 years ago. The advent of magnetic resonance imaging (MRI), arteriography, CAT scans, and other imaging technologies in the 1960s and 1970s suddenly made physical abnormalities of many of the body’s systems visible to physicians. Many of those abnormalities could then be treated with easy-to-explain interventions — embolizing to close off passages that should not be open, inserting stents to open those that should not be closed. But the lymphatic system was notoriously hard to image, so it was left out of that medical revolution of a generation ago.

“Imaging drives many fields,” said Dr. Itkin, who is also an associate professor of Radiology at the Perelman School of Medicine. “The more you can see, the better you can treat.”

The drive for better imaging in lymphatics belatedly emerged from the first treatments for the lymphatic system, which were themselves relatively recent. Twenty years ago, one of the fathers of interventional radiology, Constantin Cope, MD, conceptualized the idea of accessing the lymphatic system through the abdomen to treat traumatic cases of a condition involving leakage of lymph into the chest, called chylothorax. This idea initially sounded like science fiction to other experts in the field, but, slowly, the concept emerged as the main treatment approach. As Dr. Cope neared retirement, Dr. Itkin came to Penn to learn these techniques. He ultimately continued the tradition and refined the eight-hour surgical procedure into a 40-minute one.

In 2012, Dr. Itkin also began to make progress on a new imaging method, the intranodal lymphangiogram. In this method, he injected dye into the lymph node in a patient’s groin, making it possible to see the lymphatic anatomy almost immediately. This technically simple replacement of a traditional lymphangiogram technique made lymphatic interventions easier to perform and more widely accepted by other physicians. But this method still lacked the level of detail of cross sectional imaging methods such as MRI and computerized tomography.

The next step forward for lymphatic imaging was the lucky outcome of a conversation after a recreational basketball game between Dr. Itkin and Dr. Dori. Until that day, the pair had never worked together, and Dr. Dori had never given much thought to the lymphatic system. But Dr. Itkin had given a lot of thought to pediatric cardiology, trying for some time to find collaborators at CHOP to explore the possible role of lymphatic flows in complications of congenital heart disease.

Together, Dr. Dori and Dr. Itkin conceptualized the idea of MRI lymphangiography. This technique utilizes the same approach as the intranodal lymphangiogram but delivers a magnetic resonance contrast agent.

“Suddenly we discover the whole world of lymphatic abnormalities,” Dr. Itkin said. “Nobody had ever done that before. We can actually light up almost the whole lymphatic system and see abnormalities there.”

Showing Success With Plastic Bronchitis

Before long, they tried their new imaging technique on a patient with the devastating condition plastic bronchitis, in which the lungs suffuse with fluid that hardens into rubbery casts. With that first patient, it was immediately clear to Drs. Itkin and Dori that some lymph from the thoracic duct was leaking into the lungs — and they have since found a similar flow pattern in patients with other conditions. Dr. Itkin hypothesizes that such lymphatic leaks into the lungs are a normal variant that some people are born with, and that typically does not cause major medical problems.

But it predisposes some people to plastic bronchitis. Although this condition can occur at any age and without any specific triggering event, doctors see it most commonly in children who have undergone a Fontan operation for congenital heart disease. The researchers suggest that this occurs because, in children who have congenital heart failure on the right side, soft tissues are congested, and the amount of fluid that the lymphatic system would normally absorb and carry away exceeds the system’s capacity. Far too much excess lymph flow can then accumulate in the lungs in patients prone to these flow leakages.

Now that they can see the abnormal flows in plastic bronchitis, Drs. Dori and Itkin are treating them with a minimally invasive procedure that is as simple to explain as the revolutionary, imaging-driven treatment changes in many other fields a generation ago: While imaging the abnormal flows in a patient, they selectively embolize lymphatic passageways to stop the fluid from leaking into the lungs.

“Predictability is almost 100 percent,” Dr. Itkin said. “It’s a simple plumbing problem.”

In 2016, the team caught the world’s attention with the publication of their results treating 18 patients with plastic bronchitis. Fifteen of the 17 patients who underwent their new intervention procedure had a significant improvement in symptoms nearly a year later, they reported in the journal Circulation. Previously, the only intervention that offered some patients long-term relief from plastic bronchitis was a heart transplant. This effort confirmed the role of the lymphatic system in the mechanism of the disease. And their success is likely just the first of many to emerge from the team’s lymphatics discoveries.

Flowing Toward the Frontiers in Research

“We have opened a small door to enormous opportunities to discover new diseases and explanations for known diseases,” Dr. Itkin said. “And we’re already working on that.”

The team’s efforts have been designated as a CHOP Frontier Program, a type of program awarded priority funding to combine cutting-edge clinical discovery with fundamental research in critical areas of medicine where CHOP has unique strengths. Frontier funding gives the team the opportunity to further refine their imaging techniques, including the development of different dye agents to better show lymph in different areas of the body. For example, the liver and intestinal lymphatic systems generate a high volume of lymph, but the exact role of the lymphatic system in liver and intestinal disease is still poorly understood. The team is investigating the role of the lymphatic system in the liver disease ascites, as well as in a group of rare diseases, lymphangiomatosis.

A large part of the Frontier Program funding from CHOP is further helping to establish a comprehensive research program focused on lymphatics. The center has hired research assistants to gather data and create a database to track patients seen for suspected lymphatic disorders in a prospective study, and they are establishing a basic science research lab to better understand the lymphatic system in model organisms.

The lymph itself is opening up new possibilities for study in immunology as well.

“We now have the first-time opportunity to sample the lymphatic system from live human beings and analyze it,” Dr. Itkin said. “We are working closely with the Penn Institute for Immunology, of which CHOP is a member, with multiple studies planned and already going on to understand the immune function of the lymphatic system better than ever before. This has enormous implications in areas such as HIV and cancer immune therapy.”

For now, this intensive study and treatment innovation in lymphatics is unique to CHOP and Penn, found nowhere else in the world.

“This is kind of a new organ system,” Dr. Dori said. “It’s extraordinarily rare in medicine to fall on something like this, an organ system that has been ignored because people couldn’t see it.”

New Genetics Collaborative Follows Unique Blueprint to Individualize Medicine

New Genetics Collaborative Follows Unique Blueprint to Individualize Medicine

It was only 15 years ago that the first human genome sequence was revealed, the result of a huge National Institutes of Health project that spanned over a decade and cost $2.7 billion. This spurred a period of genomic discovery that has changed exponentially how we understand human health, with the field of pediatric medicine at the forefront. Today, mostly due to advances in technology that have dramatically reduced the cost and turnaround time of genomic sequencing, the newly established Roberts Individualized Medical Genetics Center (Roberts IMGC) at Children’s Hospital of Philadelphia can coordinate a genetic testing plan that provides patients and families accurate and comprehensive results within a few weeks.

“It is revolutionizing what we do in medicine,” said Ian Krantz, MD, an attending physician in the division of Human Genetics at CHOP, who also codirects the Roberts IMGC along with Livija Medne, MS, LCGC, a senior genetic counselor. “We now have this power to do next-generation sequencing, and as tests have become more and more complex, and we’re able to understand more and more of the genome, testing in genetics has broader applications across all fields of pediatric medicine.”

This unprecedented growth of genomics was the impetus for creation of the $50 million Roberts Collaborative for Genetics and Individualized Medicine that launched in September at CHOP. It is the first program in the nation that will apply genetic testing technology to individualize diagnostics in pediatrics and then translate patients’ unique genetic blueprints to inform clinical management, family education and counseling, innovative research, and eventually new therapeutics.

A $25 million gift by the Roberts family made the Collaborative possible. CHOP is matching the gift with $25 million in internal funding, and together they will support multidisciplinary efforts that harness the energy and enthusiasm of genomics experts across the institution, including the Roberts IMGC, the division of Human Genetics, the division of Genomic Diagnostics, the Center for Applied Genomics, the department of Biomedical and Health Informatics, The Raymond G. Perelman Center for Cellular and Molecular Therapeutics, and others.

“We are extremely grateful to the Roberts family for this remarkable gift, which will help the Children’s Hospital of Philadelphia usher in a new era of genetics and broaden the scope of genetic medicine across all clinical areas of the hospital,” said Madeline Bell, president and CEO of CHOP. “Research is core to CHOP’s mission, and growing CHOP’s Research Institute is fundamental to our strategy and commitment to breakthroughs.”

CHOP’s new integrated approach that capitalizes on understanding the genetic underpinnings of childhood diseases already is making a difference in young lives. Dr. Krantz shared the story of 9-year-old Emily, who came to the Roberts IMGC after experiencing two years of progressive hearing loss. She had genetic testing for a panel of about 75 genes that are known causes of hearing loss, but the tests came back normal. Two years later, Emily returned after developing some visual loss. Dr. Krantz and his genetics team dug deeper for answers and analyzed Emily’s entire genome — all 20,000 genes in a single test.

“The results showed that she had a rare, one-in-a-million diagnosis for a progressive neurological disorder that would lead to death in early adulthood,” Dr. Krantz said. “Her genetic changes caused a problem in the way she metabolized a vitamin called riboflavin. This was very important for the family to know because both parents carried the same genetic mutation. We could counsel them about recurrence risk and prognosis. And even more exciting is that there was a treatment.”

Emily went on high dose therapy for the missing vitamin, and although her symptoms may not be reversible, her condition has stabilized. The genetics team also tested her asymptomatic 5-year-old brother and found that he also has the gene mutation. He is receiving treatment as a preventive strategy, and hopefully he will not develop any symptoms.

This family’s experience is a good example of where Dr. Krantz sees genomic medicine heading in the next decade — toward the screening of all newborns and individuals with genetic testing technology to give clinicians the opportunities to intervene early, such as by recommending lifestyle changes or prescribing pharmacologic therapies. Genetic testing may help to identify risk factors for many of the common diagnoses that adults face, such as diabetes, hypertension, and Alzheimers, that may be able to be managed and treated during childhood in order to improve outcomes throughout lifetimes, Dr. Krantz suggested.

The biggest stumbling block currently for genomic medicine is uncertainty. Scientists do not yet understand everything that they see in the genome, and that can sometimes be anxiety-provoking for families and clinicians. It also could lead to unnecessary tests that could increase healthcare costs. For instance, genetic testing may reveal that a child has a potential risk for a heart problem, but it may be unclear if the identified mutation will actually result in a damaging physical change. As a precaution, the child might need to visit a cardiologist once a year for an echocardiogram.

“Until we find a balance, or study and understand that the benefits outweigh those costs, people are a little hesitant to make genetic screening universal,” Dr. Krantz said.

In the meantime, the Roberts IMGC has three pediatric geneticists, Cara Skraban, MD; Kosuke Izumi, MD, PhD; and Matthew Deardorff, MD, PhD; and two genetic counselors, Emma Bedoukian, MS, LSCG, and Jennifer Tarpinian, LSGC, who ensure that families receive thorough clinical evaluations, education, and counseling before and after genetic testing on its usefulness and limitations. They also discuss families’ choices about the type of results that they want back. In some cases, families may only want answers to the possible genetic problems that their child is experiencing, while others may also want to know about secondary findings that could be medically important. The counselors meet with families about the results to explain their potential significance and put them in touch with specialists if needed.

So far, the Roberts IMGC has worked with about 2,000 patient referrals, and they continue to see about 100 patients a month, a number that Dr. Krantz expects will expand along with the availability of affordable genetic testing. As more medical insurance companies begin to acknowledge the utility of genetic testing, Roberts IMGC clinical coordinator Jasmine Montgomery navigates the nuances of pre-authorization and billing so that families do not end up with big balances to pay.

In many ways, genetic testing could be seen as a long-time investment in children’s healthy futures because it provides insights into their genetic predispositions that are never static. A central mission of the Roberts Collaborative is to integrate patients’ genetic makeup into their electronic health records so that this valuable information is always accessible and portable.

“We can test a 6-month-old’s genome today and not find an answer, but two years from now, we may go back and re-analyze that information and find one,” Dr. Krantz said.

Genomic medicine straddles both the clinical and research sides of CHOP. It may guide physicians in patient management, but it also generates a huge amount of data that, with appropriate consent from families, researchers can leverage to make discoveries to improve care. They can search for new genes or associations, figure out how changes in suspected disease genes are functioning, and translate that knowledge into developing therapies. Part of the Roberts IMGC’s goal is to invite every patient that they see to participate in a protocol approved by the Institutional Review Board to have their samples put in a biorepository to drive research. Already, the Roberts IMGC has found six brand-new genes that they are evaluating.

“I think the world is going to change dramatically,” Dr. Krantz said. “And it’s happening really, really fast, as far as medicine goes. It challenges all of us in genomics to constantly be at the cutting edge and stay on top of these breakthroughs so that we can translate them directly back to our patients, which is our mission here at CHOP.”

Research Affinity Groups Creating Strong Ties, Patterns for Success

Research Affinity Groups Creating Strong Ties, Patterns for Success

Affectionately known by their acronym, RAGS, Research Affinity Groups at Children’s Hospital of Philadelphia’s Research Institute are like the bits of cloth that a resourceful crafter weaves together to create a colorful tapestry. In the same way, two new RAGS launched this year — the Global Health RAG and the mHealth RAG — assemble investigators from varied disciplines with common research interests to form strong ties and intertwine novel ideas and approaches that are the fabric of pediatric research.

Investigators who join the Global Health RAG, led by Elizabeth Lowenthal, MD, MSCE, research director for CHOP’s Global Health Center, can learn from their own backyard about the challenges unique to international pediatric research. They also can find out about existing resources and infrastructure available within CHOP, the Penn Center for Global Health, and other affiliated groups such as the Penn Center for AIDS Research (CFAR) that currently support research projects in 14 countries, including regions in sub-Saharan Africa, Latin America, and Asia. Many of these low-income communities have huge populations of children who are suffering from treatable, preventable illnesses.

One researcher’s journey to advance international pediatric research took him back to his homeland. Osayame Ekhaguere, MBBS, a CHOP neonatology fellow from Nigeria, is leading a randomized trial that seeks to improve infant immunization rates there. He will test an intervention that involves sending reminder text messages, calls, and emails to parents before their scheduled immunization visits are due.

In the Dominican Republic, where rates of anemia are high, a recent Global Health Center resident, Ryan Close, MD, is studying if giving families an iron ingot shaped like a fish and instructions on how to cook with it could be a successful long-term dietary supplementation strategy to support children’s growth and development.

With funding from a pilot grant through CHOP’s Global Health Center, orthopedic surgeon David Spiegel, MD, is assessing the long-term outcomes of a procedure to repair clubfoot in children living in Nepal.

While their results could catalyze improvements in pediatric health worldwide, these projects still have a long road ahead. Global Health RAG members will help them navigate some of the practical and ethical considerations that often come up when working in resource-limited settings, such as financial management, data security in settings with limited internet access, onboarding foreign research staff, and reporting results to appropriate international stakeholders.

“I hope the Global Health RAG will bring us all together and give us some inspiration on how we can expand and strengthen our programs and systems within the institution to allow us to have strong collaborations on the other end,” Dr. Lowenthal said. “I’d like to hear from CHOP researchers about the amazing global health research they’re doing and what their dreams are so that we can help them to find potential collaborators and move their ideas forward.”  

Another brave new world for pediatric researchers is the uncharted territory of mHealth, or mobile health, which incorporates an array of communication technologies — from basic text messages, apps and social media; to more complex wearable devices that link to electronic health records; to futuristic ideas such as implantable and ingestible devices — to connect with young patients and families.

“mHealth is a new paradigm of research in a lot of ways,” said Nadia Dowshen, MD, an adolescent medicine specialist at CHOP and an assistant professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania.

Dr. Dowshen is a co-chair of the mHealth RAG along with co-chairs Lisa Schwartz, PhD, a CHOP psychologist and assistant professor of Pediatrics at Penn, and Linda Fleisher, PhD, MPH, a senior scientist in CHOP’s Center for Injury Research and Prevention, and a senior fellow in Penn’s Leonard Davis Institute of Health Economics.

An important aspect of mHealth, the three co-chairs pointed out, is that mobile technology is constantly changing. The mHealth RAG members will help each other keep pace with this fast-moving field to ensure that their research activities remain relevant and are aligned with the latest mHealth trends. Also, mHealth gives researchers opportunities to understand human health and behavior in more detailed ways, but the amount and type of data that it generates will require bioinformatics specialists who can relate their knowledge of mHealth data management and analysis.

For example, Dr. Dowshen conducted a mHealth trial to improve adolescents’ adherence to antiretroviral medication using two-way text messaging and an app with interactive features. She kept track of every text sent and received by the 25 participants during the six-month study. Previous research relied on electronic signals from pill boxes or bottles to record adherence, but Dr. Dowshen found that her patients with HIV did not routinely use them to store their medication in order to protect their confidentiality. Collecting mHealth data through text messaging was feasible and acceptable for youth and allowed Dr. Dowshen to look at patterns of adolescents’ adherence to antiretroviral therapy in a way that previously would not have been possible.

mHealth certainly has the potential to encourage patients to take more responsibility for their health and improve their quality of care; however, more evidence is needed to determine the best approaches for mHealth, from policy to implementation. Researchers will need to act quickly, as consumers’ expectations for mobile patient engagement continue to rise.

“Patients and families certainly want to use these new ways of communicating, but there is a lot of research to be done to understand how best to do that, who uses it, who doesn’t use it, and in what situations,” Dr. Fleisher said. “Although mHealth seems ubiquitous already, there is much we don’t know.”

An internal survey conducted by the mHealth Working Group revealed that almost 50 percent of the 173 CHOP researchers who responded were interested in learning more about mHealth, and almost 35 percent were currently conducting mHealth research or quality improvement projects. Those already involved in mHealth research said they would welcome support in the areas of in-house development, information systems, and vetting commercial and academic partners. As more research funding opportunities for mHealth begin to emerge, it is likely the mHealth RAG will attract even more investigators who want to interlace mHealth research methods into their projects.

“The mHealth Research Affinity Group will get the key players and stakeholders together to compare notes, experiences, and expertise to determine how we can best move mHealth research forward at CHOP,” Dr. Schwartz said.

Childhood Cancer Research Effort Shoots for the Moon

Childhood Cancer Research Effort Shoots for the Moon

A parent experiencing a cancer diagnosis in his child knows a unique pain. Often, that pain transforms to passion directed against the disease. Rarely, that passion ignites a rocket powering massive change. This was clearly the case for former U.S. Vice President Joe Biden. In the wake of the loss of his adult son Beau to brain cancer in 2015, Biden took the helm of an ambitious national effort to dramatically accelerate progress against cancer in all its forms.

“The goal of this initiative is simple — to double the rate of progress. To make a decade’s worth of advances in five years,” Biden said upon the February 2016 launch of the initiative, dubbed the Cancer Moonshot. The effort is designed to increase public and private resources to fight cancer while breaking down silos to bring cancer fighters together. It is built on the premise that together, a coordinated strategy and well thought-out flight plan can reach a lofty shared goal like NASA’s effort to reach the moon.

Fortunately for the many advocates and scientists focused on childhood cancer, a prominent leader in pediatrics was among those helping to plot the scientific course for this initiative in its planning stages. As a member of the Blue Ribbon Panel for the Cancer Moonshot initiative, Peter Adamson, MD, a pediatric oncologist at Children’s Hospital of Philadelphia and professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania, was one of a select group of experts from academia, industry, and advocacy, who guided the National Cancer Institute (NCI) on how to achieve this goal.

“It was very important that the NCI recognized that out of all the potential areas for accelerating research, childhood cancer must be a priority,” said Dr. Adamson, who also chairs the Children’s Oncology Group (COG). “Cancers in children are often fundamentally different from cancers that occur in adults. The approaches to treatment may differ, and the scientific opportunities may prove unique.”

Childhood cancer has also historically been underrepresented in research and research funding, and the need for progress on more effective and targeted treatments remains urgent. Childhood cancer is the leading cause of death from disease in children, and even those cancers that have high survival rates leave many children with lifelong health difficulties related to their treatments.

As co-chair of the Blue Ribbon Panel’s working group focused on pediatric cancer, one of seven such groups addressing major topic areas, Dr. Adamson convened leaders from across the country to identify innovative areas of science that were poised to make transformative advancements with the appropriate investments. Two of Dr. Adamson’s colleagues from CHOP, Stephen Hunger, MD, director of the Center for Childhood Cancer Research, and John Maris, MD, a pediatric oncologist and co-head of the Pediatric Cancer Dream Team, served as members of the working group, which took a broad view of the state of the science and considered recommendations solicited from the public. The chairs of multiple working groups met as the ideas began to take shape, in order to identify cross-cutting themes and develop shared recommendations.

The Moonshot effort comes at a key junction in pediatric cancer research and cancer research in general. Technologies for sequencing the human genome, once seen as the great frontier in developing more precise treatments, have yielded a number of findings of genetic mutations that drive various types of cancer. As this technology has become inexpensive, fast, and ubiquitous, however, scientists are beginning to reach its limits.

One limitation: Pediatric cancers turn out to have fewer mutations than adult cancers, leaving a need for further explanation through epigenetic or other mechanisms. Another limit: Sequencing studies reveal that many cancers that appear to be a single type under a microscope in reality comprise distinct molecular subtypes that may respond to distinct treatment approaches. As a consequence of making already-rare cancers even rarer, these findings make it all the more necessary for national and international collaborations to make new discoveries and test new therapies. Such collaborations and sharing infrastructure that have already been part of efforts through the NCI, COG, and other groups, are poised to reach new levels as the Cancer Moonshot plan gets off the ground.

The Blue Ribbon Panel’s scientific roadmap, adopted in September 2016 by the NCI’s National Cancer Advisory Board (on which Dr. Adamson is also a member), encompassed 13 transformative research recommendations. Many of them span multiple types of cancer and address the most critical needs for large-scale infrastructure and collaboration. Three recommendations in particular have direct relevance to the greatest challenges facing pediatric cancer today.

One of the key recommendations for pediatric cancer research focuses on cancer therapy resistance — as experts recognize that if cancer returns after treatment, it often is far deadlier than a newly diagnosed cancer.

A second area of pediatric cancer research that the Blue Ribbon Panel chose to highlight is fusion oncoproteins. These proteins arise as a result of two genes becoming inappropriately fused together, like two stuck pages in a cookbook. The protein those fused genes then produce is akin to preparing a mixed-up recipe, such as a dish that is half creamy English trifle, half meaty shepherd’s pie. Serving those unpleasant entrees in specific cell types turns out to be essential in driving many childhood cancers, including certain leukemias, brain tumors, and many types of sarcomas. Better organized and better funded efforts can fill the large knowledge gaps about how these fusion proteins drive cancer and lead to new therapies that target these proteins.

Likewise, more work remains to be done to advance therapies that harness the body’s immune system to attack cancer. At CHOP, research on Dr. Maris’ Dream Team and in the T-cell therapy research of Stephan Grupp, MD, PhD, and colleagues, are prime examples of immunotherapies’ emergence as some of the most promising approaches to cancer. Yet research thus far suggests that molecular targets that the immune system will need to attack in pediatric cancers are likely to be distinct from those in adult cancers. The Blue Ribbon Panel therefore recommended creating cancer immunotherapy clinical trials networks for both pediatric and adult cancers. The networks would coordinate efforts nationwide both for developing new therapies and testing them effectively.

“I see a way forward to develop specific treatments for cancers that have defied targeted treatment for many years,” Dr. Adamson said. “Knowing the drivers of the cancers, but not understanding how those drivers work, and not knowing how to develop a therapy for them, is perhaps one of the more frustrating situations not only for clinicians and scientists, but most importantly for patients and families. We still use drugs developed in the 50s, 60s, and 70s to treat these cancers. If we can change the paradigm and understand how these fundamental genetic changes in the tumor lead to cancer and how we can develop a therapy towards that, then we will begin in earnest to enter an era of precision medicine that is both more effective and less toxic.”